PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Dalfampridine Extended-release Tablets
** Rx ONLY**
** 10 mg**
** PHARMACIST: Dispense the accompanying Medication Guide to each patient**
** 60 tablets**
** **

5 WARNINGS AND PRECAUTIONS

5.1 Seizures

Dalfampridine extended-release tablets can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily (2 times the maximum recommended dosage) in controlled clinical studies of 9 to 14 weeks duration with dalfampridine in patients with MS. In open-label extension trials in MS patients, the incidence of seizures during treatment with dalfampridine 15 mg twice daily (1.7/100PY) was over 4 times higher than the incidence during treatment with 10 mg twice daily (0.4/100PY). In the post-marketing period seizures have been reported. The majority of seizures occurred at the recommended dose and in patients without a history of seizures, and generally within days to weeks of starting therapy.

Dalfampridine extended-release tablets has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on an EEG, as these patients were excluded from clinical trials. The risk of seizures in patients with epileptiform activity on an EEG is unknown, and could be substantially higher than that observed in dalfampridine extended-release tablets clinical studies. Permanently discontinue dalfampridine extended- release tablets in patients who have a seizure while on treatment. Dalfampridine extended-release tablets are contraindicated in patients with a history of seizures [see Contraindications (4)].

5.2 Renal Impairment

Dalfampridine extended-release tablets are eliminated through the kidneys primarily as unchanged drug [see Clinical Pharmacology (12.3)].

Because patients with moderate to severe renal impairment (CrCl ≤50mL/min) would require a dose lower than 10 mg twice daily and no strength smaller than 10 mg is available, dalfampridine extended-release tablets are contraindicated in these patients [see Contraindications (4)].

In patients with mild renal impairment (CrCl 51 to 80 mL/min), dalfampridine extended-release tablets plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that may be associated with an increased risk of seizures [see Warnings and Precautions (5.1)].

5.3 Concurrent Treatment with Other Forms of 4-Aminopyridine

Avoid concomitant use with other forms of 4-aminopyridine (4-AP, fampridine) since the active ingredient is the same. Instruct patients to discontinue use of any product containing 4-aminopyridine prior to initiating treatment with dalfampridine extended-release tablets in order to reduce the potential for dose-related adverse reactions.

5.4 Anaphylaxis

Dalfampridine extended-release tablets can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. Dalfampridine extended- release tablets are contraindicated in patients with a history of hypersensitivity to dalfampridine extended-release tablets or 4-aminopyridine. Inform patients of the signs and symptoms of anaphylaxis and instruct them to discontinue dalfampridine extended-release tablets and seek immediate medical care should these signs and symptoms occur.

7 DRUG INTERACTIONS

7.1 OCT2 Inhibitors

Concurrent treatment with OCT2 inhibitors, such as cimetidine, may cause increased exposure to dalfampridine [see Clinical Pharmacology (12.3)]. Elevated levels of dalfampridine increase the risk of seizures [see Warnings and Precautions (5.1, 5.2)]. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine extended-release tablets should be considered against the risk of seizures in these patients.

7.2 Baclofen

No interaction was identified between dalfampridine and baclofen [see Clinical Pharmacology (12.3)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of action

The mechanism by which dalfampridine exerts its therapeutic effect has not been fully elucidated. Dalfampridine is a broad spectrum potassium channel blocker. In animal studies, dalfampridine has been shown to increase conduction of action potentials in demyelinated axons through inhibition of potassium channels.

12.2 Pharmacodynamics

Dalfampridine extended-release tablets does not prolong the QTc interval and does not have a clinically important effect on QRS duration.

12.3 Pharmacokinetics

Absorption and Distribution
Orally administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Absolute bioavailability of dalfampridine extended- release 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 dalfampridine extended-release 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 to 99%). The apparent volume of distribution is 2.6 L/kg.

There is no apparent difference in pharmacokinetic parameter values following administration of dalfampridine extended-release tablets to either healthy volunteers or patients with MS.
When dalfampridine is taken with food, there is a slight increase in Cmax (12 to 17%) and a slight decrease in AUC (4 to 7%). These changes in exposure are not clinically significant, and therefore the drug may be taken with or without food [see Dosage and Administration (2.2)].

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 apparent elimination half-life of dalfampridine following administration of the extended release tablet formulation of dalfampridine 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.

Specific Populations

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

Geriatric
A population pharmacokinetic analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to necessitate a modification of dose.

Gender
A population pharmacokinetic analysis suggested that female patients would be expected to have higher maximum dalfampridine plasma concentration than male patients. The magnitude of these differences is small and does not necessitate any dose modification.

Renal Impairment [see Contraindications (4) and Warnings and Precautions (5.2)]. The pharmacokinetics of dalfampridine was studied in 9 male and 11 female subjects with varying degrees of renal function. Elimination of the drug is significantly correlated with the creatinine clearance. Total body clearance of dalfampridine was reduced by about 45% in patients with mild renal impairment (CrCl 51 to 80 mL/min), by about 50% in patients with moderate renal impairment (CrCl = 30 to 50 mL/min), and by about 75% in patients with severe renal impairment (CrCl <30 mL/min). The terminal half- life of dalfampridine is about 3.3 times longer in patients with severe renal impairment but is not prolonged in patients with mild or moderate renal impairment.

Hepatic Impairment
The pharmacokinetics of dalfampridine in hepatically impaired subjects has not been studied. Since dalfampridine is primarily excreted unchanged in the urine, hepatic impairment is not expected to significantly affect dalfampridine pharmacokinetics or recommended dosing.

Race
There were too few non-Caucasians in the patient population to evaluate the effect of race.

Drug Interactions
Effects of Co-administered Drugs on Dalfampridine
Interferon
Dalfampridine kinetics were not affected by co-administration of subcutaneous injections of 8 million units interferon beta-1b.

Baclofen

Based on a population analysis, dalfampridine kinetics were not affected by baclofen.

Cimetidine
In a single-dose clinical study, 23 healthy volunteers took the OCT2 inhibitor cimetidine 400 mg every 6 hours concurrently with dalfampridine 10 mg single dose. The test-reference ratio for AUC0–∞ was 125% (90% confidence interval: 121% to 130%) due to a reduction in the clearance of dalfampridine [see Drug Interactions (7.1)].

Effects of Dalfampridine on Co-administered Drugs

In vitro data with human liver microsomes showed that dalfampridine was not a direct or time-dependent inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Dalfampridine is not likely to affect the pharmacokinetics of drugs that are substrates of these enzymes.

Other in vitro studies with cultured human hepatocytes with 0.025 μM, 0.25 μM, 2.5 μM, and 25 μM dalfampridine had little or no effect on CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 enzyme activities. Consequently, the potential for dalfampridine to induce human hepatocytes at therapeutic concentrations is remote.
In vitro, dalfampridine is not a substrate or an inhibitor for the p-glycoprotein transporter. The pharmacokinetics of dalfampridine extended- release tablets are unlikely to be affected by drugs that inhibit the p-glycoprotein transporter, and dalfampridine is not likely to affect the pharmacokinetics of drugs that are substrates of the p-glycoprotein transporter.