Dalfampridine extended release tablets: 1 year of postmarketing safety experience in the US

Abstract

Background: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.Objective:To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs) for dalfampridine-ER since product launch.Methods: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.Results: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.Conclusion: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.

Monitoring long-term efficacy of fampridine in gait-impaired patients with multiple sclerosis

“…Fampridine-induced changes in clinical walking tests were not correlated with the self-assessed change in ambulatory performance in the double-blind core study (figure e-1 of long-term PR fampridine treatment. [15][16][17] The proportion of patients experiencing AEs and SAEs was in line with previous reports. 15,16 The frequency of AEs was not different between double-blind treatment with PR fampridine and placebo, indicating that PR fampridine was likely not responsible for the AEs in PwMS treated with the drug.…”

Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis

“…11 No new safety signals were observed, and, overall, TEAEs were consistent with what has been observed in previous controlled trials and in postmarketing surveillance. 1,2,4,5 In conclusion, this study provides evidence that dalfampridine-ER tablets, 5 mg twice daily, are not effective for improving walking in patients with MS. Although the primary endpoint of this study was not achieved, additional analyses with similarities to those used in previous trials showed that dalfampridine-ER 10 mg twice daily seems to be the minimally effective dose for improvement of walking.…”

“…3 Postmarketing safety data for 1 and 2 years suggested a safety profile in clinical practice similar to that observed in the clinical trials. 4,5 As part of the postmarketing commitment, evaluation of the efficacy and safety of a lower 5-mg dose of dalfampridine-ER tablets was required. The purpose of the present study was to evaluate the efficacy and tolerability of dalfampridine-ER 5 mg twice daily.…”

Walking impairment in patients with multiple sclerosis – a new therapeutic approach and clinical potential of dalfampridine extended release tablets

“…68 A total of four seizure-related adverse events were reported during the extension studies among the patients who were treated with dalfampridine-ER in the parent trial (1.5%); Descriptive analysis was performed to provide information on all postmarketing AEs that were spontaneously reported. 73 The most frequently reported AEs, with a prevalence of $2% of all reported cases and reported as the percent of total AEs, included dizziness (5.7%), insomnia (4.5%), balance disorder (3.9%), headache (3.2%), nausea (2.8%), urinary tract infection (2.4%), asthenia (2.0%), and back pain (2.0%). These were also the most common AEs reported during clinical development, and all are included in the current US product label.…”