Dalfampridine (dalfampridine)

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Dalfampridine is administered orally as an extended-release tablet. The drug may be given with or without food.

Dalfampridine doses should be taken approximately 12 hours apart.

The extended-release tablets should be swallowed whole and should not be divided, crushed, chewed, or dissolved.

Store dalfampridine extended-release tablets at 25degreesC; excursions are permitted to 15-30degreesC.

If a dose is missed, patients should not double the dose or take extra doses. The next dose should be taken at the regularly scheduled time.

Dalfampridine is metabolized by cytochrome P-450 (CYP) isoenzyme 2E1 and, possibly, other unidentified CYP isoenzymes.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Dalfampridine/Cimetidine; Dolutegravir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cimetidine and dolutegravir inhibit the organic cation transporter 2 (OCT2). Dalfampridine is eliminated mainly via the kidneys with active renal secretion by OCT2.(1-3)

CLINICAL EFFECTS: The concurrent administration of dalfampridine with an inhibitor of OCT2 may result in elevated levels of dalfampridine and signs of toxicity. Elevated levels of dalfampridine may increase the risk of seizures.(1,2)

PREDISPOSING FACTORS: Renal impairment.

PATIENT MANAGEMENT: The US manufacturer of dalfampridine states that the potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures. If concurrent use is warranted, carefully monitor patients for adverse effects. Permanently discontinue dalfampridine in patients who have a seizure while on treatment.(1) The UK and Canadian manufacturers of dalfampridine states that concurrent use of dalfampridine and OCT2 inhibitors is contraindicated.(4,5)

DISCUSSION: In a single dose clinical study in 23 healthy volunteers, the combined use of cimetidine (400 mg every 6 hours) increased the area-under-curve (AUC) of cimetidine approximately 25% due to a reduction in the clearance of dalfampridine.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Dalfampridine/Oct2 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Agents that inhibit the organic cation transporter 2 (OCT2) may inhibit the excretion of dalfampridine by OCT2 in the kidneys.(1,2)

CLINICAL EFFECTS: Concurrent use of OCT2 renal transport inhibitors may result in increased levels of and toxicity from dalfampridine.(1,2)

PREDISPOSING FACTORS: The risk of seizures from dalfampridine may be increased in patients with a history of head trauma or prior seizure; CNS tumor; CNS infections; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antidepressants, theophylline, systemic steroids).

PATIENT MANAGEMENT: Consider the potential benefits against the risks of concurrent use of dalfampridine with OCT2 renal transport inhibitors. If concurrent use is appropriate, monitor for toxicities of dalfampridine and consider dosage reduction of dalfampridine.(1,2)

DISCUSSION: In a study, givinostat increased the levels of creatinine (OCT2 substrate) by 4.76 umol/L from baseline.(1) In a study, trilaciclib increased the area-under-curve (AUC) and maximum concentration (Cmax) of metformin (an OCT2, MATE1, and MATE-2K substrate) by approximately 65% and 81%, respectively. Renal clearance of metformin was decreased by 37%. Trilaciclib did not cause significant changes in the pharmacokinetics of topotecan (a MATE1 and MATE-2K substrate).(2) OCT2 inhibitors linked to this monograph include: abemaciclib, arimoclomol, bictegravir, brepocitinib, givinostat, isavuconazole, ranolazine, trilaciclib, trimethoprim, tucatinib, and vimseltinib.(3)

Sodium Channel Blocker; Potassium Channel Blocker/Lacosamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (sodium channel blockers and potassium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including sodium channel blockers and potassium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) A case report of a 49 year old male with refractory complex partial and generalized seizures described the development of ventricular tachycardia four months after addition of lacosamide 400 mg/day to the existing regimen of carbamazepine, lamotrigine, clonazepam, and valproate. The patient's ECG showed first-degree AV block, posterior left fascicular block, and severe widening of the QRS complex, all of which resolved upon discontinuation of lacosamide.(2)

*History of seizures.

*Moderate or severe renal impairment (Clcr 50 mL/minute or less).

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

• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Seizure disorder

• Kidney disease with likely reduction in glomerular filtration rate (GFr)

There are no moderate contraindications for this drug.

The most common adverse effects occurring in 2% or more of patients and at a rate greater than placebo with dalfampridine include urinary tract infections, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain.

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Seizure disorder

More Frequent

• Ataxia
• Back pain
• Constipation
• Dizziness
• Dyspepsia
• General weakness
• Headache disorder
• Insomnia
• Nausea
• Paresthesia
• Pharyngitis
• Sore throat
• Urinary tract infection

Rare or Very Rare

• Urticaria
• Vertigo
• Vomiting

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The safety and efficacy of dalfampridine have not been established in patients younger than 18 years of age.

There are no adequate data on the developmental risk associated with dalfampridine use in pregnant women. In animal studies, decreased offspring viability and growth were reported at clinically relevant doses.

Administration of oral dalfampridine to pregnant rats and rabbits throughout organogenesis resulted in no evidence of developmental toxicity in either species. The highest doses tested (10 mg/kg/day in rats, 5 mg/kg/day in rabbits), which were associated with maternal toxicity, are approximately 5 times the maximum recommended human dose ona body surface area basis.

There are no data on the presence of dalfampridine in human milk; its effects on the breastfed infant and milk production are also unknown. The benefits of dalfampridine therapy to the woman as well as the benefits of breast-feeding should be weighed against the potential risk to the infant from exposure to the drug or from the underlying maternal condition.

Modification of dalfampridine dosage is not necessary based solely on age. However, the drug is eliminated by the kidneys and the fact that mild renal impairment is common in adults 50 years of age or older should be considered.

There is insufficient experience with use of dalfampridine in geriatric patients 65 years of age or older to determine whether such individuals respond differently than younger individuals.

Dalfampridine is 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 or older. Pharmacokinetic analysis showed that dalfampridine clearance modestly decreased with increasing age, but not sufficiently to necessitate age-based dose modification. Other reported clinical experience has identified no differences in responses between the elderly and younger patients. Because the risk of adverse reactions (including seizures) may be greater in patients with impaired renal function, it is particularly important to determine estimated Clcr in geriatric patients prior to initiation of dalfampridine.