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Dalfampridine

Pronunciation

(dal FAM pri deen)

Index Terms

  • 4 - aminopyridine
  • 4 - AP
  • EL - 970
  • Fampridine
  • Fampridine - SR

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release 12 Hour, Oral:

Ampyra: 10 mg

Brand Names: U.S.

  • Ampyra

Pharmacologic Category

  • Potassium Channel Blocker

Pharmacology

Nonspecific potassium channel blocker which improves conduction in focally demyelinated axons by delaying repolarization and prolonging the duration of action potentials. Enhanced neuronal conduction is thought to strengthen skeletal muscle fiber twitch activity, thereby, improving peripheral motor neurologic function.

Absorption

Rapid and complete

Distribution

Vd: 2.6 L/kg

Metabolism

Limited metabolism; in vitro data suggests hepatic metabolism to 3-hydroxy-4-aminopyridine occurs primarily via CYP2E1; further conjugated to 3-hydroxy-4-aminopyridine sulfate; metabolites are inactive

Excretion

Urine (96%; 90% of total dose as unchanged drug); feces (0.5%)

Time to Peak

Plasma: 3-4 hours

Half-Life Elimination

5.2-6.5 hours; prolonged in severe renal impairment (~3 times longer)

Protein Binding

Negligible; predominantly unbound to plasma proteins

Special Populations: Renal Function Impairment

Total body clearance of dalfampridine is reduced by ~45% in patients with mild renal impairment (CrCl 51-80 mL/minute), by ~50% in patients with moderate renal impairment (CrCl 30-50 mL/minute), and by ~75% in patients with severe renal impairment (CrCl <30 mL/minute).

Special Populations: Elderly

Clearance modestly decreased with increasing age, but not significantly enough to necessitate a dose modification.

Special Populations: Gender

A pharmacokinetic analysis suggested that women would be expected to have slightly higher Cmax than men.

Use: Labeled Indications

Treatment to improve walking in patients with multiple sclerosis (MS)

Contraindications

Hypersensitivity to dalfampridine, 4-aminopyridine, or any component of the formulation; history of seizure; moderate or severe renal impairment (CrCl ≤50 mL/minute)

Canadian labeling: Additional contraindications (not in U.S. labeling): Mild, moderate, severe renal impairment (CrCl ≤80 mL/minute); concomitant use with compounded 4-aminopyridine or other forms of fampridine; concomitant use with drugs that inhibit organic cation transporter 2 (OCT2), such as cimetidine or quinidine

Dosing: Adult

Multiple sclerosis: Oral: 10 mg every 12 hours (maximum daily dose: 20 mg); no additional benefit seen with doses >20 mg daily

Missed doses: Do not administer double or extra doses if a dose is missed.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Note: Creatinine clearance is estimated with Cockcroft-Gault formula.

U.S. labeling:

Mild renal impairment (CrCl 51-80 mL/minute): No dosage adjustment recommended by the manufacturer; however, use with extreme caution as risk of seizure may be increased secondary to reduced clearance.

Moderate-to-severe renal impairment (CrCl ≤50 mL/minute): Use is contraindicated.

Canadian labeling:

Mild-to-severe impairment (CrCl ≤80 mL/minute): Use is contraindicated.

Dosing: Hepatic Impairment

No dosage adjustment required; drug undergoes minimal metabolism and is primarily excreted unchanged in the urine.

Administration

May be administered with or without food. Do not chew, crush, dissolve, or divide tablet.

Dietary Considerations

May be taken with or without food.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Cimetidine: May increase the serum concentration of Dalfampridine. Management: Recommendations differ significantly between international labelings in regards to the concomitant use of dalfampridine (referred to as fampridine in Canada) and cimetidine. Consult appropriate product labeling. Monitor therapy

MetFORMIN: May increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

QuiNIDine: May increase the serum concentration of Dalfampridine. Management: Recommendations differ significantly between international labelings in regards to the concomitant use of dalfampridine (referred to as fampridine in Canada) and quinidine. Consult appropriate product labeling. Monitor therapy

Adverse Reactions

>10%: Genitourinary: Urinary tract infection (12%)

1% to 10%:

Central nervous system: Insomnia (9%), dizziness (7%), headache (7%), equilibrium disturbance (5%), paresthesia (4%), seizure (≤4%; dose-dependent)

Gastrointestinal: Nausea (7%), constipation (3%), dyspepsia (2%)

Neuromuscular & skeletal: Weakness (7%), back pain (5%), acute exacerbations of multiple sclerosis (4%)

Respiratory: Nasopharyngitis (4%), pharyngolaryngeal pain (2%)

<1% (Limited to important or life-threatening): Anaphylaxis, confusion, hypersensitivity reaction

Warnings/Precautions

Concerns related to adverse reactions:

• Anaphylaxis: May cause anaphylaxis or severe allergic reactions; symptoms have included respiratory compromise, urticaria, and angioedema (throat and tongue). Discontinue immediately and administer appropriate medical care if a severe allergic reaction occurs.

• Seizures: Associated with a dose-dependent risk of seizure; seizures may occur within days to weeks after treatment initiation and have been reported more frequently in patients with no history of seizures. Discontinue use and do not reinitiate therapy if seizure occurs during treatment. Use is contraindicated in patients with a history of seizures. Assess risk of seizure prior to treatment initiation; use caution or avoid in patients who may have a lower seizure threshold due to predisposing factors.

• Urinary tract infection: Urinary tract infections were reported more frequently in patients receiving dalfampridine (compared to placebo),

Disease-related concerns:

• Renal impairment: Use in renal impairment is associated with an increased risk of seizure and other adverse events, primarily neurologic effects, due to increased serum concentrations; elimination is predominately via the kidneys as unchanged drug. U.S. labeling contraindicates use in moderate-to-severe renal impairment (CrCl ≤50 mL/minute). Canadian labeling contraindicates use in mild, moderate, and severe renal impairment (CrCl ≤80 mL/minute).

Concurrent drug therapy issues:

• 4-aminopyridine formulations: Sustained release products available in the U.S. (dalfampridine) or in Canada (fampridine) should not be administered with other 4-aminopyridine formulations (eg, compounded immediate release fampridine).

Other warnings/precautions:

• Name confusion: The chemical entity of 4-aminopyridine is referred to with a generic name of dalfampridine in the U.S. and with a generic name of fampridine in Canada.

Monitoring Parameters

Renal function (baseline and at least annually thereafter); EEG; walking ability

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies, including decreased growth and death.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dyspepsia, headache, insomnia, back pain, rhinitis, pharyngitis, or constipation. Have patient report immediately to prescriber severe dizziness, syncope, significant asthenia, dysuria, change in balance, dyspnea, or parasthesia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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