How should Ampyra (dalfampridine) be dosed and monitored in a multiple sclerosis patient with gait impairment, considering his estimated glomerular filtration rate and any history of seizures?

Ampyra (Dalfampridine) Dosing and Monitoring in Multiple Sclerosis

Ampyra should be dosed at 10 mg orally twice daily (approximately 12 hours apart) and is absolutely contraindicated in patients with moderate-to-severe renal impairment (CrCl ≤50 mL/min) or any history of seizures. 1

Dosing Protocol

• The fixed dose is 10 mg twice daily, taken with or without food 1
• Tablets must be swallowed whole—never divide, crush, chew, or dissolve them, as this destroys the extended-release formulation and increases seizure risk 1
• If a dose is missed, patients should skip it and resume the regular schedule; doubling doses is dangerous 1
• Doses higher than 10 mg twice daily provide no additional walking benefit but substantially increase seizure risk 1, 2

Absolute Contraindications

History of seizures: Dalfampridine is contraindicated in any patient with a prior seizure, regardless of cause or timing 1, 3. The majority of seizures in post-marketing surveillance occurred in patients without seizure history, typically within days to weeks of starting therapy 1.

Moderate or severe renal impairment (CrCl ≤50 mL/min): The drug is eliminated renally as unchanged compound, and no lower-strength tablet exists to allow dose reduction 1, 4. Patients with CrCl ≤50 mL/min will accumulate dangerous plasma levels 1.

Renal Function Monitoring Requirements

Before initiating therapy: Calculate estimated creatinine clearance using the Cockcroft-Gault equation (multiply by 0.85 for women) 1:

CrCl = [(140 - age) × weight in kg] / (72 × serum creatinine in mg/dL)

During therapy: Monitor CrCl at least annually, as renal function declines with age and disease progression 1

Special Consideration for Mild Renal Impairment (CrCl 51-80 mL/min)

• Patients with mild renal impairment achieve plasma levels approaching those seen with 15 mg twice daily (1.5 times the maximum recommended dose), significantly increasing seizure risk 1
• Mild renal impairment is common after age 50, making CrCl estimation particularly critical in older MS patients 1
• The potential walking benefit must be carefully weighed against elevated seizure risk in this population 1
• If prescribing to patients with CrCl 51-80 mL/min, counsel extensively about seizure warning signs and maintain heightened vigilance 1

Mechanism and Expected Efficacy

• Dalfampridine blocks voltage-dependent potassium channels exposed during axonal demyelination, restoring electrical conduction along damaged axons 2, 5
• Approximately 35% of treated patients are "responders" who achieve clinically meaningful improvement in walking speed 2, 6
• Trough plasma concentrations of 13-15 ng/mL are required to maintain efficacy, with steady state achieved within 39 hours 4
• Improvement in walking speed is independent of MS disease course (relapsing-remitting, secondary progressive, or primary progressive) 5

Safety Monitoring

Seizure risk: The incidence at the approved 10 mg twice daily dose is 0.4 per 100 patient-years, but increases to 1.7 per 100 patient-years at 15 mg twice daily (over 4-fold higher) 1. Permanently discontinue dalfampridine if a seizure occurs 1.

Common adverse effects: Insomnia, dizziness, headache, nausea, and weakness are most frequent 3. These are generally mild and do not require discontinuation 5.

Anaphylaxis: Rare but serious reactions including respiratory compromise, urticaria, and angioedema have occurred 1. Instruct patients to discontinue immediately and seek emergency care if these develop 1.

Critical Drug Interaction

• Avoid concomitant use with any other formulation of 4-aminopyridine (4-AP, fampridine), as the active ingredient is identical and combined use causes dose-related toxicity 1
• Dalfampridine has minimal drug-drug interaction potential: it is not a substrate for p-glycoprotein, does not affect CYP450 enzymes, and has low protein binding 4

Common Pitfalls to Avoid

Do not use in patients with any seizure history: Even remote or provoked seizures are absolute contraindications 1. Patients with epileptiform activity on EEG were excluded from trials, and their seizure risk is unknown but likely substantially higher 1.

Do not prescribe without calculating CrCl: Serum creatinine alone is insufficient, particularly in elderly or low-body-weight patients who may have normal creatinine but significantly reduced CrCl 1.

Do not exceed 10 mg twice daily: Higher doses offer no additional benefit for walking but dramatically increase seizure risk 1, 2.