2.1 Dosage Information

The maximum recommended dosage of dalfampridine 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 can be taken with or without food. Administer tablets whole; do not divide, crush, chew, or dissolve dalfampridinetablets.

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, and monitored at least annually during treatment with dalfampridine. CrCl can be estimated using the following equation (multiply by 0.85 for women):

CrCl = (140 − age) × weight (kg)

               SerumCr (mg / dl) ×72

2.4 Dosage in Patients with Renal Impairment

In patients with mild renal impairment (CrCl 51 to 80 mL/min),  dalfampridine 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 should be carefully considered against the risk of seizures in these patients [see  Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].  Dalfampridine is contraindicated in patients with moderate or severe renal impairment (CrCl≤50 mL/min).

5.1 Seizures

Dalfampridine can cause seizures. Increased incidence of seizures has been observed at 20 mg twic e 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 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 clinical studies. Permanently discontinue dalfampridinein patients who have a seizure while on treatment. Dalfampridineis contraindicated in patients with a history of seizures [see Contraindications (4)] .

5.2 Renal Impairment

Dalfampridine is 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 is contraindicated in these patients [see Contraindications (4)] .

In patients with mild renal impairment (CrCl 51 to 80 mL/min), dalfampridine 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 in order to reduce the potential for dose-related adverse reactions.

5.4 Anaphylaxis

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

6.1 Controlled 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 tablets10 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 and that led to discontinuation more frequently compared to placebo were headache (dalfampridine 0.5%, placebo 0%), balance disorder ( dalfampridine0.5%, placebo 0%), dizziness ( dalfampridine 0.5%, placebo 0%), and confusional state ( dalfampridine 0.3%, placebo 0%).

Table 1 lists adverse reactions that occurred in ≥2% of patients treated with dalfampridine extended-release tablets10 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 -Treated Adult MS Patients and More Frequent with Dalfampridine Compared to Placebo in Controlled Clinical Trials

Other Adverse Reactions

Dalfampridine has been evaluated in a total of 1,952 subjects, including 917 MS patients. A total of 741 patients have been treated with dalfampridine 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 dalfampridinein 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.

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 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)].

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with use of dalfampridine in pregnant women. Administration of dalfampridine to animals during pregnancy and lactation resulted in decreased offspring viability and growth at clinically relevant doses [ see Data]. In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Oral administration of dalfampridine to pregnant rats and rabbits throughout organogenesis resulted in no evidence of developmental toxicity in either species. The highest doses tested (10 mg/kg/day in rats, 5 mg/kg/day in rabbits), which were associated with maternal toxicity, are approximately 5 times the MRHD on a body surface area (mg/m 2) basis.

Oral administration of dalfampridine (0, 1, 3, and 9 to 6 mg/kg/day; high dose reduced during the second week of dosing) to female rats throughout pregnancy and lactation resulted in decreased offspring viability at the highest dose tested and decreased body weight in offspring at the mid and high doses. The no-effect dose for pre-and postnatal developmental toxicity in rats (1 mg/kg/day) is less than the MRHD on a mg/m 2 basis.

8.2 Lactation

Risk Summary

There are no data on the presence of dalfampridine in human milk, the effects of dalfampridine on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dalfampridine and any potential adverse effects on the breastfed infant from dalfampridine or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of  in patients younger than 18 years of age have not been established.

8.5 Geriatric Use

Clinical studies of dalfampridine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. A population PK analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to necessitate a modification of dose with age. Other reported clinical experience has identified no differences in responses between the elderly and younger patients.

Dalfampridine is known to be substantially excreted by the kidneys and the risk of adverse reactions, including seizures, is greater with increasing exposure of dalfampridine. Because elderly patients are more likely to have decreased renal function, it is particularly important to know the estimated creatinine clearance (CrCl) in these patients [see Warnings and Precautions (5.2)].

8.6 Impaired Renal Function

Clearance of dalfampridine is decreased in patients with renal impairment and is significantly correlated with creatinine clearance (CrCl) [see Clinical Pharmacology (12.3)] . Dalfampridine is contraindicated in patients with moderate or severe renal impairment (CrCl ≤50 mL/min) [see Contraindications (4)]. The risk of seizures in patients with mild renal impairment (CrCl 51 to 80 mL/min) is unknown, but dalfampridine 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. If unknown, estimated creatinine clearance should be calculated prior to initiating treatment with dalfampridine [see  Dosage and Administration (2.3) and Warnings and Precautions (5.2)] .

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 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 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 2.6 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 to ∞ 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 are unlikely to be affected by drugs that inhibit the p­glycoprotein transporter, and dalfampridine is not likely to affect the pharmacokinetics of drugs that are substrates of the p-glycoprotein transporter.

13.1 Carcinogenesis, 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.