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: 2.91). 06/2012; 11(4):651-7. DOI: 10.1517/14740338.2012.697896
Source: PubMed


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.

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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: BACKGROUND: Medication used to treat multiple sclerosis (MS) can be categorized as disease-modifying therapies, symptomatic therapies, or treatment of acute exacerbations. Dalfampridine is the first symptomatic therapy approved by the Food and Drug Administration to improve walking in patients with MS. OBJECTIVE: This article reviews the pharmacology, pharmacodynamic properties, and pharmacokinetic properties of dalfampridine, as well as its clinical efficacy, safety profile, pharmacoeconomic considerations, and place in therapy. METHODS: Three PubMed searches were conducted for original articles published in English between 1966 and August 2012 with human study participants. Articles concerning the pharmacology, pharmacokinetic properties, pharmacodynamic properties, efficacy, and safety profile of dalfampridine were evaluated. RESULTS: Dalfampridine theoretically works to improve conduction and enhance walking by inhibiting potassium channels in the axonal membrane and by prolonging action potentials in demyelinated neurons. The efficacy of dalfampridine has been reported in 2 Phase III clinical trials in patients with MS. When comparing dalfampridine 10 mg twice daily with placebo, these studies found a statistically significant improvement in walking (42.9% vs 9.3% and 35% vs 8%; P < 0.001). However, clinical trials and postmarketing surveillance have found a statistically significant increased risk of seizures with dalfampridine. CONCLUSIONS: Dalfampridine has a unique mechanism of action, leading to its approval as the first symptomatic therapy for MS to improve walking speed. The increased risk of seizures can be a significant safety concern and will require health care providers to be diligent in monitoring patients and to ensure adequate patient education. The addition of dalfampridine as symptomatic therapy for MS may lead to additional novel products in the future.
    Clinical Therapeutics 11/2012; 34(11). DOI:10.1016/j.clinthera.2012.10.003 · 2.73 Impact Factor
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    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 those 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; 29(12). DOI:10.1185/03007995.2012.749221 · 2.65 Impact Factor
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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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