AMPYRA® (dalfampridine)

AMPYRA® (dalfampridine)

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AMPYRA® (dalfampridine)

AMPYRA (dalfampridine) is a potassium channel blocker, available in a 10 mg tablet strength. Each tablet contains 10 mg dalfampridine, formulated as an extended-release tablet for twice-daily oral administration. Dalfampridine is also known by its chemical name, 4-aminopyridine

AMPYRA (dalfampridine) extended-release tablets are available in a 10 mg strength and are white to off-white, biconvex, oval shaped, film-coated, non-scored tablets with flat edge, debossed with “A10” on one side, containing 10 mg of dalfampridine. Inactive ingredients consist of colloidal silicon dioxide, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, and titanium dioxide.

Dalfampridine is a fine white powder with a molecular weight of 94.1, CAS 504-24-5, and a molecular formula of C5H6N2. At ambient conditions, dalfampridine is soluble in water, methanol, acetone, tetrahydrofuran, isopropanol, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, and ethanol.

Indications and usage

AMPYRA® (dalfampridine) is a potassium channel blocker indicated to improve walking in adult patients with multiple sclerosis (MS). This was demonstrated by an increase in walking speed

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.

Dosage and administration

  • The maximum recommended dosage is 10 mg twice daily (approximately 12 hours apart). There is no evidence of additional benefit with doses greater than 10 mg twice daily. Adverse reactions, including seizures, were more frequent at higher doses.
  • Take with or without food. Administer tablets whole; do not divide, crush, chew, or dissolve
  • Patients should not take double or extra doses if they miss a dose.
  • Estimated creatinine clearance (CrCl) should be known before initiating treatment with AMPYRA. In patients with mild renal impairment (CrCl 51–80 mL/min), AMPYRA may reach plasma levels associated with a greater risk of seizures, and the potential benefits of AMPYRA should be carefully considered against the risk of seizures in these patients

Contraindications

  • History of seizure
  • Moderate or severe renal impairment (CrCl≤50 mL/min)
  • History of hypersensitivity to AMPYRA or 4-aminopyridine

Warnings and precautions

Seizures: AMPYRA can cause seizures. Increased incidence of seizures has been observed at 20 mg twice daily (2 times the maximum recommended dosage) in controlled clinical studies of 9–14 weeks duration with dalfampridine in patients with MS.

Renal Impairment: AMPYRA is eliminated through the kidneys primarily as unchanged drug. 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, AMPYRA is contraindicated in these patients

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 AMPYRA in order to reduce the potential for dose-related adverse reactions.

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

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Adverse reactions

The most common adverse events (incidence ≥2% and at a rate greater than the placebo rate) for AMPYRA were urinary tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain

Drug interactions

OCT2 Inhibitors: 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 AMPYRA should be considered against the risk of seizures in these patients.

Baclofen: No interaction was identified between dalfampridine and baclofen

Use in specific populations

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

Lactation: 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 AMPYRA and any potential adverse effects on the breastfed infant from AMPYRA or from the underlying maternal condition.

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

Geriatric Use: Clinical studies of AMPYRA 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.

Overdosage

Three cases of overdose were reported in controlled clinical trials with AMPYRA, involving two MS patients. The first patient took six times the currently recommended dose (60 mg) and was taken to the emergency room with altered mental state. The second patient took 40 mg doses on two separate occasions. In the first instance, she experienced a complex partial seizure and, in the second instance, a period of confusion. Both patients recovered by the following day without sequelae.

Several cases of overdose are found in the scientific literature in which various formulations of dalfampridine were used, resulting in numerous adverse events including seizure, confusion, tremulousness, diaphoresis, and amnesia. In some instances, patients developed status epilepticus, requiring intensive supportive care and were responsive to standard therapy for seizures. In one published case report, an MS patient who ingested 300 mg of 4-aminopyridine (dalfampridine) developed a condition that resembled limbic encephalitis. This patient developed weakness, reduced awareness, memory loss, hypophonic speech, and temporal lobe hyperintensities on MRI. The patient’s speech and language and ambulation improved over time, and an MRI at 4 months after the overdose no longer showed signal abnormalities. At one year, the patient continued to have difficulty with short term memory and learning new tasks.

Storage

Store at 25°C (77°F). Excursions permitted 15ºC to 30ºC (59ºF to 86ºF).

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