Dalfampridine (Monograph)

Brand name: Ampyra
Drug class: Protective Agents

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

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Introduction

Broad spectrum potassium channel blocker; formerly known as fampridine (4-aminopyridine, 4-AP).

Uses for Dalfampridine

Multiple Sclerosis

Used to improve walking in patients with multiple sclerosis (MS); designated an orphan drug by FDA for relief of symptoms of MS.

Although only a portion of MS patients respond to dalfampridine treatment, 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.

Insufficient data regarding effects on other MS symptoms (e.g., motor function assessed using manual muscle testing, visual function, cognitive function, fatigue).

Although dalfampridine is not a disease-modifying therapy and is not addressed in current guidelines for treatment of MS, some experts endorse its use to improve walking in patients with MS but recommend that treatment be continued only in patients who demonstrate a response.

Dalfampridine Dosage and Administration

General

Pretreatment Screening

• Determine estimated Cl_cr. Estimating Cl_cr is particularly important in patients ≥50 years of age since mild renal impairment is common in this age group.

Patient Monitoring

• Monitor Cl_cr at least annually during dalfampridine treatment.

Administration

Oral Administration

Administer orally with or without food.

Administer doses approximately 12 hours apart.

Swallow tablet whole; do not divide, crush, chew, or dissolve.

If a dose is missed, do not double dose or take extra doses. Take the next dose at the regularly scheduled time.

Dosage

Adults

Multiple Sclerosis

Oral

10 mg twice daily. Give doses approximately 12 hours apart.

No evidence of additional benefit at higher dosages; higher dosages associated with more frequent adverse effects, including seizures.

Has been used for up to 9–24 weeks in clinical studies.

Special Populations

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment. Hepatic impairment not expected to affect pharmacokinetics or dosage recommendations.

Renal Impairment

Contraindicated in patients with moderate or severe renal impairment (Cl_cr ≤50 mL/minute). Manufacturer does not provide dosage recommendations for patients with mild renal impairment.

Geriatric Patients

Dosage modification not necessary based solely on age. Eliminated by kidneys; consider that mild renal impairment is common in adults ≥50 years of age.

Cautions for Dalfampridine

Contraindications

• History of seizures.

• Moderate or severe renal impairment (Cl_cr ≤50 mL/minute).

• History of hypersensitivity to dalfampridine or 4-aminopyridine; reactions have included anaphylaxis.

Warnings/Precautions

Seizures

Dalfampridine can cause seizures. Contraindicated in patients with history of 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 were receiving other drugs that increase risk of seizures or lower 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.

If a seizure occurs, permanently discontinue dalfampridine therapy.

Renal Impairment

Dalfampridine is primarily eliminated through kidneys as unchanged drug. Patients with moderate to severe renal impairment (Cr_Cl≤50 mL/min) require a dose lower than 10 mg twice daily; no strength smaller than 10 mg is available and the drug is contraindicated in these patients.

In patients with mild renal impairment (Cr_Cl 51–80 mL/min), plasma levels of dalfampridine may approach those seen at a dose of 15 mg twice daily, which has been associated with an increased risk of seizures.

Concurrent Treatment with Other Aminopyridines

Do not use in patients receiving other aminopyridines, including extemporaneously prepared formulations, since the active ingredient is the same.

Prior to initiation of dalfampridine, discontinue use of any product containing 4-aminopyridine (formerly known as fampridine) to reduce the risk of dose-related adverse effects.

Anaphylaxis

Anaphylaxis and severe allergic reactions reported. Signs and symptoms of such reactions have included respiratory compromise, urticaria, and angioedema of throat and/or tongue.

If an anaphylactic or other serious allergic reaction occurs, discontinue dalfampridine and seek immediate medical care.

Specific Populations

Pregnancy

No adequate data on developmental risk associated with use in pregnant women. In animal studies, decreased offspring viability and growth reported at clinically relevant doses.

Lactation

Not known whether distributed into human milk. Effects of the drug on nursing infants and milk production not known.

Consider known benefits of breast-feeding along with mother's clinical need for dalfampridine and any potential adverse effects of the drug or underlying maternal condition on the infant.

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

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. Although modification of dalfampridine dosage is not necessary based solely on age, mild renal impairment is common in adults ≥50 years of age. Because risk of adverse reactions (including seizures) may be greater in patients with impaired renal function, it is particularly important to determine estimated Cl_cr in this age group prior to initiation of dalfampridine.

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment. Hepatic impairment not expected to affect pharmacokinetics or dosage recommendations.

Renal Impairment

Clearance of dalfampridine is decreased in patients with renal impairment and is correlated with Cl_cr.

Prior to initiation of dalfampridine, determine estimated Cl_cr (e.g., Cockcroft-Gault equation). Also determine estimated Cl_cr at least annually during therapy.

Contraindicated in patients with moderate or severe renal impairment (Cl_cr ≤50 mL/minute).

In patients with mild renal impairment (Cl_cr 51–80 mL/minute), clearance is reduced by 45%. Plasma concentrations may approach those seen with dosage of 15 mg twice daily, a dosage associated with an increased risk of seizures. Weigh potential benefits against risk of seizures.

Because mild renal impairment is common in adults ≥50 years of age, even when serum creatinine is normal, it is particularly important to estimate Cl_cr in this age group.

Common Adverse Effects

Common adverse effects (≥2%): urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, relapse of MS, paresthesia, nasopharyngitis, constipation, dyspepsia, pharyngolaryngeal pain.

Drug Interactions

Metabolized by CYP isoenzyme 2E1 and, possibly, other unidentified CYP isoenzymes.

Does not inhibit CYP isoenzymes 1A2, 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.

OCT2 Inhibitors

Decreased clearance and increased AUC of dalfampridine, which may increase seizure risk. Consider the risks and benefits of concomitant use of OCT2 inhibitors and dalfampridine.

Specific Drugs

Dalfampridine Pharmacokinetics

Absorption

Bioavailability

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 those 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 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 occurring 3–4 hours after the dose.

Food

Administration of dalfampridine extended-release tablets 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.

Distribution

Extent

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.

Elimination

Metabolism

Small amount 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.

Elimination Route

Eliminated in urine (95.9%) and feces (0.5%).

Majority 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.

Half-life

Dalfampridine: 5.2–6.5 hours.

3-Hydroxy-4-aminopyridine sulfate: 7.6 hours.

Special Populations

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 (Cl_cr 51–80 mL/minute), about 50% in those with moderate renal impairment (Cl_cr 30–50 mL/minute), and about 75% in those with severe renal impairment (Cl_cr <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.

Stability

Storage

Oral

Extended-release Tablets

25°C (excursions permitted to 15–30°C).

Actions

• 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 (K_v) 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 K_v channels in microglia, macrophages, dendritic cells, and/or T lymphocytes) also may be involved.

• Does not prolong QT_c interval; does not have a clinically important effect on QRS duration.

Advice to Patients

• Advise patients to read the medication guide prior to initiating dalfampridine therapy and each time the prescription is refilled.

• Cousel patients to take dalfampridine exactly as prescribed. The tablets should be swallowed whole; tablets should not be divided, crushed, chewed, or dissolved.

• 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.

• Advise patients that dalfampridine can cause seizures, even in patients without a history of seizures. Risk of seizure is increased if a higher than recommended dosage is used or if patient has renal impairment. Advise patients to inform a clinician if the patient has a history of seizures or has renal impairment. Immediately discontinue dalfampridine and contact a clinician if a seizure occurs during treatment.

• Risk of anaphylaxis. Advise patients to discontinue dalfampridine and seek medical care if they develop signs and symptoms of anaphylaxis.

• Counsel patients that CNS-related adverse effects (e.g., vertigo, dizziness) can occur and may impair ability to drive or use machinery.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Inform clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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.

Dalfampridine (Ampyra) is available through certain specialty pharmacies.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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