Dalfampridine 10 mg Tablet, Extended Release, 60-count — NDC 42571-275-60 (Billing 42571-0275-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics Dalfampridine does not prolong the QTc interval and does not have a clinically important effect on QRS duration.

12.3Pharmacokinetics Absorption and Distribution Orally administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Absolute bioavailability of extended release dalfampridine 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 (C max ), 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 (T max ). In comparison, C max 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

2.6L/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 C max (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… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics Absorption and Distribution Orally administered dalfampridine is rapidly and completely absorbed from the gastrointestinal tract. Absolute bioavailability of extended release dalfampridine 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 (C max ), 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 (T max ). In comparison, C max 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

2.6L/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 C max (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… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Dalfampridine does not prolong the QTc interval and does not have a clinically important effect on QRS duration.

14 CLINICAL STUDIES The effectiveness of dalfampridine in improving walking in patients with multiple sclerosis was evaluated in two adequate and well controlled trials involving 540 patients. Patients in these two clinical trials had a mean disease duration of 13 years and a mean Kurtzke Expanded Disability Status Scale (EDSS) score of 6. Trial 1 was a randomized, placebo-controlled, parallel group, 21-week study (one week post screening, two-week, single-blind placebo run-in, 14-week double-blind treatment, and 4-week no treatment follow-up) in 301 patients with multiple sclerosis at 33 centers in the U.S. and Canada: 229 patients assigned to dalfampridine extended-release tablets 10 mg twice daily and 72 patients assigned to placebo.

A total of 283 patients (212 dalfampridine extended-release tablets and 71 placebo) completed all study visits. Patient inclusion criteria included the ability to walk 25 feet in 8 to 45 seconds. Patient exclusion criteria included a history of seizures or evidence of epileptiform activity on a screening EEG, and onset of an MS exacerbation within 60 days.

Trial 2 was a randomized, placebo-controlled, parallel group, 14-week study (one week post- screening, two weeks of single-blind, placebo run-in, nine weeks of double-blind treatment, and two weeks of no-treatment follow-up) in 239 patients with multiple sclerosis at 39 centers in the U.S. and Canada: 120 patients assigned to 10 mg twice daily and 119 assigned to placebo. A total of 227 patients (113 dalfampridine extended-release tablets and 114 placebo) completed all study visits. The patient inclusion and exclusion criteria used in Trial 1 were employed in Trial 2, and in addition patients with severe renal impairment were also excluded.

The primary measure of efficacy in both trials was walking speed (in feet per second) as measured by the Timed 25-foot Walk (T25FW), using a responder analysis. A responder was defined as a patient who showed faster walking speed for at least three visits out of a possible four during the double-blind period than the maximum value achieved in the five non-double blind no treatment visits (four before the double-blind period and one after). A significantly greater proportion of patients taking dalfampridine extended-release tablets 10 mg twice daily were responders, compared to patients taking placebo, as measured by the T25FW (Trial 1: 34.8% vs.

8.3%; Trial 2: 42.9% vs. 9.3%). The increased response rate in the dalfampridine group was observed across all four major types of MS disease course.

During the double-blind treatment period, a significantly greater proportion of patients taking dalfampridine extended-release tablets 10 mg twice daily had increases in walking speed of at least 10%, 20%, or 30% from baseline, compared to placebo (Figure 1 and Figure 2). Figure 1: Average walking speed change (%) from baseline during the double-blind phase of Trial 1 Figure 2: Average walking speed change (%) from baseline during the double-blind phase of Trial 2 In Trial 1 and Trial 2, consistent improvements in walking speed were shown to be associated with improvements on a patient self-assessment of ambulatory disability, the 12-item Multiple Sclerosis Walking Scale (MSWS-12), for both drug and placebo treated patients.

However, a drug-placebo difference was not established for that outcome measure. The majority of patients in these trials (63%) were using immunomodulatory drugs (interferons, glatiramer acetate, or natalizumab), but the magnitude of improvement in walking ability was independent of concomitant treatment with these drugs. No differences in effectiveness based on degree of impairment, age, gender, or body mass index were detected.

There were too few non-Caucasians in the patient population to evaluate the effect of race. figure 1 figure 2

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two-year dietary carcinogenicity studies of dalfampridine were conducted in mice and rats. In mice, the doses tested (approximately 2, 12.5, and 80 mg/kg/day) were associated with plasma exposures (AUC) up to 11 times the plasma AUC in humans at the maximum recommended human dose (MRHD) of 20 mg/day. There was no evidence of drug-related carcinogenicity.

In rats, the doses tested (approximately 2, 6, and 18 mg/kg/day) were approximately 1, 3, and 9 times the MRHD on a body surface area (mg/m 2 ) basis. There was a significant increase in uterine polyps at the highest dose tested. Mutagenesis Dalfampridine was negative in in vitro (bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration) and in vivo (mouse bone marrow, rat erythrocyte micronucleus) genetic toxicology assays.

Impairment of Fertility Oral administration of dalfampridine (0, 1, 3, and 9 mg/kg/day) to male and female rats prior to and throughout mating, and continuing in females through early pregnancy (to gestation day 13) or throughout pregnancy and lactation resulted in no adverse effects on fertility. Reduced offspring viability and body weight were observed at 9 mg/kg/day. The no-effect dose for adverse effects on fertility (9 mg/kg/day) and reproductive performance (3 mg/kg/day) are 4 times and similar to, respectively, the MRHD on a mg/m 2 basis.