Clinical overview of the seizure risk of dalfampridine.

Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA.
Expert Opinion on Drug Safety (Impact Factor: 2.74). 06/2012; 11(4):651-7. DOI: 10.1517/14740338.2012.697896
Source: PubMed

ABSTRACT INTRODUCTION: Dalfampridine extended release tablets (dalfampridine-ER; known as prolonged-, modified or sustained-release fampridine in some countries) is a potassium channel blocker approved at 10 mg taken every 12 h, for the improvement of walking in patients with multiple sclerosis (MS). This has been demonstrated by an increase in walking speed. Its mechanism of action and narrow therapeutic range suggest the need to evaluate the seizure risk in treated MS patients. AREAS COVERED: This paper discusses the seizure risk in clinical trials, and postmarketing experience of dalfampridine, relative to that in patients with MS. Electroencephalography as a predictive screening tool for seizure risk in dalfampridine-treated patients is also discussed. EXPERT OPINION: The apparent seizure risk at the recommended dose of dalfampridine among patients with no prior seizure history may not be greater than the risk already present in the MS population. For MS patients, dalfampridine represents a promising new therapy for the improvement of walking impairment; its quick onset of action allows rapid determination of therapeutic response. The lack of prognostic value of electroencephalography for determining seizure risk suggests that treatment can be initiated without further screening when patients have no other contraindications. Strict adherence to the prescribed dosing regimen is essential.

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    ABSTRACT: Introduction: Multiple sclerosis (MS) is the most frequent cause of neurological impairment and sustained disability in young adults. Currently approved disease-modifying drugs do not directly ameliorate the most common symptoms, such as walking impairment. Dalfampridine (DAL), currently approved in all forms of MS, might represent an answer to unmet needs in the symptomatic treatment of MS. Areas covered: The main pharmacological and clinical properties and safety issues of DAL, an extended-release formulation of 4-aminopyridine (4-AP), a broad-spectrum voltage-dependent potassium channel blocker, are described. Relevant publications were identified from a search of PubMed from 1966 to June 2014 (search terms 'dalfampridine OR fampridine OR 4-aminopyridine). DAL, 10 mg twice daily, improves walking ability in approximately one-third and walking speed in about 25% of patients, independently from disease course, compared with placebo; it also improves leg strength. Treatment is generally well tolerated, although there is a dose-dependent increased risk of seizures, especially with dosages > 10 mg twice daily. Expert opinion: DAL represents an option in the symptomatic treatment of MS. Improved ambulation can impact quality of life, motivation and adherence, enhancing the successful management of MS. It has still to be established whether this favorably impacts costs associated with MS.
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    ABSTRACT: Prolonged-release (PR) fampridine (Fampyra®), a potassium channel blocker, is the first agent to be specifically indicated for the improvement of walking in patients with multiple sclerosis (MS). In clinical trials in patients with MS with impaired walking, PR fampridine 10 mg twice daily improved walking ability to a significantly greater extent than placebo, with improvements being maintained with long-term therapy. PR fampridine 10 mg twice daily is generally well tolerated.
    Drugs & Therapy Perspectives 12/2012; 28(12). DOI:10.1007/BF03262139
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    ABSTRACT: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine in some countries) were approved in the US to improve walking in patients with multiple sclerosis, as demonstrated by improvement in walking speed. Postmarketing safety experience is available from exposure of approximately 46,000 patients in the US from product approval through March 2011. To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs) for dalfampridine-ER since product launch. AE data were extracted from the safety database from product launch through March 31, 2011; AEs were classified using the Medical Dictionary for Regulatory Activities. Seizure cases were reviewed for patient demographics, time to event from treatment onset, and presence of additional risk factors. THE MOST FREQUENTLY REPORTED POSTMARKETING AES WERE SIMILAR TO THOSE REPORTED DURING CLINICAL DEVELOPMENT: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain (all included in US product labeling). New clinically significant findings are related to lack of efficacy and inappropriate dosing. Of the approximately 46,000 patients exposed, 85 seizures were reported (∼5.4/1000 patient-years), of which 82 were reported or confirmed by a health care practitioner (∼5.2/1000 patient-years). Beyond the intrinsic multiple sclerosis-related seizure risk, more than half of the 85 cases (62%) had an additional potential risk factor for seizure including a previous history of convulsions, renal impairment, incorrect dosing, or use of concurrent medications with a labeled seizure risk. Duration of treatment prior to the seizure ranged from one dose to 365 days; 26/85 (31%) patients suffered a seizure within a week of starting treatment. Spontaneous safety data from the US postmarketing experience were consistent with the safety profile seen during clinical development. Although first-year seizure incidence was not substantially different from that observed in dalfampridine-ER clinical trials, patients should be monitored for concomitant use of drugs that lower seizure threshold.
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