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: Walking impairment is a clinical hallmark of multiple sclerosis (MS). Dalfampridine-ER, an extended-release formulation of dalfampridine (also known by its chemical name, 4-aminopyridine, and its international nonproprietary name, fampridine), was developed to maintain drug plasma levels within a narrow therapeutic window, and assessed for its ability to improve walking in MS. The putative mechanism of action of dalfampridine-ER is restoration of axonal conduction via blockade of the potassium channels that become exposed during axonal demyelination. Two pivotal phase III clinical trials demonstrated that dalfampridine-ER 10-mg tablets administered twice daily improved walking speed and patient-reported perceptions of walking in some patients. Dalfampridine-ER was generally well tolerated, and, at the approved dose, risk of seizure was neither elevated relative to placebo nor higher than the rate in the MS population. Dalfampridine-ER (AMPYRA®) was approved in the United States for the treatment of walking in patients with MS as demonstrated by an increase in walking speed. The use of the dalfampridine-ER is contraindicated in patients with a history of seizure. It is the first pharmacologic therapy for this indication and has been incorporated into clinical management of MS.
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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: This study aimed to characterize the prescribing of dalfampridine extended release (D-ER) 10 mg tablet treatment in people with multiple sclerosis (MS). A retrospective cohort study was performed using Medco pharmacy and medical claims. Medical claims were used to identify MS patients with more than one prescription for D-ER with 1 year of prior continuous enrollment (n=704). These patients were matched 2:1 on age, sex, and health insurance source with a comparison group of MS patients who were treatment naïve for D-ER (n=1,403). Categorical data were analyzed by χ (2) test; ordinal data by Wilcoxon rank sum test; and continuous data by Student's t-test. Most patients were women aged 45-64 years. In the year preceding D-ER initiation, the prevalence of seizure and renal impairment was numerically lower in the D-ER cohort relative to those who were D-ER naïve (seizure: 3.1% versus 4.7%, respectively; renal impairment: 4.3% versus 5.1%, respectively); however, prescriptions for antiepileptic drugs in the two cohorts were comparable. In the year preceding treatment initiation, 62% of the D-ER cohort was prescribed MS-specific disease-modifying therapies relative to 45% who were D-ER naïve. Seizure and renal impairment rates among D-ER-naïve patients were consistent with published literature, yet rates among those prescribed D-ER during the year preceding treatment initiation were slightly lower than rates among D-ER-naïve patients. Given that D-ER is contraindicated in patients with history of seizure or moderate or severe renal impairment, lower rates may indicate that risk-minimization strategies contributed to the lower prevalence.
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