Class: Other Miscellaneous Therapeutic Agents
Chemical Name: 4-aminopyridine
Molecular Formula: C5H6N2
CAS Number: 504-24-5
Dalfampridine was formerly known as fampridine (4-aminopyridine; 4-AP); broad spectrum potassium channel blocker.
Uses for Dalfampridine
Used to improve walking in patients with multiple sclerosis (MS); designated an orphan drug by FDA for relief of symptoms of MS.
In clinical studies in MS patients who received the recommended dalfampridine dosage, walking improvement was demonstrated by increased walking speed in a timed 25-foot walk (T25FW). In those who responded to dalfampridine (approximately 35–43%), walking speed increased 25–29% and was maintained until the drug was discontinued.
Although only a portion of MS patients respond to dalfampridine treatment with walking improvement, improved walking during such treatment has been demonstrated in all MS disease types (relapsing remitting, primary progressive, secondary progressive, progressive relapsing). It is not clear what magnitude of improvement in walking speed results in improved walking ability or quality of life. Although consistent improvements in walking speed were shown to be associated with improvements on patient self-assessment of ambulatory disability (12-item Multiple Sclerosis Walking Scale; MSWS-12), the average MSWS-12 score during dalfampridine treatment was not different than that reported with placebo.
The magnitude of walking improvement reported with dalfampridine is independent of concomitant therapy with biologic response modifiers used for the management of MS (interferon, glatiramer acetate, natalizumab).
Data insufficient regarding safety and efficacy for management of other MS symptoms (e.g., motor function assessed using manual muscle testing, visual function, cognitive function, fatigue).
Dalfampridine Dosage and Administration
Determine estimated Clcr prior to initiating dalfampridine; monitor Clcr at least annually during therapy. Estimating Clcr is particularly important in patients ≥50 years of age since mild renal impairment is common in this age group. (See Renal Impairment under Cautions.)
Distribution of dalfampridine is restricted; the drug is available only through certain specialty pharmacies. Specific information regarding the dalfampridine distribution process is available from the manufacturer at 888-881-1918 or [Web].
Administer orally with or without food. (See Food under Pharmacokinetics.)
Give doses approximately 12 hours apart.
Swallow whole tablet; do not divide, crush, chew, or dissolve.
If a dose is missed, do not double dosage or take extra doses. Take the next dose at the regularly scheduled time.
Treatment to Improve WalkingOral
10 mg twice daily. Give doses approximately 12 hours apart.
Has been used for up to 9–14 weeks in clinical studies.
Maximum 10 mg twice daily with doses given approximately 12 hours apart. Higher dosage does not result in additional therapeutic benefit and is associated with increased risk of adverse reactions (e.g., seizures). (See Seizures under Cautions.)
Pharmacokinetics not evaluated in adults with hepatic impairment. Hepatic impairment not expected to affect pharmacokinetics or dosage recommendations.
Patients with moderate or severe renal impairment (Clcr ≤50 mL/minute): Contraindicated.
Patients with mild renal impairment (Clcr 51–80 mL/minute): Clearance is reduced by about 45% and plasma concentrations may approach those seen with dosages that may be associated with an increased risk of seizures. Weigh potential benefits against risk of seizures. (See Renal Impairment under Cautions.) Manufacturer does not provide dosage recommendations for such patients; only available as an extended-release tablet containing 10 mg of dalfampridine.
Adults 50 Years of Age or Older
Dosage modification not necessary based solely on age. Eliminated by kidneys; consider that mild renal impairment is common in adults ≥50 years of age. (See Renal Impairment under Dosage and Administration.)
Cautions for Dalfampridine
History of seizures. (See Seizures under Cautions.)
Moderate or severe renal impairment (Clcr ≤50 mL/minute). (See Renal Impairment under Cautions.)
Anaphylactic reactions reported rarely.
If anaphylactic or other serious allergic reaction occurs, discontinue dalfampridine and do not restart the drug.
Dalfampridine can cause seizures.
Postmarketing reports indicate majority of seizures have occurred in patients receiving recommended dosage (generally within days to weeks after starting the drug) and in patients without a history of seizures. Some patients had been receiving other drugs that could have increased risk of seizures or lowered seizure threshold; in addition, age-related renal dysfunction and resultant increases in plasma dalfampridine concentrations could have contributed to risk of seizures.
High dosage (e.g., 15 or 20 mg twice daily) increases risk of seizures. In open-label extension studies in MS patients, incidence of seizures was more than 4 times greater at dosage of 15 mg twice daily compared with recommended dosage (10 mg twice daily).
Altered mental state, confusion, and seizures (including status epilepticus requiring intensive supportive care) reported following overdosage.
Contraindicated in patients with prior history of seizures. Has not been evaluated in patients with a history of seizures or with evidence of epileptiform activity on EEG; such patients were excluded from clinical trials. Risk of seizures in patients with epileptiform activity on EEG is unknown and could be substantially higher than that observed in clinical trials.
Although risk of seizures in patients with mild renal impairment (Clcr 51–80 mL/minute) who receive usual dosage is unknown, plasma concentrations in such patients may approach those reported with dosages that may be associated with increased risk of seizures. (See Renal Impairment under Cautions.)
If a seizure occurs, discontinue dalfampridine and do not restart the drug.
Concurrent Treatment with Other Aminopyridines
Because of increased risk of dose-related adverse effects, do not use in patients receiving other aminopyridines, including extemporaneously prepared formulations; dalfampridine formerly was known as fampridine (4-aminopyridine, 4-AP), since the active ingredient is the same.
Prior to initiation of dalfampridine, discontinue use of any product containing 4-aminopyridine.
Urinary Tract Infections
Urinary tract infections (UTIs) reported more frequently in patients receiving dalfampridine (12%) than in patients receiving placebo (8%).
If UTI occurs, evaluate and treat as clinically indicated.
In animal studies, decreased offspring viability and growth reported at a dosage similar to maximum recommended human dosage.
Not known whether distributed into human milk. Discontinue nursing or the drug.
Safety and efficacy not established in patients <18 years of age.
Insufficient experience with dalfampridine in geriatric patients ≥65 years of age to determine whether such individuals respond differently than younger individuals.
Substantially eliminated by kidneys; geriatric patients are more likely to have decreased renal function. Because risk of adverse reactions (including seizures) may be greater in patients with impaired renal function, it is particularly important to determine estimated Clcr in this age group prior to initiation of dalfampridine. (See Renal Impairment under Cautions.)
Pharmacokinetics not evaluated in patients with hepatic impairment. Hepatic impairment not expected to affect pharmacokinetics or dosage recommendations.
Clearance of dalfampridine is decreased in patients with renal impairment and is correlated with Clcr.
Prior to initiation of dalfampridine, determine estimated Clcr (e.g., Cockcroft-Gault equation). Also determine estimated Clcr at least annually during therapy.
Contraindicated in patients with moderate or severe renal impairment (Clcr ≤50 mL/minute).
In patients with mild renal impairment (Clcr 51–80 mL/minute), carefully weigh potential benefits against risk of seizures. Plasma concentrations attained with usual dosage (10 mg twice daily) may approach those seen with 15 mg twice daily, a dosage that may be associated with an increased risk of seizures. (See Seizures under Cautions.)
Because mild renal impairment is common in adults ≥50 years of age, even when Sc is normal, it is particularly important to estimate Clcr in this age group.
Common Adverse Effects
Urinary tract infections, insomnia, dizziness, headache, nausea, asthenia, tremor, fatigue, upper respiratory tract infection, back pain, balance disorder, MS relapse or worsening, paresthesia, muscle spasm, peripheral edema, nasopharyngitis, constipation, dyspepsia, pharyngolaryngeal pain.
Interactions for Dalfampridine
Metabolized by CYP isoenzyme 2E1 and, possibly, other unidentified CYP isoenzymes.
Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5; does not induce 1A2, 2B6, 2C9, 2C19, 2E1, or 3A4/5.
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Pharmacokinetic interactions unlikely with drugs metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5.
Drugs Affecting or Affected by P-glycoprotein Transport
Not an inhibitor or substrate of the P-glycoprotein transport system; pharmacokinetic interactions unlikely with drugs that are inhibitors or substrates of this transport system.
Concomitant use of sub-Q interferon beta-1b does not affect pharmacokinetics of dalfampridine
Rapidly and completely absorbed from GI tract.
Bioavailability of dalfampridine (formerly known as fampridine [4-aminopyridine; 4-AP]) extended-release tablets is 96% compared with an extemporaneously prepared aqueous oral solution of the drug.
Extended-release dalfampridine tablets result in delayed absorption and a slower increase to lower peak plasma concentrations compared with an aqueous oral solution of the drug; extent of absorption (AUC) is not affected.
Plasma concentrations and AUC increase proportionally with dose.
Pharmacokinetics in adults with MS similar to that reported in healthy adults.
In adults 29–56 years of age with MS who received a single 10-mg dalfampridine extended-release tablet, mean peak plasma concentration was 25.23 ng/mL and was attained 3.92 hours after the dose. In healthy fasting adults, a single 10-mg extended-release tablet of the drug resulted in peak concentrations of 17.3–21.6 ng/mL occurring 3–4 hours after the dose.
Administration of a dalfampridine extended-release tablet with food results in a 12–17% increase in peak plasma concentrations and a 4–7% decrease in AUC of the drug; not considered clinically important.
Studies using IV dalfampridine indicate the drug is distributed into CSF.
Not known whether distributed into human milk.
Plasma Protein Binding
1–3% bound to plasma proteins.
A small portion of a dalfampridine dose is metabolized by CYP isoenzymes to 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate. These metabolites have no pharmacologic activity on potassium channels. In vitro studies indicate CYP2E1 is the major enzyme responsible for 3-hydroxylation of dalfampridine; other unidentified CYP enzymes play a minor role in 3-hydroxylation of the drug.
Following oral administration, 95.9% of a dalfampridine dose is eliminated in urine and 0.5% is eliminated in feces.
The majority of the dose is eliminated in urine (90.3%) as unchanged dalfampridine; 4.3% is eliminated as 3-hydroxy-4-aminopyridine and 2.6% is eliminated as 3-hydroxy-4-aminopyridine sulfate.
Dalfampridine: 5.2–6.5 hours.
3-Hydroxy-4-aminopyridine sulfate: 7.6 hours.
Geriatric adults: Clearance of dalfampridine is modestly decreased with increasing age; age-related decrease in clearance not considered clinically important.
Females: Females may have higher maximum dalfampridine plasma concentrations than males; not considered clinically important.
Renal impairment: Total body clearance reduced about 45% in adults with mild renal impairment (Clcr 51–80 mL/minute), about 50% in those with moderate renal impairment (Clcr 30–50 mL/minute), and about 75% in those with severe renal impairment (Clcr <30 mL/minute). Mean half-life in otherwise healthy adults with mild or moderate renal impairment is 7.4 or 8.1 hours, respectively; mean half-life in those with severe renal impairment is 14.3 hours.
Hepatic impairment: Pharmacokinetics not evaluated in patients with hepatic impairment. Hepatic impairment not expected to have a clinically important effect on dalfampridine pharmacokinetics.
25°C (may be exposed to 15–30°C).
Aminopyridine; broad spectrum potassium channel blocker.
Dalfampridine was formerly known as fampridine (4-aminopyridine; 4-AP), and is commercially available as extended-release tablets. Dalfampridine has been prepared extemporaneously as immediate-release capsules or oral solution.
Dalfampridine has a relatively narrow therapeutic index with concentration-dependent adverse effects. Compared with the immediate-release preparations, commercially available extended-release dalfampridine tablets provide an improved pharmacokinetic profile (e.g., lower peak plasma concentrations, more stable and sustained plasma concentrations) and allow use of a twice-daily dosage regimen.
Mechanism of action responsible for improved walking in MS patients not fully elucidated.
Selectively blocks fast, voltage-gated potassium channels (Kv) in excitable tissues and nonexcitable cells such as B cells and T lymphocytes. In vitro and animal studies indicate increased conduction of action potentials in demyelinated axons; this effect appears to be dose dependent. Other mechanisms of action (e.g., potentiation of synaptic transmission and skeletal muscle twitch tension, immunomodulatory effects on Kv channels in microglia, macrophages, dendritic cells, and/or T lymphocytes) also may be involved.
Does not prolong QTc interval; does not have a clinically important effect on QRS duration.
Advice to Patients
Importance of patient reading the medication guide prior to initiating dalfampridine therapy and each time the prescription is refilled.
Importance of taking dalfampridine exactly as prescribed. Swallow tablet whole; do not divide, crush, chew, or dissolve.
Advise patients not to take a double dose if they miss a dose. Importance of not taking more than 2 tablets in a 24-hour period and ensuring that there is an interval of approximately 12 hours between doses.
Importance of storing dalfampridine at 25°C, although the drug may be exposed to 15–30°C.
Advise patients that dalfampridine can cause seizures, even in patients without a history of seizures. Risk of seizure is increased if higher than recommended dosage is used or if patient has renal impairment.
Importance of immediately informing clinician if patient has a history of seizures or has renal impairment. Importance of discontinuing dalfampridine and contacting clinician if a seizure occurs during treatment.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Distribution of dalfampridine is restricted; available only through certain specialty pharmacies. (See Restricted Distribution under Dosage and Administration.)
Tablets, extended-release, film-coated
AHFS DI Essentials™. © Copyright 2021, Selected Revisions February 23, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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