Dalfampridine

1 INDICATIONS AND USAGE Dalfampridine extended-release tablets are indicated as a treatment to improve walking in adult patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed [see Clinical Studies (14) ]. Dalfampridine is a potassium channel blocker indicated to improve walking in adult patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed ( 1 , 14 ).

2 DOSAGE AND ADMINISTRATION The maximum recommended dosage is 10 mg twice daily (approximately 12 hours apart). There is no evidence of additional benefit with doses greater than 10 mg twice daily. Adverse reactions, including seizures, were more frequent at higher doses. (2.1) Take with or without food. Administer tablets whole; do not divide, crush, chew, or dissolve (2.2) Patients should not take double or extra doses if they miss a dose. (2.2) Estimated creatinine clearance (CrCl) should be known before initiating treatment with dalfampridine extended-release tablets. In patients with mild renal impairment (CrCl 51 to 80 mL/min), dalfampridine extended-release tablets may reach plasma levels associated with a greater risk of seizures, and the potential benefits of dalfampridine extended-release tablets should be carefully considered against the risk of seizures in these patients (2.3, 5.2, 8.6) 2.1 Dosage Information The maximum recommended dosage of dalfampridine extended-release tablet is one 10 mg tablet twice daily and should not be exceeded. Take doses approximately 12 hours apart. There is no evidence of additional benefit at doses greater than 10 mg twice daily. Adverse reactions, including seizures, and discontinuations because of adverse reactions were more frequent at higher doses. 2.2 Administration Instructions Dalfampridine extended-release tablet can be taken with or without food. Administer tablets whole; do not divide, crush, chew, or dissolve dalfampridine extended-release tablets. If a dose is missed, patients should not take double or extra doses. 2.3 Renal Monitoring Prior to and During Treatment Estimated creatinine clearance (CrCl) should be known before initiating treatment with dalfampridine extended-release tablets, and monitored at least annually during treatment with dalfampridine extended-release tablets. CrCl can be estimated using the following equation (multiply by 0.85 for women): dalfampridine-equa 2.4 Dosage in Patients with Renal Impairment In patients with mild renal impairment (CrCl 51 to 80 mL/min), dalfampridine extended-release tablet plasma levels may approach those seen at a dose of 15 mg twice daily, a dose that is 1.5 times the maximum recommended dose and may be associated with an increased risk of seizures. As mild renal impairment is common after age 50, estimating CrCl is particularly important in these patients. The potential benefits of dalfampridine extended-release tablet should be carefully considered against the risk of seizures in these patients [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology (12.3)]. Dalfampridine extended-release tablet is contraindicated in patients with moderate or severe renal impairment (CrCl≤50 mL/min).

6 ADVERSE REACTIONS The following serious adverse reactions are described in more detail elsewhere in the labeling: •Seizures [see Warnings and Precautions ( 5.1 )] •Anaphylaxis [see Warnings and Precautions ( 5.4 )] The most common adverse events (incidence ≥2% and at a rate greater than the placebo rate) for dalfampridine extended-release tablets were urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with dalfampridine extended-release tablets 10 mg twice daily experienced one or more adverse reactions leading to discontinuation, compared to 2% (5/238) of placebo-treated patients. The adverse reactions leading to discontinuation of at least 2 patients treated with dalfampridine extended-release tablets and that led to discontinuation more frequently compared to placebo were headache (dalfampridine extended-release tablets 0.5%, placebo 0%), balance disorder (dalfampridine extended-release tablets 0.5%, placebo 0%), dizziness (dalfampridine extended-release tablets 0.5%, placebo 0%), and confusional state (dalfampridine extended-release tablets 0.3%, placebo 0%). Table 1 lists adverse reactions that occurred in ≥2% of patients treated with dalfampridine extended-release tablets 10 mg twice daily, and more frequently than in placebo-treated patients, in controlled clinical trials. Table 1: Adverse Reactions with an Incidence ≥2% of dalfampridine extended-release tablets-Treated Adult MS Patients and More Frequent with dalfampridine extended-release tablets Compared to Placebo in Controlled Clinical Trials Adverse Reaction Placebo (N=238) % Dalfampridine extended-release tablets 10 mg twice daily (N=400) % Urinary tract infection 8 12 Insomnia 4 9 Dizziness 4 7 Headache 4 7 Nausea 3 7 Asthenia 4 7 Back pain 2 5 Balance disorder 1 5 Multiple sclerosis relapse 3 4 Paresthesia 3 4 Nasopharyngitis 2 4 Constipation 2 3 Dyspepsia 1 2 Pharyngolaryngeal pain 1 2 Other Adverse Reactions Dalfampridine extended-release tablets has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with dalfampridine extended-release tablets for over six months, 501 for over one year and 352 for over two years. The experience in open-label clinical trials is consistent with the safety profile observed in the placebo-controlled clinical trials. As in controlled clinical trials, a dose-dependent increase in the incidence of seizures has been observed in open-label clinical trials with dalfampridine extended-release tablets in patients with MS as follows: dalfampridine extended-release tablets 10 mg twice daily 0.41 per 100 person-years (95% confidence interval 0.13 to 0.96); dalfampridine 15 mg twice daily 1.7 per 100 person-years (95% confidence interval 0.21 to 6.28). 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use with dalfampridine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: vomiting, vertigo.

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 (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 2.6 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 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 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 AUC 0–∞ 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.