AMPYRA® (dalfampridine)

Pharmacodynamics
AMPYRA does not prolong the QTc interval and does not have a clinically important effect on QRS duration.

Pharmacokinetics----------------------------
Absorption and Distribution:
Orally administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Absolute bioavailability of extended release AMPYRA tablets has not been assessed, but relative bioavailability is 96% when compared to an aqueous oral solution. The extended release tablet delays absorption of dalfampridine relative to the solution formulation, giving a slower rise to a lower peak concentration (Cmax), with no effect on the extent of absorption (AUC). Single AMPYRA tablet 10 mg doses administered to healthy volunteers in a fasted state gave peak concentrations ranging from 17.3 ng/mL to 21.6 ng/mL occurring 3 to 4 hours post-administration (Tmax). In comparison, Cmax with the same 10 mg dose of dalfampridine in an oral solution was 42.7 ng/mL and occurred approximately 1.3 hours after dosing. Exposure increased proportionally with dose.

Dalfampridine is largely unbound to plasma proteins (97-99%). The apparent volume of distribution is 2.6 L/kg.

There is no apparent difference in pharmacokinetic parameter values following administration of AMPYRA tablets to either healthy volunteers or patients with MS.

When dalfampridine is taken with food, there is a slight increase in Cmax (12-17%) and a slight decrease in AUC (4-7%). These changes in exposure are not clinically significant, and therefore the drug may be taken with or without food [see Dosage and Administration].

Metabolism and Elimination:
Dalfampridine and metabolites elimination is nearly complete after 24 hours, with 95.9% of the dose recovered in urine and 0.5% recovered in feces. Most of the excreted radioactivity in urine was parent drug (90.3%). Two metabolites were identified: 3-hydroxy-4-aminopyridine (4.3%) and 3-hydroxy-4-aminopyridine sulfate (2.6%). These metabolites have been shown to have no pharmacologic activity on potassium channels.

The elimination half-life of dalfampridine following administration of the extended release tablet formulation of AMPYRA is 5.2 to 6.5 hours. The plasma half-life of the sulfate conjugate is approximately 7.6 hours and the half-life of 3-hydroxy-4-aminopyridine could not be calculated because concentrations for most subjects were close to or below the limit of quantitation.

In vitro studies with human liver microsomes indicate that CYP2E1 was the major enzyme responsible for the 3-hydroxylation of dalfampridine. The identity of the CYP enzymes suspected of playing a minor role in the 3-hydroxylation of dalfampridine could not be established unequivocally

Renally impaired patients: AMPYRA is contraindicated in patients with moderate or severe renal impairment (CrCl≤50 mL/min); the risk of seizures in patients with mild renal impairment (CrCl 51-80 mL/min) is unknown, but AMPYRA plasma levels in these patients may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures; estimated CrCl should be known before initiating treatment with AMPYRA.

AMPYRA should not be taken with other forms of 4-aminopyridine (4-AP, fampridine), since the active ingredient is the same.
Urinary tract infections were reported more frequently as adverse reactions in patients receiving AMPYRA 10 mg twice daily compared to placebo.

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USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm.

Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother.
Pediatric use: Safety and effectiveness of AMPYRA in patients younger than 18 years of age have not been established

Renal Impairment: Clearance of dalfampridine is decreased in patients with renal impairment; AMPYRA is contraindicated in patients with moderate or severe renal impairment (CrCl≤50 mL/min); AMPYRA plasma levels in patients with mild renal impairment (CrCl 51-80 mL/min) may approach those seen at a dose of 15 mg twice daily, a dose which may be associated with an increased risk of seizures.

Geriatric use: Because elderly patients are more likely to have decreased renal function, it is particularly important to know the estimated CrCl in these patients before initiating AMPYRA treatment

Renal impairment: AMPYRA is contraindicated in patients with moderate or severe renal impairment; the risk of seizures in patients with mild renal impairment is unknown, but AMPYRA plasma levels in these patients may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures.

NDC 10144-427-60 bottles of 60 tablets

Store at 25°C (77°F). Excursions permitted 15-30ºC (59-86ºF).

Distributed by: Acorda Therapeutics, Inc.
Hawthorne, NY 10532

Issued 01/2010

AMPYRA™ is a trademark of Acorda Therapeutics, Inc.
Manufactured for Acorda under license from Elan Pharma International Ltd. (EPIL), Ireland, utilizing EPIL's MatriX Drug Absorption System (MXDAS™ technology).
MXDAS™ is a trademark of Elan Pharma International Ltd. (EPIL).
U.S. Patent Nos.: US 5,540,938 and US 5,370,879
©2010, Acorda Therapeutics, Inc. All rights reserved.