Dalfampridine …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.06.2021
Released 01.25.2010
Expires For CME 03.06.2024

Dalfampridine

Author: K K Jain MD†

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Dalfampridine

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Introduction

Historical note and terminology

Dalfampridine is an extended-release formulation of fampridine (4-aminopyridine). 4-aminopyridine has a restricted use as an extremely effective bird poison sold under the brand name Avitrol, which is highly toxic to all mammals, including humans, if dosages are exceeded. Compounded forms of the active agent of sustained-release fampridine have been used in clinical practice for many years and shown to improve walking ability in patients with multiple sclerosis. Clinical trials have now been completed that demonstrate effectiveness of the drug with statistical significance and clinically meaningful end points (14). In 2010, the FDA approved dalfampridine (Ampyra™), which is the first oral therapy for multiple sclerosis. Approval of dalfampridine will enable patients to obtain a consistent exact dosage in a guaranteed time-released formula and avoids the risk of getting an uncertain preparation from a compounding pharmacy with possible adverse effects. A life-threatening accidental overdose of fampridine due to a compounding pharmacy error has been reported (27).

Pharmacology

Pharmacodynamics. The exact mode of action is not known, but dalfampridine is a blocker of voltage-gated potassium channels that can increase action potential duration and amplitude, leading to improved conduction in demyelinated nerve fibers and to increased neurotransmitter release at synaptic endings (02). Therapeutic plasma concentrations associated with improved walking are in the range of 0.25 µM, but no specific potassium channel subtype has yet been characterized with significant sensitivity to dalfampridine in this range (08). Findings of 1 study challenge the conventional view that fampridine facilitates synaptic and neuromuscular transmission by blocking voltage-gated potassium channels and suggests instead that fampridine can directly target presynaptic high voltage-activated calcium channels to potentiate neurotransmitter release independent of potassium channels (34).

Pharmacokinetics. Dalfampridine, a sustained-release oral preparation of fampridine, is rapidly absorbed but absolute bioavailability has not been assessed. The extended-release tablet has a relative bioavailability of 96% when compared to an aqueous oral solution, with delayed absorption giving a slower rise to a lower maximum plasma concentration with no effect on the extent of absorption. Peak concentrations are reached 3 to 4 hours post-administration. Dalfampridine was nearly completely and rapidly eliminated as unchanged drug via urinary excretion in trials on healthy volunteers, suggesting that it is unlikely to undergo substantial metabolic transformation (04). The mean terminal disposition half-life is 6.4 hours in healthy individuals. Pharmacokinetics of dalfampridine has been studied in clinical trials of patients with multiple sclerosis in which the dose was titrated (33). Significant findings of this study were:

	(1) The steady-state pharmacokinetic profile of fampridine sustained-release 20 mg twice daily administered for 2 weeks appeared to support the use of twice daily dosing in this population.
	(2) This dosage was generally well tolerated.

Clinical trials

A phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison study of sustained-release fampridine in multiple sclerosis patients showed significantly more consistent responders, as judged by improvement in walking, compared to the placebo group (10).

A randomized, multicenter, double-blind, controlled, phase 3 trial assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis (12). Fampridine improved walking ability, which was a clinically meaningful therapeutic benefit. Another phase 3 trial was designed to confirm efficacy and further define safety and pharmacodynamics of fampridine (11). Dalfampridine produced clinically meaningful improvement in walking ability in a subset of patients with multiple sclerosis with the effect maintained between doses. A review of clinical trials concluded that dalfampridine improved walking speed in approximately one third of multiple sclerosis patients (21).

Results of ENABLE, a 48-week, open-label, phase 4 study of dalfampridine, showed improvement of patient-perceived physical and psychological health impact of multiple sclerosis with walking impairment in a real-life setting (17). In a randomized, double-blind placebo-controlled crossover study, dalfampridine did not show an effect on accelerometer-measured ambulatory activity in persons with multiple sclerosis-related walking difficulty (05). A randomized clinical trial has shown that dalfampridine benefits timed ambulation but not cognition (26).

A substudy of a randomized, double-blind, placebo-controlled trial originally designed to explore the effect of dalfampridine on the speed of information processing in patients with multiple sclerosis (EU Clinical Trials Register number 2013-002558-64) showed that dalfampridine improved static balance (23).

A meta-analysis of controlled clinical trials has shown that dalfampridine is effective for improving walking ability, finger dexterity, and cognitive function in patients with multiple sclerosis (35).

Goals and duration of treatment

Clinical trials show that a subgroup of patients treated with dalfampridine experience an improvement in walking ability as demonstrated by an increase in walking speed, which is sustained for at least 14 weeks. Further use in clinical practice may help to determine the extent to which the drug may impact other functions and may also provide hints as to which patients are most likely to respond positively to the therapy. Extensions of the 2 phase 3 trials showed that consistent improvements in walking speed were sustained above baseline for up to 2.5 years of dalfampridine extended release treatment (06). In managed care populations, improved walking by dalfampridine treatment could potentially help contain some of the direct and indirect costs associated with care of multiple sclerosis (18). A study found that prior authorization of dalfampridine in accordance with FDA-approved labeling, by selecting appropriate subjects for initial therapy, improved safety and minimized dalfampridine costs (09). An open-label observational study showed that improvement in maximum walking distance as well as in motor and cognitive fatigue persisted beyond 1 year (24). An observational study has shown that dalfampridine may improve cognition and fatigue in persons with multiple sclerosis (31). Another study of dalfampridine in multiple sclerosis showed beneficial effects of dalfampridine on cognition, depression, and fatigue, which were not limited to patients who responded to dalfampridine with improved mobility measures (16).

Combination of physical therapy with extended-release dalfampridine therapy improves gait speed more than the use of the drug alone (22). Results of a review of the medical records of patients with multiple sclerosis suggests that a timed 25-foot walk (T25FW) alone might not be enough for assessing improvement and that adding patient-reported ambulation inventory can improve the evaluation of therapeutic response (15).

Special considerations

Creatinine clearance should be calculated prior to initiating treatment with dalfampridine because impairment of renal function can lead to a rise of plasma levels of the drug. The approved 10 mg twice daily dose is contraindicated in the United States in patients with moderate or severe renal impairment. The pharmacokinetics of dalfampridine extended release 7.5 mg twice daily in subjects with mild renal impairment is comparable to 10 mg twice daily in patients with multiple sclerosis who had normal renal function (25).

Pediatric. Safety and effectiveness of dalfampridine in patients younger than 18 years of age have not been established.

Geriatric. Dalfampridine clearance decreases slightly with increasing age, but not sufficiently to necessitate a modification of dose with age.

Pregnancy. Oral administration of dalfampridine in studies on rats did not cause any adverse effects on fertility. There are no adequate and well-controlled studies of dalfampridine in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at doses similar to the maximum recommended human dose of 20 mg/day. Dalfampridine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Voltage-gated potassium channels regulate uterine muscle contractibility and blocking of these channels could affect uterine contraction. The effect of dalfampridine on labor and delivery in humans is unknown. It is not known whether dalfampridine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dalfampridine, a decision should be made whether to discontinue nursing or to discontinue the drug.

Anesthesia. There is no published information available for the interaction of fampridine with anesthetic agents.

References

01: Bethoux F, Fatemi A, Fowler E, et al. Safety, tolerability, and sensorimotor effects of extended-release dalfampridine in adults with cerebral palsy: a pilot study. Clin Ther 2017;39(2):337-46. PMID 28131322
02: Bever CT, Judge SI. Sustained-release fampridine for multiple sclerosis. Expert Opin Investig Drugs 2009;18(7):1013-24. PMID 19548855
03: Birnbaum G, Iverson J. Dalfampridine may activate latent trigeminal neuralgia in patients with multiple sclerosis. Neurology 2014;83(18):1610-2. PMID 25261505
04: Blight AR, Henney HR 3rd. Pharmacokinetics of 14C-radioactivity after oral intake of a single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers. Clin Ther 2009;31(2):328-35. PMID 19302905
05: Brown TR, Simnad VI. A randomized crossover trial of dalfampridine extended release for effect on ambulatory activity in people with multiple sclerosis. Int J MS Care 2016;18(4):170-6. PMID 27551241
06: Chwieduk CM, Keating GM. Dalfampridine extended release: in multiple sclerosis. CNS Drugs 2010;24(10):883-91. PMID 20839898
07: Claassen J, Teufel J, Kalla R, Spiegel R, Strupp M. Effects of dalfampridine on attacks in patients with episodic ataxia type 2: an observational study. J Neurol 2013;260(2):668-9. PMID 23183922
08: Dunn J, Blight A. Dalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. Curr Med Res Opin 2011;27(7):1415-23. PMID 21595605
09: Gleason PP, Phillips J, Fenrick BA, Delgado-Riley A, Starner CI. Dalfampridine prior authorization program: a cohort study. J Manag Care Pharm 2013;19(1):18-25. PMID 23383704
10: Goodman AD, Brown TR, Cohen JA, et al. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology 2008;71(15):1134-41. PMID 18672472
11: Goodman AD, Brown TR, Edwards KR, et al; MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68(4):494-502. PMID 20976768
12: Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 2009;373:732-8. PMID 19249634
13: Haut SR, Bienen EJ, Miller A. Clinical overview of the seizure risk of dalfampridine. Expert Opin Drug Saf 2012;11(4):651-7. PMID 22703551
14: Kachuck NJ. Sustained release oral fampridine in the treatment of multiple sclerosis. Expert Opin Pharmacother 2009;10(12):2025-35. PMID 19586420
15: Klineova S, Farber R, Friedman J, Farrell C, Lublin FD, Krieger S. Objective and subjective measures of dalfampridine efficacy in clinical practice. Mult Scler J Exp Transl Clin 2018;4(3):2055217318786742.** PMID 30090641
16: Korsen M, Kunz R, Schminke U, Runge U, Kohlmann T, Dressel A. Dalfampridine effects on cognition, fatigue, and dexterity. Brain Behav 2016;7(1):e00559.** PMID 28127507
17: Macdonell R, Nagels G, Laplaud DA, et al. Improved patient-reported health impact of multiple sclerosis: the ENABLE study of PR-fampridine. Mult Scler 2016;22(7):944-54. PMID 26447066
18: Miravalle AA. Guidelines and best practices for appropriate use of dalfampridine in managed care populations. Am J Manag Care 2011;17 Suppl 5 Improving:S154-60. PMID 21761954
19: Moster ML, Sergott RC, Leiby BE. Dalfampridine treatment in nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol 2017;37(3):348-9. PMID 28538037
20: Panicucci E, Cohen M, Bourg V, Rocher F, Thomas P, Lebrun C. De novo convulsive status epilepticus in patients with multiple sclerosis treated with dalfampridine. Mult Scler 2019;25(4):618-21.** PMID 30375922
21: Pikoulas TE, Fuller MA. Dalfampridine: a medication to improve walking in patients with multiple sclerosis. Ann Pharmacother 2012;46(7-8):1010-5. PMID 22764324
22: Plummer P, Bohling CJ, Nickles LE, et al. Case report: combining dalfampridine with multicomponent exercise and gait training in a person with multiple sclerosis. Int J MS Care 2018;20(5):238-43.** PMID 30374254
23: Prosperini L, Castelli L, De Giglio L, Bonanno V, Gasperini C, Pozzilli C. Dalfampridine to improve balance in multiple sclerosis: substudy from a randomized placebo-controlled trial. Neurotherapeutics 2020;17(2):704-9. PMID 31820274
24: Ruck T, Bittner S, Simon OJ, et al. Long-term effects of dalfampridine in patients with multiple sclerosis. J Neurol Sci 2014;337(1-2):18-24. PMID 24290498
25: Samara E, Winkle P, Pardo P, et al. Pharmacokinetics of dalfampridine extended release 7.5-mg tablets in healthy subjects and individuals with mild and moderate renal impairment: an open-label study. J Clin Pharmacol 2014;54(1):53-60.** PMID 24150835
26: Satchidanand N, Drake A, Smerbeck A, et al. Dalfampridine benefits ambulation but not cognition in multiple sclerosis. Mult Scler 2020;26(1):91-8. PMID 30566030
27: Schwam E. Severe accidental overdose of 4-aminopyridine due to a compounding pharmacy error. J Emerg Med 2009;41(1):51-4. PMID 19443164
28: Simpson DM, Goldenberg J, Kasner S, et al. Dalfampridine in chronic sensorimotor deficits after ischemic stroke: a proof of concept study. J Rehabil Med 2016;47(10):924-31. PMID 26540083
29: Smith W, Swan S, Marbury T, Henney H 3rd. Single-dose pharmacokinetics of sustained-release fampridine (fampridine-SR) in healthy volunteers and adults with renal impairment. J Clin Pharmacol 2010;50(2):151-9. PMID 19966074
30: Tegetmeyer H. Treatment options for nystagmus [Article in German]. Klin Monbl Augenheilkd 2015;232(2):174-80. PMID 25121801
31: Triche EW, Ruiz JA, Olson KM, Lo AC. Changes in cognitive processing speed, mood, and fatigue in an observational study of persons with multiple sclerosis treated with dalfampridine-ER. Clin Neuropharmacol 2016;39(2):73-80. PMID 26818040
32: Uygunoglu U, Gunduz A, Tutuncu M, Akalin MA, Saip S, Siva A. The effects of dalfampridine on hereditary spastic paraparesis. Eur Neurol 2016;76(3-4):152-3. PMID 27606838
33: Vollmer T, Blight AR, Henney HR 3rd. Steady-state pharmacokinetics and tolerability of orally administered fampridine sustained-release 10-mg tablets in patients with multiple sclerosis: a 2-week, open-label, follow-up study. Clin Ther 2009;31(10):2215-23. PMID 19922892
34: Wu ZZ, Li DP, Chen SR, Pan HL. Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit. J Biol Chem 2009;284(52):36453-61. PMID 19850918
35: Zhang E, Tian X, Li R, et al. Dalfampridine in the treatment of multiple sclerosis: a meta-analysis of randomised controlled trials. Orphanet J Rare Dis 2021;16(1):87. PMID 33588903**

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Dalfampridine

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Ion channels and neurologic disorders
Multiple sclerosis
Multiple sclerosis: treatment of its symptoms
Neuropharmacology

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Multiple sclerosis (condensed)

	• A phase 2 trial of dalfampridine in chronic spinal cord injury showed some improvement of spasticity. No further development has been reported.
	• Episodic ataxia type 2 (07)
	• A double-blind, placebo-controlled, randomized clinical trial of dalfampridine in patients with chronic stroke deficits showed effect on sensorimotor function of the lower extremities with an improvement in walking speed (28).
	• Pharmacological treatment option for nystagmus (30)
	• Dalfampridine has been shown to reduce spasticity and improve hand dexterity in patients with hereditary spastic paraparesis who complain of walking impairments (32).
	• Nonarteritic anterior ischemic optic neuropathy (19)
	• A phase 1, double-blind, placebo-controlled clinical trial showed that dalfampridine is not effective in adult cerebral palsy (01).

Dalfampridine …

Dalfampridine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Also in This Category

Autoantibodies: mechanism and testing

Multiple sclerosis: treatment of its symptoms

Anti-GQ1b antibody syndrome

Serotonin syndrome

Paraneoplastic syndromes

Anti-IgLON5 disease

Balo concentric sclerosis

Anti-LGI1 encephalitis

Dalfampridine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

Multiple sclerosis: treatment of its symptoms

Anti-GQ1b antibody syndrome

Serotonin syndrome

Paraneoplastic syndromes

Anti-IgLON5 disease

Balo concentric sclerosis

Anti-LGI1 encephalitis

This is an article preview.
Start a Free Account
to access the full version.