d. 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 dalfampridine in patients who have a seizure while on treatment. dalfampridine is 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. dalfampridine is contraindicated in patients with a history of hypersensitivity to dalfampridine or 4‑aminopyridine. 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.

age of dalfampridine extended-release tablets 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 tablets 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): crcl = (140 - age) x 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 extended-release tablets 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 tablets 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 tablets is contraindicated in patients with moderate or severe renal impairment (crcl≤50 ml/min).

in practice. in three placebo-controlled clinical trials of up to 14 weeks duration, 4% (15/400) of patients treated with dalfampridine 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 and that led to discontinuation more frequently compared to placebo were headache (dalfampridine 0.5%, placebo 0%), balance disorder (dalfampridine 0.5%, 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 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-treated adult ms patients and more frequent with dalfampridine compared to placebo 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 adverse reaction placebo (n=238) % dalfampridine 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 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 dalfampridine in patients with ms as follows: dalfampridine 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.

ughout 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 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 )] .

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.

he extent of absorption (auc). single dalfampridine 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 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 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 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.

apparent volume of distribution is 2.6 l/kg. there is no apparent difference in pharmacokinetic parameter values following administration of dalfampridine 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 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 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.

emale 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.

roughout 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.

ng 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 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 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 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. fig1.jpg fig2.jpg

o and dizziness, associated with the use of dalfampridine might impair their ability to drive or use machinery should they develop these symptoms. drug interactions instruct patients to notify their healthcare provider prior to starting any new medication, including over-the-counter drugs. storage advise patients to store dalfampridine extended-release tablets at 20˚ to 25˚c (68˚ to 77˚f). [see usp controlled room temperature.] advise patients to safely throw away dalfampridine extended-release tablets that are out of date or no longer needed. distributed by: hikma pharmaceuticals usa inc. berkeley heights, nj 07922 c50000461/02 revised december 2021