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Generic Name: Dalfampridine
Class: Other Miscellaneous Therapeutic Agents
Chemical Name: 4-aminopyridine
Molecular Formula: C5H6N2
CAS Number: 504-24-5

Warning(s)

REMS:

FDA approved a REMS for dalfampridine to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of dalfampridine and consists of the following: communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Dalfampridine was formerly known as fampridine (4-aminopyridine; 4-AP);1 13 14 broad spectrum potassium channel blocker.1 13 14 22

Uses for Ampyra

Multiple Sclerosis

Used to improve walking in patients with multiple sclerosis (MS);1 designated an orphan drug by FDA for relief of symptoms of MS.23

In clinical studies in MS patients who received the recommended dalfampridine dosage, walking improvement was demonstrated by increased walking speed in a timed 25-foot walk (T25FW).1 2 3 20 In those who responded to dalfampridine (approximately 35–43%), walking speed increased 25–29%2 3 20 and was maintained until the drug was discontinued.2 20

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Although only a portion of MS patients respond to dalfampridine treatment with walking improvement, improved walking during such treatment has been demonstrated in all MS disease types (relapsing remitting, primary progressive, secondary progressive, progressive relapsing).2 20 It is not clear what magnitude of improvement in walking speed results in improved walking ability or quality of life.20 Although consistent improvements in walking speed were shown to be associated with improvements on patient self-assessment of ambulatory disability (12-item Multiple Sclerosis Walking Scale; MSWS-12), the average MSWS-12 score during dalfampridine treatment was not different than that reported with placebo.1 20

The magnitude of walking improvement reported with dalfampridine is independent of concomitant therapy with biologic response modifiers used for the management of MS (interferon, glatiramer acetate, natalizumab).1 2

Data insufficient regarding safety and efficacy for management of other MS symptoms (e.g., motor function assessed using manual muscle testing, visual function, cognitive function, fatigue).6 12 14 18 20

Ampyra Dosage and Administration

General

  • Determine estimated Clcr prior to initiating dalfampridine; monitor Clcr at least annually during therapy.1 Estimating Clcr is particularly important in patients ≥50 years of age since mild renal impairment is common in this age group.1 (See Renal Impairment under Cautions.)

Restricted Distribution

  • Distribution of dalfampridine is restricted; the drug is available only through certain specialty pharmacies.21 22 Specific information regarding the dalfampridine distribution process is available from the manufacturer at 888-881-1918 or .21

Administration

Oral Administration

Administer orally with or without food.1 (See Food under Pharmacokinetics.)

Give doses approximately 12 hours apart.1

Swallow whole tablet; do not divide, crush, chew, or dissolve.1

If a dose is missed, do not double dosage or take extra doses.1 Take the next dose at the regularly scheduled time.1

Dosage

Adults

Multiple Sclerosis
Treatment to Improve Walking
Oral

10 mg twice daily.1 Give doses approximately 12 hours apart.1

Has been used for up to 9–14 weeks in clinical studies.1 2 3

Prescribing Limits

Adults

Oral

Maximum 10 mg twice daily with doses given approximately 12 hours apart.1 Higher dosage does not result in additional therapeutic benefit and is associated with increased risk of adverse reactions (e.g., seizures).1 (See Seizures under Cautions.)

Special Populations

Hepatic Impairment

Pharmacokinetics not evaluated in adults with hepatic impairment.1 Hepatic impairment not expected to affect pharmacokinetics or dosage recommendations.1

Renal Impairment

Patients with moderate or severe renal impairment (Clcr ≤50 mL/minute): Contraindicated.1

Patients with mild renal impairment (Clcr 51–80 mL/minute): Clearance is reduced by about 45% and plasma concentrations may approach those seen with dosages that may be associated with an increased risk of seizures.1 Weigh potential benefits against risk of seizures.1 (See Renal Impairment under Cautions.) Manufacturer does not provide dosage recommendations for such patients; only available as an extended-release tablet containing 10 mg of dalfampridine.1

Adults 50 Years of Age or Older

Dosage modification not necessary based solely on age.1 Eliminated by kidneys;1 consider that mild renal impairment is common in adults ≥50 years of age.1 (See Renal Impairment under Dosage and Administration.)

Cautions for Ampyra

Contraindications

  • History of seizures.1 (See Seizures under Cautions.)

  • Moderate or severe renal impairment (Clcr ≤50 mL/minute).1 (See Renal Impairment under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Anaphylactic reactions reported rarely.1

If anaphylactic or other serious allergic reaction occurs, discontinue dalfampridine and do not restart the drug.1

Seizures

Dalfampridine can cause seizures.1 2 3 4 8 24

Postmarketing reports indicate majority of seizures have occurred in patients receiving recommended dosage (generally within days to weeks after starting the drug) and in patients without a history of seizures.1 24 Some patients had been receiving other drugs that could have increased risk of seizures or lowered seizure threshold; in addition, age-related renal dysfunction and resultant increases in plasma dalfampridine concentrations could have contributed to risk of seizures.24

High dosage (e.g., 15 or 20 mg twice daily) increases risk of seizures.1 In open-label extension studies in MS patients, incidence of seizures was more than 4 times greater at dosage of 15 mg twice daily compared with recommended dosage (10 mg twice daily).1

Altered mental state, confusion, and seizures (including status epilepticus requiring intensive supportive care) reported following overdosage.1 8

Contraindicated in patients with prior history of seizures.1 Has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on EEG; such patients were excluded from clinical trials.1 Risk of seizures in patients with epileptiform activity on EEG is unknown and could be substantially higher than that observed in clinical trials.1

Although risk of seizures in patients with mild renal impairment (Clcr 51–80 mL/minute) who receive usual dosage is unknown, plasma concentrations in such patients may approach those reported with dosages that may be associated with increased risk of seizures.1 24 (See Renal Impairment under Cautions.)

If a seizure occurs, discontinue dalfampridine and do not restart the drug.1

Concurrent Treatment with Other Aminopyridines

Because of increased risk of dose-related adverse effects, do not use in patients receiving other aminopyridines, including extemporaneously prepared formulations; dalfampridine formerly was known as fampridine (4-aminopyridine, 4-AP), since the active ingredient is the same.1

Prior to initiation of dalfampridine, discontinue use of any product containing 4-aminopyridine.1

Urinary Tract Infections

Urinary tract infections (UTIs) reported more frequently in patients receiving dalfampridine (12%) than in patients receiving placebo (8%).1

If UTI occurs, evaluate and treat as clinically indicated.1

Specific Populations

Pregnancy

Category C.1

In animal studies, decreased offspring viability and growth reported at a dosage similar to maximum recommended human dosage.1

Lactation

Not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Geriatric Use

Insufficient experience with dalfampridine in geriatric patients ≥65 years of age to determine whether such individuals respond differently than younger individuals.1

Substantially eliminated by kidneys;1 11 geriatric patients are more likely to have decreased renal function.1 Because risk of adverse reactions (including seizures) may be greater in patients with impaired renal function,1 it is particularly important to determine estimated Clcr in this age group prior to initiation of dalfampridine.1 (See Renal Impairment under Cautions.)

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment.1 Hepatic impairment not expected to affect pharmacokinetics or dosage recommendations.1

Renal Impairment

Clearance of dalfampridine is decreased in patients with renal impairment and is correlated with Clcr.1

Prior to initiation of dalfampridine, determine estimated Clcr (e.g., Cockcroft-Gault equation).1 Also determine estimated Clcr at least annually during therapy.1

Contraindicated in patients with moderate or severe renal impairment (Clcr ≤50 mL/minute).1

In patients with mild renal impairment (Clcr 51–80 mL/minute), carefully weigh potential benefits against risk of seizures.1 24 Plasma concentrations attained with usual dosage (10 mg twice daily) may approach those seen with 15 mg twice daily, a dosage that may be associated with an increased risk of seizures.1 24 (See Seizures under Cautions.)

Because mild renal impairment is common in adults ≥50 years of age, even when Sc is normal, it is particularly important to estimate Clcr in this age group.1 24

Common Adverse Effects

Urinary tract infections,1 2 3 insomnia,1 2 3 5 12 dizziness,1 2 3 5 9 12 headache,1 2 3 9 12 nausea,1 2 3 5 12 asthenia,1 2 3 9 12 tremor,12 fatigue,2 3 upper respiratory tract infection,2 3 back pain,1 2 balance disorder,1 2 3 MS relapse or worsening,1 3 paresthesia,1 3 5 12 muscle spasm,3 peripheral edema,3 nasopharyngitis,1 constipation,1 dyspepsia,1 pharyngolaryngeal pain.1

Interactions for Ampyra

Metabolized by CYP isoenzyme 2E1 and, possibly, other unidentified CYP isoenzymes.1

Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5;1 does not induce 1A2, 2B6, 2C9, 2C19, 2E1, or 3A4/5.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions unlikely with drugs metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.1

Drugs Affecting or Affected by P-glycoprotein Transport

Not an inhibitor or substrate of the P-glycoprotein transport system; pharmacokinetic interactions unlikely with drugs that are inhibitors or substrates of this transport system.1

Specific Drugs

Drug

Interaction

Comments

Interferon beta

Concomitant use of sub-Q interferon beta-1b does not affect pharmacokinetics of dalfampridine1

Ampyra Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed from GI tract.1 9 10 11

Bioavailability of dalfampridine (formerly known as fampridine [4-aminopyridine; 4-AP]) extended-release tablets is 96% compared with an extemporaneously prepared aqueous oral solution of the drug.1

Extended-release dalfampridine tablets result in delayed absorption and a slower increase to lower peak plasma concentrations compared with an aqueous oral solution of the drug; extent of absorption (AUC) is not affected.1 9 11

Plasma concentrations and AUC increase proportionally with dose.1 9 12 13

Pharmacokinetics in adults with MS similar to that reported in healthy adults.1 9

In adults 29–56 years of age with MS who received a single 10-mg dalfampridine extended-release tablet, mean peak plasma concentration was 25.23 ng/mL and was attained 3.92 hours after the dose.9 In healthy fasting adults, a single 10-mg extended-release tablet of the drug resulted in peak concentrations of 17.3–21.6 ng/mL occurring 3–4 hours after the dose.1 11

Food

Administration of a dalfampridine extended-release tablet with food results in a 12–17% increase in peak plasma concentrations and a 4–7% decrease in AUC of the drug; not considered clinically important.1

Distribution

Extent

Studies using IV dalfampridine indicate the drug is distributed into CSF.13

Not known whether distributed into human milk.1

Plasma Protein Binding

1–3% bound to plasma proteins.1

Elimination

Metabolism

A small portion of a dalfampridine dose is metabolized by CYP isoenzymes to 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate.1 These metabolites have no pharmacologic activity on potassium channels.1 In vitro studies indicate CYP2E1 is the major enzyme responsible for 3-hydroxylation of dalfampridine; other unidentified CYP enzymes play a minor role in 3-hydroxylation of the drug.1

Elimination Route

Following oral administration, 95.9% of a dalfampridine dose is eliminated in urine and 0.5% is eliminated in feces.1

The majority of the dose is eliminated in urine (90.3%) as unchanged dalfampridine;1 4.3% is eliminated as 3-hydroxy-4-aminopyridine and 2.6% is eliminated as 3-hydroxy-4-aminopyridine sulfate.1

Half-life

Dalfampridine: 5.2–6.5 hours.1 9 11

3-Hydroxy-4-aminopyridine sulfate: 7.6 hours.1

Special Populations

Geriatric adults: Clearance of dalfampridine is modestly decreased with increasing age; age-related decrease in clearance not considered clinically important.1

Females: Females may have higher maximum dalfampridine plasma concentrations than males;1 9 not considered clinically important.1

Renal impairment: Total body clearance reduced about 45% in adults with mild renal impairment (Clcr 51–80 mL/minute), about 50% in those with moderate renal impairment (Clcr 30–50 mL/minute), and about 75% in those with severe renal impairment (Clcr <30 mL/minute).1 Mean half-life in otherwise healthy adults with mild or moderate renal impairment is 7.4 or 8.1 hours, respectively; mean half-life in those with severe renal impairment is 14.3 hours.11

Hepatic impairment: Pharmacokinetics not evaluated in patients with hepatic impairment.1 Hepatic impairment not expected to have a clinically important effect on dalfampridine pharmacokinetics.1

Stability

Storage

Oral

Extended-release Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Aminopyridine;1 13 14 broad spectrum potassium channel blocker.1 13 14

  • Dalfampridine was formerly known as fampridine (4-aminopyridine; 4-AP),1 13 and is commercially available as extended-release tablets.1 Dalfampridine has been prepared extemporaneously as immediate-release capsules or oral solution.4 7 10 13 17

  • Dalfampridine has a relatively narrow therapeutic index with concentration-dependent adverse effects.2 5 9 10 11 14 Compared with the immediate-release preparations, commercially available extended-release dalfampridine tablets provide an improved pharmacokinetic profile (e.g., lower peak plasma concentrations, more stable and sustained plasma concentrations) and allow use of a twice-daily dosage regimen.1 2 9 10 11

  • Mechanism of action responsible for improved walking in MS patients not fully elucidated.1 14 16 19

  • Selectively blocks fast, voltage-gated potassium channels (Kv) in excitable tissues and nonexcitable cells such as B cells and T lymphocytes.13 14 20 In vitro and animal studies indicate increased conduction of action potentials in demyelinated axons;1 13 14 16 20 this effect appears to be dose dependent.13 16 20 Other mechanisms of action (e.g., potentiation of synaptic transmission and skeletal muscle twitch tension, immunomodulatory effects on Kv channels in microglia, macrophages, dendritic cells, and/or T lymphocytes) also may be involved.13 14 16 20

  • Does not prolong QTc interval;1 7 10 does not have a clinically important effect on QRS duration.1 10

Advice to Patients

  • Importance of patient reading the medication guide prior to initiating dalfampridine therapy and each time the prescription is refilled.1

  • Importance of taking dalfampridine exactly as prescribed.1 Swallow tablet whole; do not divide, crush, chew, or dissolve.1

  • Advise patients not to take a double dose if they miss a dose.1 Importance of not taking more than 2 tablets in a 24-hour period and ensuring that there is an interval of approximately 12 hours between doses.1

  • Importance of storing dalfampridine at 25°C, although the drug may be exposed to 15–30°C.1

  • Advise patients that dalfampridine can cause seizures, even in patients without a history of seizures.1 Risk of seizure is increased if higher than recommended dosage is used or if patient has renal impairment.1

  • Importance of immediately informing clinician if patient has a history of seizures or has renal impairment.1 Importance of discontinuing dalfampridine and contacting clinician if a seizure occurs during treatment.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of dalfampridine is restricted;21 22 available only through certain specialty pharmacies.21 22 (See Restricted Distribution under Dosage and Administration.)

Dalfampridine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release, film-coated

10 mg

Ampyra

Acorda

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Acorda Therapeutics Inc. Ampyra (dalfampridine) extended-release tablets prescribing information. Ardsley, NY; 2012 Aug.

2. 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. [PubMed 19249634]

3. Goodman AD, Brown TR, Cohen JA et al. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology. 2008; 71:1134-41. [PubMed 18672472]

4. Bever CT, Young D, Anderson PA et al. The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial. Neurology. 1994; 44:1054-9. [PubMed 8208399]

5. Schwid SR, Petrie MD, McDermott MP et al. Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Neurology. 1997; 48:817-21. [PubMed 9109861]

6. Solari A, Uitdehaag B, Giuliani G et al. Aminopyridines for symptomatic treatment in multiple sclerosis. Cochrane Database Syst Rev. 2002; :CD001330. [PubMed 12804404]

7. Isoda WC, Segal JL. Effects of 4-aminopyridine on cardiac repolarization, PR interval, and heart rate in patients with spinal cord injury. Pharmacotherapy. 2003; 23:133-6. [PubMed 12587799]

8. Burton JM, Bell CM, Walker SE et al. 4-aminopyridine toxicity with unintentional overdose in four patients with multiple sclerosis. Neurology. 2008; 71:1833-4. [PubMed 19029525]

9. Vollmer T, Henney HR. Pharmacokinetics and tolerability of single escalating doses of fampridine sustained-release tablets in patients with multiple sclerosis: a Phase I-II, open-label trial. Clin Ther. 2009; 31:2206-14. [PubMed 19922891]

10. Vollmer T, Blight AR, Henney HR. 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; 31:2215-23. [PubMed 19922892]

11. Smith W, Swan S, Marbury T et al. Single-Dose pharmacokinetics of sustained-release fampridine (Fampridine-SR) in healthy volunteers and adults with renal impairment. J Clin Pharmacol. 2010; 50:151-9. [PubMed 19966074]

12. Goodman AD, Cohen JA, Cross A et al. Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study. Mult Scler. 2007; 13:357-68. [PubMed 17439905]

13. Hayes KC. The use of 4-aminopyridine (fampridine) in demyelinating disorders. CNS Drug Rev. 2004; 10:295-316. [PubMed 15592580]

14. Judge SI, Bever CT. Potassium channel blockers in multiple sclerosis: neuronal Kv channels and effects of symptomatic treatment. Pharmacol Ther. 2006; 111:224-59. [PubMed 16472864]

15. van Diemen HA, Polman CH, van Dongen MM et al. 4-Aminopyridine induces functional improvement in multiple sclerosis patients: a neurophysiological study. J Neurol Sci. 1993; 116:220-6. [PubMed 8336169]

16. Smith KJ, Felts PA, John GR. Effects of 4-aminopyridine on demyelinated axons, synapses and muscle tension. Brain. 2000; 123 ( Pt 1):171-84. [PubMed 10611131]

17. Blight AR, Henney HR. Pharmacokinetics of 14C-radioactivity after oral intake of a single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers. Clin Ther. 2009; 31:328-35. [PubMed 19302905]

18. Smits RC, Emmen HH, Bertelsmann FW et al. The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. Neurology. 1994; 44:1701-5. [PubMed 7936300]

19. Davis FA, Stefoski D, Quandt FN. Mechanism of action of 4-aminopyridine in the symptomatic treatment of multiple sclerosis. Ann Neurol. 1995; 37:684. [PubMed 7755367]

20. US Food and Drug Administration, Center for Drug Evaluation and Research. Medical review(s) NDA application number 22-250s000. From FDA website.

21. Ampyra distribution guide. From website. Accessed 2010 Apr 20.

22. Ampyra (dalfampridine) extended-release tablets risk evaluation and mitigation strategy (REMS). From FDA website.

23. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA web site. Accessed 2012 Sep 28.

24. Food and Drug Administration. FDA Drug Safety Communication: Seizure risk for multiple sclerosis patients who take Ampyra (dalfampridine). 2012 Jul 23. From FDA website.

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