Epub ahead of print: Cornblath CR et al. The Safety Profile of Dalfampridine Extended Release in Multiple Sclerosis Clinical Trials.Clin Ther. 2012 Apr 11.
BACKGROUND: Dalfampridine (fampridine outside the United States) is a broad-spectrum potassium channel blocker. This means it works by manipulating the flow of potassium ions into and out of nerve cells. Dalfampridine extended-release tablets have been approved by the FDA and EMA to improve walking speed in MSers.
OBJECTIVE: The objective is to review the safety profile of dalfampridine extended-release tablets with respect to its expected use in MSers.
METHODS: The authors reviewed published data relevant to MSer safety profiles based on searches of articles in PubMed published up to December 31, 2010, using the search terms fampridine OR dalfampridine OR 4-aminopyridine AND (multiple sclerosis) in combination with toxicity, safety, clinical trial, pharmacokinetics, and seizures. These searches were supplemented with data derived from the approved package insert and relevant sections of the New Drug Application (22-250) as submitted to the FDA.
RESULTS: The literature searches returned 58 unique citations, of which 26 were considered relevant for characterizing the safety profile of dalfampridine; excluded citations were as follows: reviews (19), evaluation of 3,4-diaminopyridine (4), intravenous dosing (2), inadequate information on patient doses (2), preclinical models (2), and “other” (3). Dalfampridine is nearly completely (approximately 96%) eliminated unchanged in urine, with limited transformation to 2 inactive metabolites and low risk for interaction with drugs metabolized by hepatic P450 cytochromes.
“This means it is unlikely to interact with other drugs in the liver.”
However, in MSers with renal impairment mean peak plasma concentrations were 68%-101% higher and apparent clearance was 43%-73% lower relative to those without impairment, precluding dalfampridine use in MSers with moderate or severe renal impairment.
Dalfampridine has a narrow therapeutic range. At the therapeutic dose of 10 mg twice daily, adverse events were generally mild to moderate and, consistent with the mechanism of action of dalfampridine, were primarily related to stimulatory effects on the nervous system.
A thorough study suggested a low risk of induction of QT prolongation and associated cardiac arrhythmias in healthy individuals at therapeutic (10 mg, twice daily) or supratherapeutic (30 mg, twice daily) doses.
“The QT interval refers to effects on the electrical conduction system in the heart.”
Although the incidence of seizures was dose related, data from the clinical trials of dalfampridine extended-release tablets suggest that the risk of seizure at the therapeutic dose, in MSers with no history of seizure, is not likely to be higher than background rates in MS.
“This is good news as this has always been a concern of using this drug.”
CONCLUSION: In MSers, dalfampridine has a narrow therapeutic range but an acceptable safety profile when used at the therapeutic dose of 10 mg twice daily.
“We are still having problems getting this drug funded under the NHS. The PCTs or Commissioner are unconvinced whether or not this drug impacts on the quality of life of MSers with walking difficulties. One PCT asked us if the drug prevents falls and hence fractures. A good questions as this may be construed to be a positive in relation to impact on QoL. The harsh facts are that until NICE reviews fampridine and we get a green light, i.e. it is deemed cost-effective to be used in the NHS, PCTs and Commissioners will always have a reason to say no. It is a pity as a minority of MSers respond very well to this drug.”
Other posts of interest on this blog in relation to fampridine:
12 Mar 2012
On 21 October 2009, there was a suggestion on this blog that fampridine might have a negative effect due to the additional strain put on damaged nerves, which obviously put me right off. “There is now good evidence that …
21 Jan 2011
“The Committee adopted a negative opinion recommending that fampridine, from Biogen-Idec Ltd, should not be granted a marketing authorisation. Fampyra was intended to be used to improve the walking ability of adult …
21 May 2011
Following the re-examination of its previous negative opinion, the European Medicines Agency has granted fampridine a conditional marketing authorisation; i.e. it has been licensed in Europe to improve the walking of PwMS …
21 Oct 2009
For these reasons I am wary about the long-term use of Fampridine in MS-related motor fatigue. I am worried that Fampridine may speed up the rate of disability progression. I stand to be proved incorrect on this; we will only …
01 Feb 2010
The drug was previously known as fampridine sustained release. Given at doses greater than the recommended 10 mg twice a day, dalfampridine can cause seizures. The most common adverse events reported in clinical …
15 Feb 2012
Re: “Fampyra or Fampridine” and “There is nothing to support the idea that MS symptoms can be pharmaceutically treated.” There is a very good scientific rationale for why fampridine works in MS and the trial results are …
28 Jul 2011
More recently the drug Fampridine has been licensed to improve walking speed in MS’ers; I suspect that MS’ers with heat sensitivity or fatigue-related conduction block will be more likely to be fampridine responders (see …
11 Nov 2011
Drugs like Fampridine and Nerispridine are said to improve walking in MS’ers with walking difficulties yet I have not seen MS welfare advocates, including this blog, champion the rights of MS’ers to gain access to these …