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: 2.62). 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: Fampridine is indicated to improve walking in adult multiple sclerosis (MS) patients. Indications vary between countries and the prescribing neurologist should be aware of the labeling and indication in his own country. The prolonged-release formulation of 4-aminopyridine has reduced the risk of seizure to a level near the intrinsic MS risk, and the risk can be further minimized if it emphasized that patients should not exceed the recommended dose of 10 mg twice a day, should not catch up on missed doses and should not divide, crush or chew tablets. It is imperative to check the renal function before and during treatment and make sure the patient does not get concomitant medications affecting the renal elimination. The use of fampridine is considered safe, and the side effects are often mild and acceptable. Approximately one-third of MS patients treated with fampridine will experience an improvement of their walking speed above 20% on the timed 25-foot walk test (T25FW), which is considered to be clinically relevant.
    Expert Review of Neurotherapeutics 12/2013; 13(12):1309-17. · 2.96 Impact Factor
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    ABSTRACT: Abstract Background: In January 2010, dalfampridine extended release tablets (dalfampridine-ER [AMPYRA*]; prolonged-, modified or sustained-release fampridine [FAMPYRA(†)] in some countries), 10 mg to be administered twice daily approximately 12 hours apart, were approved by the US Food and Drug Administration. This was the first drug indicated to improve walking in patients with MS. Scope: Publications describing the pharmacokinetics of dalfampridine-ER or the immediate release formulation were identified from a search of PubMed through June 2012 using the search terms "dalfampridine OR fampridine OR 4-aminopyridine" AND "pharmacokinetics" and were supplemented with unpublished studies made available by Acorda Therapeutics, Inc. Findings: Pharmacokinetic studies show dose proportionality, with dalfampridine-ER having a more favorable profile than immediate-release dalfampridine. With twice-daily dosing of dalfampridine-ER, time to peak plasma concentration (3.2-3.9 hours) and apparent terminal plasma half-life (5.6-6.4 hours) are approximately twice that of immediate-release formulations, with comparable overall exposure and peak plasma concentrations (21.6 ng/mL) that were maintained at levels approximately 50% lower than immediate release. Steady state is achieved within 39 hours; pharmacokinetics are predictable based on single dosing. Trough plasma concentrations of 13-15 ng/mL are required to maintain efficacy. Renal excretion is predominantly as unchanged compound, and renal clearance in healthy individuals exceeds the glomerular filtration rate. Since dalfampridine-ER exposure increases with renal impairment, it is contraindicated in patients with moderate or severe impairment in the US, and in patients with any renal impairment in the European Union. Conclusions: Dalfampridine-ER has low protein binding, is not a substrate for p-glycoprotein and does not affect CYP450 enzymes, suggesting a low potential for drug-drug interactions. Because of the narrow therapeutic range and risk of adverse events, including seizure, with increasing plasma concentrations, the recommended dose and regimen of dalfampridine-ER should not be exceeded and not be used with other dalfampridine formulations. A limitation of this review is that it includes some data that have not yet been published.
    Current Medical Research and Opinion 11/2012; · 2.37 Impact Factor
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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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