Martin Bradley discusses the complexities of mexiletine use following the licensing of NaMuscla® for the treatment of myotonia in adults with non‑dystrophic myotonic disorders
Mexiletine is a sodium channel blocker, and was originally developed as an anticonvulsant drug.1,2 However, it was found to have anti-arrhythmic properties, and has been approved for this indication in several countries since the 1960s.2 There is no licensed preparation of mexiletine in the UK; consequently, it is imported for use in ventricular arrhythmia because there are limited oral sodium channel blocker (class 1b) anti-arrhythmic agents available, and it is a useful agent in patients with long QT syndrome.3
The therapeutic effect of mexiletine on myotonic disorders (rare diseases caused by a malfunction of skeletal ion channels) was investigated in the 1980s.4 Since the 1990s, mexiletine has been the agent of choice for patients with myotonia according to expert opinion,5 and in 2010 and 2012, positive results from two small randomised controlled trials indicated that mexiletine was effective for this condition.6,7 Until recently, no manufacturer has taken mexiletine through regulatory approval for use in myotonia; therefore, an imported product is also used in UK neurology centres for patients with myotonic syndromes.
Since the 1990s, mexiletine has been the agent of choice for patients with myotonia …
New formulation
In December 2018, a new formulation of mexiletine, NaMuscla®, was licensed for the treatment of myotonia in adult patients with non-dystrophic myotonic disorders in the European Union.8 Because myotonia is a rare disease, NaMuscla® is classed as an orphan medicinal product (OMP) by the European Medicines Agency.8 OMPs are guaranteed a period of at least 10 years’ market exclusivity (no other, similar agents are allowed to be marketed for similar indications),9 and are also generally marketed at a premium price because of the limited volumes used. A commercial in-confidence access price for use in the NHS has been agreed. Owing to its high cost, mexiletine for use in neuromuscular disorders was added to the tariff-excluded drugs list for 2019/20.10 In a communication with trusts, NHS England confirmed that specialist neurosciences centres will be reimbursed for NaMuscla® used for non-dystrophic myotonic disorders, but that NaMuscla® or imported mexiletine capsules must be funded within the tariff by CCGs for other indications.11
Complications for provider trusts following the licensing of NaMuscla®
Although it is welcome that there is a new, UK-licensed formulation of mexiletine for use in patients with myotonia, some complications have arisen for providers related to the use of mexiletine in both neurology and cardiology patients.
Dose-related complications
Medicines and Healthcare products Regulatory Agency (MHRA) guidance states that UK-licensed products should be used in preference to unlicensed products, even when they are used off-label.12 However, NaMuscla® may be unsuitable for certain patients. NaMuscla® is only available as 167 mg mexiletine capsules (equivalent to 200 mg mexiletine hydrochloride),13 whereas mexiletine hydrochloride 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg capsules are available through import.
… complications have arisen for providers related to the use of mexiletine in both neurology and cardiology patients.
At the time of writing, it is unknown whether Lupin Healthcare (UK) Ltd, the manufacturer of NaMuscla®, intends to produce different dose formulations; however, many patients currently using mexiletine for either myotonia or arrhythmia will be on bespoke doses that are impossible to achieve with NaMuscla®. Also, because the packaging of NaMuscla® states the mexiletine base dose, whereas the unlicensed products use the hydrochloride salt dose, patients are at risk of confusion if they are given both preparations to fulfil their treatment regimen or are switched between products.
Furthermore, as mexiletine is known to occasionally have pro-arrhythmic effects, the product literature for NaMuscla® contraindicates its use in patients with ventricular tachyarrhythmia.13 This information may be confusing and worrying for patients. Although unlicensed, imported products generally have English translations of the package literature for patients, and their wording may be more appropriate for patients taking mexiletine for arrhythmia than the patient information leaflet for NaMuscla®.
For these reasons, at the time of writing, the MHRA is allowing the continued import of unlicensed products for patients currently on mexiletine and ineligible to switch to NaMuscla®, provided that there is a letter detailing the patient’s special need from the prescribing clinician as per MHRA guidance.12 Although this is helpful for specialist organisations, it is likely to remain difficult to procure mexiletine through community pharmacies for those patients receiving continued treatment in primary care. These patients may need to be repatriated to their specialist neurology centre to obtain supplies.
Financial implications
Use of NaMuscla® for arrhythmia also has a financial impact on providers. Providers are familiar with the financial consequences of a routinely used, unlicensed treatment becoming available as a licensed preparation; in the case of NaMuscla®, however, the new product is not licensed for use in arrhythmia. In most instances, the newly licensed product is more expensive, because the manufacturer needs to recoup the expense of taking the product through market authorisation. NaMuscla® is recognised as a tariff‑excluded medication, so treatment can be provided without financial loss by organisations, but only for non-dystrophic myotonic disorders.10 Because use in arrhythmia is off-label, this must be funded by providers from within the existing tariff, and the costs are likely to be significantly higher than those of the imported products. It should be noted, however, that financial reasons are not an acceptable reason for use of an unlicensed preparation over a licensed product (i.e. the ‘special needs’ requirement is not fulfilled),12 and eligible patients should be prescribed NaMuscla® rather than an unlicensed product.
Conclusion
The introduction of a newly licensed mexiletine formulation for myotonia is welcome because it provides the gold standard for product quality. However, the introduction of this new product has not come in conjunction with a new clinical evidence base, and use of mexiletine is subject to logistic and commissioning complications—although it is currently used for multiple indications, its licence only covers use in myotonia.
References
- British National Formulary. Mexiletine. NICE, 2019. bnf.nice.org.uk/drug/mexiletine.html (accessed 22 August 2019).
- Campbell R. Mexiletine. N Engl J Med 1987; 316 (1): 29–34.
- Priori S, Blomström-Lundqvist C, Mazzanti A et al for the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC). 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2015; 36 (41): 2793–2867.
- Pouget J, Serratrice G. Myotonia with muscular weakness corrected by exercise. The therapeutic effect of mexiletine. Rev Neurol (Paris) 1983; 139 (11): 665–672.
- Trip J, Drost G, van Engelen B, Faber C. Drug treatment for myotonia. Cochrane Database Syst Rev 2006; (1): CD004762.
- Logigian E, Martens W, Moxley R et al. Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. Neurology 2010; 74 (18): 1441–1448.
- Statland J, Bundy B, Wang Y et al. Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. JAMA 2012; 308 (13): 1357–1365.
- European Medicines Agency. Namuscla (mexiletine). www.ema.europa.eu/en/medicines/human/EPAR/namuscla (accessed 14 August 2019).
- European Medicines Agency. Market exclusivity: orphan medicines. www.ema.europa.eu/en/human-regulatory/post-authorisation/orphan-medicines/market-exclusivity-orphan-medicines (accessed 14 August 2019).
- NHS England. NHS England drug list version 14.1. NHS England, 2019. Available at: www.england.nhs.uk/wp-content/uploads/2019/04/nhs-england-drugs-list-v14.1.pdf
- NHS England. NaMuscla® (Mexiletine) for the treatment of myotonia in patients with non-dystrophic myotonic disorders. Specialised Services Circular (SSC) 2001. April 2019. Available online from the NHS England internal SharePoint.
- Medicines and Healthcare products Regulatory Agency. The supply of unlicensed medicinal products (“specials”). MHRA Guidance Note 14. www.gov.uk/government/publications/supply-unlicensed-medicinal-products-specials (accessed 14 August 2019).
- Lupin Healthcare (UK) Ltd. Namuscla 167 mg hard capsules—summary of product characteristics. www.medicines.org.uk/emc/product/9838 (accessed 14 August 2019).