Use Of Mexiletine Research Articles

Recommendations of an expert group for the cardiac assessment of non-dystrophic myotonia adult patients treated with mexiletine

Mexiletine (NaMuscla™) is indicated for the symptomatic treatment of myotonia in adults with non-dystrophic myotonia. A cardiac assessment is required as mexiletine may have a pro-arrhythmic effect. Long-term safety data supporting the use of mexiletine in patients with non-dystrophic myotonia combined with the extensive clinical experience of an expert group resulted in creation of an algorithm for cardiac monitoring of patients treated with mexiletine. To define the treatment algorithm, several expert workshops including three neurologists, five cardiologists from different French neuromuscular reference centers and one pharmacologist from Italy were set up. These workshops aimed to define the screening and surveillance tools required to ensure the safe use of mexiletine in patients. The recommendations are based on the summary of product characteristics (SmPC), a review of the literature on the safety of mexiletine-treated patients with non-dystrophic myotonia, and the expertise of the authors. The expert group concluded that the cardiac safety profile of mexiletine in these patients appears to be similar to that in the general population. Therefore, patients with non-dystrophic myotonia treated with mexiletine should be monitored as per any patient with cardiac problems who are prescribed a class 1b anti-arrhythmic.

Expert Insights from a Delphi-driven Neurologists' Panel: Real-world Mexiletine use in Patients with Myotonic Disorders in Italy.

Myotonic disorders, such as non-dystrophic myotonias (NDMs) and myotonic dystrophies (DMs) are characterized by a delay in muscle relaxation after a contraction stimulus. There is general consensus that protocols to treat myotonia need to be implemented. Mexiletine is the only pharmacological agent approved for the symptomatic treatment of myotonia in adult patients with NDM and is considered to be the first-line treatment for DMs; however, its production in Italy was halted in 2022 making its availability to patients problematic. A panel of 8 Italian neurologists took part in a two-round Delphi panel between June and October 2022, analyzing the current use of mexiletine in Italian clinical practice. The panelists assist 1126 patients (69% DM type1, 18% NDM and 13% DM type2). Adult NDM patients receive, on average, 400-600 mg of mexiletine hydrochloride (HCl) while adult DM patients receive 100-600 mg, per day in the long-term. The severity of symptoms is considered the main reason to start mexiletine treatment for both NDM and DM patients. Mexiletine is reckoned to have a clinical impact for both NDM and DM patients, but currently drug access is problematic. Mexiletine treatment is recognized to have a role in the reduction of the symptomatic burden for NDM and DM patients. Patient management could be improved by facilitating access to therapy and developing new drug formulations.

Use of Mexiletine in Children: A Minireview

AbstractMexiletine is well-established sodium channel blocker that acts on cardiac myocytes and neurons. It has recently been repositioned as an orphan drug in the treatment of rare neuromuscular diseases in adults with nondystrophic myotonia. It has also long been used in some rare pediatric diseases in the areas of cardiopathy, epilepsy, neuromuscular diseases, and pain disorders. Here, we review the different uses of mexiletine reported in pediatrics, stating indications, efficacy, and tolerance. Special attention by health authorities to maintain access to mexiletine in rare pediatric diseases and further pediatric research in these rare syndromes are required.

PO-04-191 RISK FACTORS AND OUTCOMES OF EARLY VENTRICULAR ARRHYTHMIAS AFTER LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION

Ventricular arrhythmias (VAs) may occur during the early post-operative period after the implantation of left ventricular assist device (LVAD). The factors associated with its development and the long-term clinical outcome are unclear. This study aimed to evaluate the risk factors and outcomes of early ventricular arrhythmias <30 days after LVAD implantation. We performed a retrospective cohort study on all patients who underwent LVAD implantation at the Mayo Clinic (Rochester, Phoenix, and Jacksonville) from January 1, 2001, to December 31, 2020. Early VAs were defined as sustained (>30 seconds) ventricular tachycardia or ventricular fibrillation occurring less than 30 days after the LVAD implantation. Detailed review of the electronic health records within the Mayo Clinic and outside medical records were performed. A total of 886 patients were included in the study, with a median age of 60 years (interquartile range [IQR]: 50-67), and 78.9% were male. A total of 195 (22.1%) patients had early VAs after LVAD implant. Pre-implant characteristics associated with early VAs were history of VAs (32.8% vs 23.9% p=0.012), history of ventricular tachycardia ablation (5.6% vs 2.0%, p=0.007), history of ICD shocks (32.3% vs 20.1%, p<0.001) and the use of mexiletine (16.4% vs 5.9%, p<0.001) and sotalol (8.2% vs 3.6% p=0.007) before LVAD. There was no difference in the subsequent risk of late VAs in patients with or without early VAs (27.7% vs. 25.8%, p=0.29). The 1-year post LVAD mortality rate was higher in patients with early VAs compared to patients without early VAs (32% vs 18%, P<0.01). Early VAs occur in 22.1% of patients undergoing LVAD implant and is associated with increased 1-year post LVAD mortality. Significant pre-implant risk factors include a history of VAs, ICD shocks, and anti-arrhythmic drug use before the procedure.

Mexiletine in the Treatment of Non-dystrophic Myotonia: Interviews with Six Medical Experts

Evidence from randomised controlled clinical trials demonstrates that mexiletine effectively controls myotonic symptoms with a well-described safety profile. Despite this, there are still a limited number of patients on this treatment, and physicians from expert neuromuscular centres may not be fully aware of the potential benefits of mexiletine treatment, including improvements in patients’ quality of life (QoL), the impact on activities of daily living, and the favourable safety profile, even in younger patients. During this ‘Meet the Experts’ interview series, five neurologists experienced in the management of non-dystrophic myotonias (NDM), and one specialist cardiologist offered their expert insights on the clinical data and real-world evidence supporting the use of mexiletine in NDM. Addressing patient concerns and encouraging treatment acceptance were highlighted as key steps to optimise outcomes from mexiletine therapy. The medical experts emphasised the importance of contextualising the favourable benefit-to-risk profile of mexiletine, particularly regarding cardiac safety concerns and drug monitoring requirements. The expert cardiologist further explained that, in their experience, the cardiac safety profile of mexiletine was no different in patients with NDM when compared to healthy controls used in clinical studies when used as directed. When considering anti-myotonia treatment in patients with NDM, medical experts stressed that decision-making should be driven by the overall degree of myotonia. Healthcare professionals (HCP), therefore, need to look beyond basic clinical assessment to understand the true impact of myotonia on patients’ everyday lives. Overall, these interviews highlighted the critical role that HCPs can play in leveraging the clinical data and managing patient expectations to ensure maximum treatment success when recommending mexiletine to patients with NDM.

Improving the understanding of how patients with non-dystrophic myotonia are selected for myotonia treatment with mexiletine (NaMuscla): outcomes of treatment impact using a European Delphi panel

BackgroundNon-dystrophic myotonias (NDMs) comprise muscle chloride and sodium channelopathies due to genetic defects of the CLCN1- and SCN4A-channels. No licensed antimyotonic treatment has been available until approval of mexiletine (NaMuscla®) for adult patients by the EMA in December 2018. This Delphi panel aimed to understand how outcomes of the pivotal phase III Mexiletine study (MYOMEX) translate to real world practice and investigate health resource use, quality of life and the natural history of NDM to support economic modelling and facilitate patient access.MethodsNine clinical experts in treating NDM took part in a two-round Delphi panel. Their knowledge of NDM and previous use of mexiletine as an off-label treatment prior to NaMuscla’s approval ensured they could provide both qualitative context and quantitative estimates to support economic modelling comparing mexiletine (NaMuscla) to best supportive care. Consensus in four key areas was sought: healthcare resource utilization (HRU), treatment with mexiletine (NaMuscla), patient quality of life (QoL), and the natural history of disease. Concept questions were also asked, considering perceptions on the feasibility of mapping the validated Individualized Neuromuscular Quality of Life (INQoL) instrument to the generic EQ-5D™, and the potential impact on caregiver QoL.ResultsConsensus was achieved for key questions including the average long-term dosage of mexiletine (NaMuscla) in practice, the criteria for eligibility of myotonia treatment, the clinical importance of QoL outcomes in MYOMEX, the higher proportion of patients with increased QoL, and the reduction in the need for mental health resources for patients receiving mexiletine (NaMuscla). While consensus was not achieved for other questions, the results demonstrated that most experts felt mexiletine (NaMuscla) reduced the need for HRU and was expected to improve QoL. The QoL mapping exercise suggested that it is feasible to map domains of INQoL to EQ-5D. Points of interest for future research were identified, including that mexiletine (NaMuscla) may slow the annual decrease in QoL of patients over their lifetime, and a significant negative impact on QoL for some caregivers.ConclusionsThis project successfully provided data from an informed group of clinical experts, complementing the currently available clinical trial data for mexiletine (NaMuscla) to support patient access decisions.

Long-term Safety and Efficacy of Mexiletine in Myotonic Dystrophy Types 1 and 2.

Myotonic dystrophy types 1 and 2 are progressive multisystem genetic disorders whose core clinical feature is myotonia. Mexiletine, an antagonist of voltage-gated sodium channels, is a recommended antimyotonic agent in the nondystrophic myotonias, but its use in myotonic dystrophy is limited because of lack of data regarding its long-term efficacy and safety profile. To address this issue, this study retrospectively evaluated patients with myotonic dystrophy receiving mexiletine over a mean time period of 32.9 months (range 0.1-216 months). This study demonstrated that 96% of patients reported some improvement in myotonia symptoms with mexiletine treatment. No clinically relevant cardiac adverse events were associated with the long-term use of mexiletine. These findings support that mexiletine is both safe and effective when used long-term in myotonic dystrophy. This study provides Class IV evidence that mexiletine is a well-tolerated and effective treatment for myotonic dystrophy types 1 and 2.

Voltage-Gated Sodium Channel Blockers: Synthesis of Mexiletine Analogues and Homologues.

Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic dystrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers was widely demonstrated, with (-)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.

Case Series of Western Sydney's Experience with the Use of Mexiletine 150 mg Twice Daily as an Antiarrhythmic Drug in Ischaemic Cardiomyopathy Patients with Automated Implantable Cardioverter Defibrillators In-situ that Have Recurrent Ventricular Arrhythmias Refractory to Standard Treatment

Case Series of Western Sydney's Experience with the Use of Mexiletine 150 mg Twice Daily as an Antiarrhythmic Drug in Ischaemic Cardiomyopathy Patients with Automated Implantable Cardioverter Defibrillators In-situ that Have Recurrent Ventricular Arrhythmias Refractory to Standard Treatment

A review of the use of mexiletine in patients with myotonic dystrophy and non-dystrophic myotonia

IntroductionMyotonia is found in a number of muscle diseases, including myotonic dystrophy and non-dystrophic myotonia. The resulting symptoms of myotonia can interfere with daily activities such as walking or climbing...

MEXILETINE USE FOR VENTRICULAR TACHYCARDIA REFRACTORY TO STANDARD ANTIARRHYTHMIC THERAPY IN THE ICD ERA

The optimal management of patients with who have refractory ventricular tachycardia (VT) despite standard antiarrhythmic drug (AAD) therapy is uncertain. The aim of this study was to describe the use of Mexiletine in a tertiary referral centre and explore its efficacy and safety in the modern ICD/VT ablation era. We conducted a retrospective cohort study of ICD recipients with an ejection fraction of <40% who were initiated on Mexiletine for refractory VA. Patients were identified through the hospital pharmacy database and clinical events were tracked through hospital records by reference to patient charts, and on-line databases. Patients were followed for up to 12 months or until a clinical event. The primary efficacy outcome was a composite of any appropriate ICD shock/sustained VT, VT ablation, or cardiac transplant/LVAD for refractory VT or documented arrhythmic death. Safety endpoints were the discontinuation of Mexiletine due to adverse reactions, hospitalization for congestive heart failure and non-arrhythmic death or death of unknown etiology. We identified 56 patients suitable for analysis on the basis of clearly documented details on the initiation of Mexiletine, and complete follow up till a clinical event or up to 12 months. The median follow up was median follow-up was 76 (2-365) days. The primary outcome occurred in 32 patients (57%) at a median of 39 (2-338) days following initiation of Mexiletine (Figure). Fourteen patients (25%) received an appropriate ICD shock and 9 patients had VT treated by ATP. Nine (16%) of patients underwent VT ablation at a median of 6 (2-101) days. A primary safety outcome occurred in 12 (21%) patients at a median of 41 (6-350) days. Four patients (7%) developed decompensated heart failure. Five patients developed adverse reactions attributed to mexiletine including, ataxia; hypotension; confusion; paraesthesia and nausea. Eleven patients (20%) remained free of clinical events at 12 months. Mexiletine has limited efficacy when used as adjunctive antiarrhythmic therapy for refractory VT. The safety profile appears reasonable in this highly morbid population. A high rate of treatment failure emphasizes the need for improved therapeutic options in this patient population. Randomized studies of Mexiletine in the contemporary ICD era may be useful.

Mexiletine for Symptoms and Signs of Myotonia in Nondystrophic Myotonia

Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network. Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact). Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. clinicaltrials.gov Identifier: NCT00832000.

NOVEL MUTATIONS ON SCN5A CAUSED FATAL ARRHYTHMIA SYNDROME IN CHINESE1

Objectives BackgroundSCN5A is encoding human sodium channel protein Nav1.5. Mutations on SCN5A have been found to induce multiple fatal arrhythmia syndromes, such as Long QT syndrome (LQTS), atrioventricular block (AVB)...

Hemodialysis as an alternative treatment of mexiletine intoxication

Mexiletine is a class IB antiarrhythmic agent. Although it is primarily used in treating ventricular arrhythmias, recent indications for use of mexiletine include chronic and neuropathic pains. At high doses, mexiletine causes drowsiness, confusion, nausea, hypotension, sinus bradycardia, paresthesia, seizures, bundle branch block, atrioventricular heart block, ventricular arrhythmias, asystole, cardiovascular collapse, and coma. A 23-year-old male patient presented to the emergency department with intentional ingestion of high-dose mexiletine. Despite decontamination and supportive treatment, his vitals deteriorated during the observation period; and he developed stupor and dysarthria. Patient then underwent hemodialysis. His vital signs and overall condition improved rapidly following hemodialysis treatment. In this case report, we aimed to emphasize hemodialysis as a useful alternative therapy for severe mexiletine intoxications.

Refractory erythromelalgia of the ears: response to mexiletine

Erythromelalgia is a rare condition characterized by burning pain, erythema, swelling, and increased temperature usually in the extremities. We present an unusual presentation of erythromelalgia of the ears in a patient who has been refractory to multiple therapies and in whom relief of symptoms was achieved with the use of mexiletine. A review of clinical presentation, pathophysiology, and therapeutic options are presented.

Effect of Mexiletine on Dynamic Allodynia Induced by Chronic Constriction Injury of the Sciatic Nerve in Rats

Static and dynamic allodynia occurred in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Static allodynia was detected within 1 day after the CCI surgery, and persisted for 28 days. Dynamic allodynia displayed a slower course of development with a late onset, and statistically significant changes were achieved between 14 and 28 days after the surgery. Mexiletine at 10 and 30 mg/kg, s.c. produced a significant and dose-dependent inhibition of CCI-induced static and dynamic allodynia on day 14 post-surgery. Pregabalin, used as a reference drug, also significantly inhibited both static and dynamic allodynia at 30 and 60 mg/kg, p.o. These findings rationalize the clinical use of mexiletine for treatment of neuropathic pain.

Mexiletine for Refractory Chronic Daily Headache: A Report of Nine Cases

To describe the use of mexiletine in the treatment of chronic daily headache in a refractory headache population. Intravenous lidocaine is a novel treatment for chronic daily headache with medication overuse and SUNCT syndrome. Mexiletine is a similar but orally active anti-arrhythmic that has been demonstrated to be an effective analgesic in various types of neuropathic pain. We looked at mexiletine as a preventative treatment for headache in refractory patients. We reviewed the medical records of all patients with an order for mexiletine. For each patient, we determined diagnosis, presence of medication overuse on initial evaluation, pain scores, and if the patient received intravenous lidocaine before starting the medication. We then contacted patients by phone to confirm their dose, to review side effects and current pain scores, and to obtain a global impression of effectiveness. We identified 9 patients with a chronic daily headache, including chronic migraine or new daily persistent headache, with significant clinical improvement while using mexiletine as a headache preventative. Each patient had failed to respond to multiple preventative and acute treatments. Seven of the 9 rated mexiletine "much more effective" and 2 "more effective" than previous preventative headache medications. The daily dose ranged from 600 mg/day to 1500 mg/day. Side effects were common and occurred in 7 patients. The majority of patients with an order for mexiletine did not respond to treatment or had intolerable side effects. The preliminary study suggests mexiletine is a useful preventative treatment for some patients with chronic daily headache, including refractory patients with medication overuse or those who have failed multiple preventatives in the past.

Mexiletine for Diabetic Peripheral Neuropathy

Objective: To evaluate the efficacy and safety of mexiletine for the treatment of painful diabetic peripheral neuropathy (DPN). Data Sources: English-language clinical studies and review articles involving human subjects were identified using MEDLINE (January 1966-January 1999). Data Synthesis: Peripheral neuropathy is a common complication of diabetes. Tricyclic antidepressants are the agents of choice for treatment of symptomatic peripheral neuropathy. However, other therapies are necessary in patients who do not respond to tricyclic antidepressants, do not tolerate their adverse effects, or have a contraindication to their use. The use of mexiletine for DPN has been evaluated in four studies. Two studies concluded that mexiletine was significantly better than placebo as treatment for DPN; another showed no difference. In the fourth study, improvement with use of mexiletine was not demonstrated, but posthoc analysis showed benefits in certain subgroups of patients, including patients with stabbing or burning pain, heat sensation, or formication. All studies excluded patients with cardiac, renal, or hepatic disease; in addition, only one study assessed quality of life, which raises questions about the safety and clinical significance of the reported benefits of mexiletine therapy. Conclusions: Four studies have evaluated the role of mexiletine in treating DPN. Although the results are not uniform, they suggest that mexiletine may be considered a potential alternative for patients unable to take tricyclic antidepressants. The long-term safety of mexiletine and its use in patients with renal, hepatic, or cardiac disease has not been established.

Determination of the enantiomeric composition of mexiletine and its four hydroxylated metabolites in urine by enantioselective capillary gas chromatography.

The enantiomers of mexiletine and four of its hydroxylated metabolites were directly separated by capillary gas chromatography using a heptakis(6-O-tert-butyl-dimethylsilyl-2,3-di-O-methyl)-beta- cyclodextrin column. The method was applied to the analysis of urine samples from cancer patients who were treated with racemic mexiletine as part of a study of the use of mexiletine in the relief of neuropathic pain. Samples analyzed before and after deconjugation of the urine with beta-glucuronidase/arylsulfatase showed a high stereoselectivity in the formation and conjugation of these compounds.

Long-term effect of mexiletine on left ventricular function and relation to suppression of ventricular arrhythmia

The effects of oral mexiletine on left ventricular (LV) ejection fraction (EF) and ventricular arrhythmias—and a possible relation between these effects—were evaluated during 3 months of therapy In 29 patients with chronic ventricular premature complexes (VPCs) and a moderately reduced to normal LVEF by 24-hour Holter monitoring and by radionuclide ventriculography at rest and during maximum tolerable exercise testing. After an average titration period of 13 days, a mean daily mexiletine dose of 739 mg was maintained throughout the treatment. At the end of titration and after 3 months of treatment, patients with a baseline LVEF ≤40% (group 2) responded with a median reduction of the hourly VPC rate by 90 and 81%, respectively, compared with 79 and 72% in those with a baseline LVEF >40% (group 1). Couplets and runs of ventricular tachycardia were almost completely suppressed in nearly all patients. A single patient had a proarrhythmic increase in VPCs during treatment. Compared with baseline, there were no significant changes in resting or exercise LVEF after 1 or 3 months of treatment in either of the 2 groups of patients. No correlation was found between treatment-induced changes in arrhythmia frequency and in resting EF. No symptoms of congestive heart failure developed. The study confirms that long-term use of mexiletine is efficacious and relatively free of cardiac depressant effects even in patients with diminished LV function.