Dalfampridine, also known as 4-aminopyridine, is an oral potassium channel blocker indicated to improve walking in patients with multiple sclerosis (MS). Among patients with MS who could walk 25 feet in 8 to 45 seconds, more patients responded to dalfampridine than to placebo. Responders were defined as those with a faster walking speed at least 3 out of 4 times during dalfampridine receipt than the maximum value 5 times without dalfampridine. In a trial, 34.8% of dalfampridine recipients were responders as compared with 8.3% of placebo recipients. In a separate trial, the respective numbers were 42.9% and 9.3%. Walking speed (feet/second) was measured by the timed 25-foot walks. The percentage of dalfampridine recipients with at least a 10%, 20%, or 30% increase in walking speed from baseline was significantly higher vs. placebo. Most patients in clinical trials were receiving immunomodulatory agents for MS, and the results were independent of other drug therapies. The major dose-limiting side effect is seizures, and patients with moderate to severe renal dysfunction cannot receive the drug. Dalfampridine was approved by the FDA in 2010.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer whole. Do not divide, crush, chew, or dissolve the extended-release, film-coated tablets.
-May administer with or without food.
-Administer tablets every 12 hours; an approximate 12-hour interval is needed between doses. Do not administer more than 10 mg every 12 hours; dalfampridine causes seizures in a dose-dependent fashion.
-Missed dose: If a dose is missed, do not administer double or extra doses.
Seizures were noted with dalfampridine during clinical trials, and the seizure risk increases with increasing dalfampridine doses. In controlled trials of up to 14 weeks duration, seizures were noted in 0.4% of placebo recipients, in 0.25% of dalfampridine 10 mg twice daily recipients, in 0% of dalfampridine 15 mg twice daily recipients, and in 3.5% of dalfampridine 20 mg twice daily recipients. In open-label extension studies, the seizure incidence with dalfampridine 15 mg twice daily was over 4 times higher than the incidence with dalfampridine 10 mg twice daily. Specifically, seizures occurred in 0.41 per 100 person years (95% CI, 0.13-0.96) with 10 mg twice daily and in 1.7 per 100 person years (95% CI, 0.21-6.28) with 15 mg twice daily. NOTE: The indicated and maximum dalfampridine dose is 10 mg twice daily. Patients with a seizure history or with evidence of epileptiform activity on an EEG were excluded from trials. If a seizure occurs, discontinue dalfampridine, and do not restart the drug.
During clinical trial evaluation of dalfampridine, the following effects were reported in at least 2% of dalfampridine-treated patients and more frequently than placebo-treated patients: urinary tract infection (12% vs 8%), back pain (5% vs 2%), pharyngitis (nasopharyngitis 4% vs 2%), and pharyngolaryngeal pain (2% vs 1%).
In clinical trials, constipation, nausea, and dyspepsia occurred more frequently with dalfampridine (3%, 7%, 2%, respectively) as compared to placebo (2%, 3%, 1%). Vomiting has been reported during post-marketing experience.
In clinical trials, insomnia occurred in 9% of dalfampridine recipients as compared with 4% of placebo recipients. Dalfampridine may also cause dizziness, headache, or asthenia. In clinical trials, 7% of dalfampridine recipients each had dizziness, headache, or asthenia whereas 4% of placebo recipients had each of the adverse events. A multiple sclerosis relapse occurred in more dalfampridine recipients: 4% as compared with 3% of placebo recipients. Further, of dalfampridine recipients, 4% had paresthesias and 5% had a balance disorder whereas 3% of placebo recipients had paresthesias and 1% had a balance disorder. Balance disorder led to dalfampridine discontinuation in 2 of 400 patients, headache led to dalfampridine discontinuation in 2 of 400 patients, and dizziness led to dalfampridine discontinuation in 2 of 400 patients. Dalfampridine may also rarely cause confusion. In trials, a confusional state led to dalfampridine discontinuation in 0.3% of dalfampridine-treated patients compared to no patients receiving placebo. Vertigo has been reported during postmarketing experience.
Dalfampridine can cause anaphylactoid reactions and severe allergic reactions including respiratory compromise, urticaria, and angioedema of the throat or tongue. Instruct patients to discontinue dalfampridine and seek immediate medical attention should these signs and symptoms occur.
Avoid concomitant use of dalfampridine 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 in order to reduce the potential for dose-related adverse reactions, including convulsions.
Dalfampridine can cause anaphylaxis and severe allergic reactions. Signs and symptoms have included respiratory compromise, urticaria, and angioedema of the throat and or tongue. The drug is contraindicated in patients with a history of hypersensitivity to dalfampridine, 4-aminopyridine, or other aminopyridine hypersensitivity. This includes a history of angioedema to the drug. Inform patients of the signs and symptoms of anaphylaxis and angioedema and instruct them to discontinue dalfampridine and seek immediate medical care should these signs and symptoms occur.
Dalfampridine is contraindicated for use by patients with a history of seizures or a seizure disorder. Seizures were noted with dalfampridine, and the seizure risk increases with increasing dalfampridine doses. Patients with a seizure history or with evidence of epileptiform activity on an EEG were excluded from trials. The seizure risk from dalfampridine in patients with epileptiform activity on EEG is unknown and may be substantially higher. If a seizure occurs, discontinue dalfampridine, and do not restart the drug.
Dalfampridine is contraindicated for use in patients with moderate or severe renal impairment (CrCl 50 mL/minute or less), including patients with renal failure. Dalfampridine is substantially excreted by the kidney, and the seizure risk is greater with increased drug exposure. In patients with mild renal impairment (CrCl 51 to 80 mL/minute), 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. Estimate creatinine clearance using the Cockroft-Gault equation in all patients before treatment with dalfampridine and at least annually after that. Because geriatric patients are more likely to have decreased renal function, it is particularly important to know the estimated CrCl in these patients.
Warn patients against performing potentially hazardous activities such as driving or operating machinery until they know how they will react to dalfampridine. Dalfampridine may cause dizziness and may impair mental or physical abilities required to perform such tasks.
Dalfampridine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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.
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 breast-feeding 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.
For improved walking (i.e., improved walking speed) in patients with multiple sclerosis:
Oral dosage:
Adults: 10 mg PO every 12 hours. No additional benefit was noted with doses greater than 10 mg twice daily, and adverse effects including seizures were more frequent with higher doses. During clinical trials, a benefit was noted as an increase in walking speed, and a benefit was observed across all 4 major types of multiple sclerosis disease courses. Most patients were also taking immunomodulatory drugs (e.g., interferons, glatiramer acetate, or natalizumab). The magnitude of improvement in walking ability was independent of concomitant treatment with an immunomodulatory drug.
Maximum Dosage Limits:
-Adults
20 mg/day PO, administered as 10 mg every 12 hours.
-Geriatric
20 mg/day PO, administered as 10 mg every 12 hours.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
CrCl 51 to 80 mL/minute: No dose adjustment is needed; however, use with caution. Dalfampridine plasma concentrations with a 10 mg PO twice daily dose in these patients may approach those observed at a dose of 15 mg twice daily in patients with normal renal function, which is a dose that may be associated with an increased seizure risk.
CrCl 50 mL/minute or less: Use is contraindicated.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
Amifampridine: (Major) Avoid use of dalfampridine and amifampridine together, due to duplicative effects and an increased risk for serious side effects, such as seizures. Both drugs are aminopyridine class potassium channel blockers. Both drugs increase the seizure risk.
Bupropion: (Moderate) Due to additive risks for seizure, extreme caution when coadministering bupropion with other drugs that lower seizure threshold (e.g., dalfampridine). Use low initial doses and increase the dose gradually. Monitor for seizure activity. Consider benefits against the risk of seizures. Consider alternatives to bupropion. Additionally, bupropion inhibits OCT2 in vitro, but the clinical relevance is not certain. Concurrent treatment with OCT2 inhibitors, such as bupropion, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures in these patients.
Bupropion; Naltrexone: (Moderate) Due to additive risks for seizure, extreme caution when coadministering bupropion with other drugs that lower seizure threshold (e.g., dalfampridine). Use low initial doses and increase the dose gradually. Monitor for seizure activity. Consider benefits against the risk of seizures. Consider alternatives to bupropion. Additionally, bupropion inhibits OCT2 in vitro, but the clinical relevance is not certain. Concurrent treatment with OCT2 inhibitors, such as bupropion, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures in these patients.
Cimetidine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as cimetidine, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures in these patients. Consider alternatives to cimetidine.
Dextromethorphan; Bupropion: (Moderate) Due to additive risks for seizure, extreme caution when coadministering bupropion with other drugs that lower seizure threshold (e.g., dalfampridine). Use low initial doses and increase the dose gradually. Monitor for seizure activity. Consider benefits against the risk of seizures. Consider alternatives to bupropion. Additionally, bupropion inhibits OCT2 in vitro, but the clinical relevance is not certain. Concurrent treatment with OCT2 inhibitors, such as bupropion, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures in these patients.
Dolutegravir: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
Dolutegravir; Lamivudine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
Dolutegravir; Rilpivirine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
Trilaciclib: (Moderate) Consider the potential benefits of treatment versus the risk of seizures if concomitant use of trilaciclib and dalfampridine is necessary. Trilaciclib is an OCT2 and MATE inhibitor that may increase dalfampridine exposure; elevated dalfampridine exposure may increase the risk of seizures.
Dalfampridine is a broad spectrum potassium channel blocker. The mechanism of dalfampridine's therapeutic effect has not been fully elucidated. In animals, inhibition of potassium channels increased action potential conduction in demyelinated axons.
Dalfampridine is administered orally. It is mostly unbound to plasma proteins. The apparent volume of distribution is 2.6 L/kg. The CYP2E1 isoenzyme is 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. Two inactive metabolites are present: 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate, but these are not pharmacologically active. The clearance of dalfampridine is significantly correlated with creatinine clearance. Dalfampridine and metabolite elimination is nearly complete after 24 hours, with 95.9% of the dose recovered in urine and 0.5% recovered in feces. The elimination half-life is 5.2 to 6.5 hours.
Affected Cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2E1, OCT2
CYP2E1 is the major enzyme responsible for the metabolism of dalfampridine. In vitro, dalfampridine is not an inducer or 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. Further, dalfampridine is neither a substrate nor an inhibitor of P-glycoprotein. Dalfampridine appears to be a substrate for organic cation transporter 2 (OCT2); concurrent treatment with OCT2 inhibitors (e.g., cimetidine) may cause increased exposure to dalfampridine and may increase the risk of seizures.
-Route-Specific Pharmacokinetics
Oral Route
Absorption of dalfampridine is rapid and complete. The relative bioavailability is 96% as compared with an aqueous oral solution. After administration of a 10 mg tablet to healthy patients in the fasted state, the maximum serum concentration (Cmax) of 17.3 to 21.6 ng/mL occurs in 3 to 4 hours. If dalfampridine is taken with food, a 12% to 17% increase in Cmax and a 4% to 7% decrease in AUC occurs; these changes in exposure are not clinically significant, and dalfampridine can be taken with or without food. Exposure of dalfampridine increases proportionally with dose.
-Special Populations
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 require dose adjustments.
Renal Impairment
The clearance of dalfampridine is significantly correlated with creatinine clearance (CrCl) and the drug is contraindicated in patients with CrCl 50 mL/minute or less. The total body clearance was reduced by about 45% in patients with a CrCl of 51 to 80 mL/minute, by about 50% in patients with a CrCl of 30 to 50 mL/minute, and by about 75% in patients with a CrCl less than 30 mL/minute. Among patients with a CrCl less than 30 mL/min, the dalfampridine terminal half-life is about 3.3 times longer than the value obtained from patients without renal impairment.
Pediatrics
Data are not available.
Geriatric
The clearance of dalfampridine modestly decreased with increasing age, but dalfampridine dose adjustment is not needed.
Gender Differences
Higher maximum dalfampridine concentrations are expected in females as compared with males. However, the magnitude of the difference is small, and dalfampridine dose adjustment is not needed.
Ethnic Differences
There were too few non-Caucasians in the patient population to evaluate the effect of race.