Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Lupin Europe GmbH, Hanauer Landstraße 139-143, 60314, Frankfurt am Main, Germany
Pharmacotherapeutic group: Cardiac therapy, antiarrhythmics, class Ib
ATC code: C01BB02
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.
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 ⅔ 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
1 Clinical Study Report refers to 200 mg dose which is the amount of mexiletine hydrochloride (corresponding to 166.62mg mexiletine base)
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 | ||
| 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 | |
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).
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.
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.
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.
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.
A linear relationship between mexiletine dose and plasma concentration has been observed in the dose range of 83 to 500 mg.
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% |
In population pharmacokinetic analyses, weight was found to influence mexiletine pharmacokinetics.
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
