Summary of medicine characteristics - Namuscla
1. NAME OF THE MEDICINAL PRODUCT
Namuscla 167 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains mexiletine hydrochloride corresponding to 166.62 mg mexiletine.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Hard capsule (capsule).
Namuscla capsules are Swedish orange hard shell gelatin capsules (20 mm) filled with white powder.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
Namuscla is indicated for the symptomatic treatment of myotonia in adult patients with non-dystrophic myotonic disorders.
4.2 Posology and method of administration
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 contraindications 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.
4.3 Contraindications
- • 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).
4.4 Special warnings and precautions for use
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.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Antiarrhythmics inducing torsades de pointes (class Ia, Ic, III antiarrhythmics):
Co-administration of mexiletine and antiarrhythmics inducing torsades de pointes (class Ia : quinidine, procainamide, disopyramide, ajmaline; class Ic : encainide, flecainide, propafenone, moricizine; class III : amiodarone, sotalol, ibutilide, dofetilide, dronedarone, vernakalant) increases the risk of potentially lethal torsades de pointes. The concomitant use of mexiletine and antiarrhythmic medicines inducing torsades de pointes is contraindicated (see section 4.3).
Other antiarrhythmics (class Ib, II, IV antiarrhythmics):
Co-administration of mexiletine and other classes of antiarrhythmics (class Ib : lidocaine, phenytoin, tocainide; class II : propranolol, esmolol, timolol, metoprolol, atenolol, carvedilol, bisoprolol, nebivolol; class IV : verapamil, diltiazem) is not recommended, unless exceptionally, because of the increased risk of adverse cardiac reactions (see section 4.4).
Pharmacokinetic interactions
Effect of other medicinal products on mexiletine
Mexiletine is a substrate for the metabolic pathways involving hepatic enzymes; inhibition or induction of these enzymes is expected to alter mexiletine plasma concentrations.
Co-administration of mexiletine with a hepatic enzyme inhibitor (CYP1A2 inhibitor: ciprofloxacin, fluvoxamine, propafenone; CYP2D6 inhibitor: propafenone, quinidine) significantly increases mexiletine exposure and thus the associated risk of adverse reactions to mexiletine.
In a single-dose interaction study, the clearance of mexiletine was decreased by 38% following the coadministration of fluvoxamine, an inhibitor of CYP1A2.
Therefore, clinical and ECG monitoring, as well as adaptation of mexiletine dosage may be indicated throughout and after treatment with a CYP1A2 or CYP2D6 inhibitor.
Co-administration of mexiletine with a hepatic enzyme inducer (CYP1A2 inducer: omeprazole;
CYP2D6 inducer: phenytoin, rifampicin) may increase the clearance and elimination rate of mexiletine due to an increased hepatic metabolism, resulting in decreased plasmatic concentrations and half-life of mexiletine.
In a clinical study, co-administration of mexiletine with phenytoin resulted in a significant decrease in exposure to mexiletine (p < 0.003) due to enhanced clearance as reflected in significantly decreased elimination half-life (17.2 to 8.4 hours, p < 0.02).
Therefore, based on the clinical response, the mexiletine dosage should be adapted during and after treatment with the enzyme inducer.
After the oral administration of single (167 mg) and multiple (83 mg twice a day during 8 days) doses of mexiletine, total clearance of mexiletine is significantly increased in smokers (1.3 to 1.7-fold) due to induction of CYP1A2, resulting in a correspondingly decreased elimination half-life and drug exposure. Mexiletine dose may need to be increased if a patient starts to smoke during mexiletine treatment and decreased if a patient stops smoking.
Effect of mexiletine on other medicinal products
The potential of mexiletine as a drug-drug-interaction perpetrator is unknown. Patients should be carefully monitored if co-treated with other medicinal products with especially emphasis to medicinal products with narrow therapeutic windows.
CYP1A2 substrates
Mexiletine is a potent inhibitor of CYP1A2; therefore, co-administration of mexiletine with medicinal products metabolised by CYP1A2 (such as theophylline, caffeine, lidocaine or tizanidine) may be associated with elevations in plasma concentrations of the concomitant medicine that could increase or prolong the therapeutic efficacy and/or the adverse reactions, especially if mexiletine is coadministered with CYP1A2 substrates with narrow therapeutic window, e.g. theophylline and tizanidine.
The CYP1A2 substrate blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in the dose of the CYP1A2 substrate should be considered.
Caffeine
In a clinical study in 12 subjects (5 healthy subjects and 7 patients with cardiac arrhythmias), the clearance of caffeine was decreased by 50% following the administration of mexiletine. Increased concentrations of caffeine occurring with the co-administration of mexiletine may be of concern in patients with cardiac arrhythmia. It is, therefore, recommended to reduce caffeine intake during treatment with mexiletine.
OCT2 substrates
The organic cation transporter 2 (OCT2) provides an important pathway for the uptake of cationic compounds in the kidney. Mexiletine may interact with drugs transported by OCT2 (such as metformin and dofetilide).
If mexiletine and other OCT2 substrates are to be used concurrently, the OCT2 substrate blood levels should be monitored, particularly when the mexiletine dose is changed. An appropriate adjustment in the dose of the OCT2 substrate should be considered.
Substrates of other enzymes and transporters
The potential interactions between mexiletine and substrates of other common enzymes and transporters have not yet been assessed; it is currently contra-indicated to use mexiletine with any substrate having a narrow therapeutic window such as digoxin, lithium, phenytoin, theophylline or warfarin (see section 4.3).
4.6 Fertility, pregnancy and lactation
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).
4.7 Effects on ability to drive and use machines
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).
4.8 Undesirable effects
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
4.9 Overdose
Symptoms
Fatal outcomes have been reported for acute overdoses at 4.4 g of mexiletine hydrochloride ingestion but survival has also been reported following acute overdose of approximately 4 g of oral mexiletine hydrochloride.
The symptoms of mexiletine overdose include neurological disorders (paresthesia, confusion, hallucination, seizure) and cardiac disorders (sinusal bradycardia, hypotension, collapse, and in extreme cases, cardiac arrest).
Overdose 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.
5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties
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 |
| 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 | ||
1 Clinical Study Report refers to 200 mg dose which is the amount of mexiletine hydrochloride (corresponding to 166.62mg mexiletine base)
| 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).
5.2 Pharmacokinetic properties
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.
5.3 Preclinical safety data
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.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Capsule content
Maize starch
Colloidal anhydrous silica
Magnesium stearate
Capsule shell
Iron (III) oxide (E 172)
Titanium dioxide (E 171)
Gelatin
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
Do not store above 30°C.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Capsules are packed in Aluminium/PVC/PVDC blisters containing 30, 50, 100 or 200 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Lupin Europe GmbH
Hanauer Landstraße 139–143,
60314 Frankfurt am Main
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/18/1325/001 – 004
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 18.12.2018