Rufinamide

Pronunciation: roo-FIN-a-mide
Class: Anticonvulsant

Trade Names

Banzel
- Tablets, oral 200 mg
- Tablets, oral 400 mg
- Suspension, oral 40 mg/mL

Pharmacology

The precise mechanism is unknown; however, modulation of the activity of sodium channels, and prolongation of the inactive state of the channel, are thought to be involved.

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Pharmacokinetics

Absorption

Well absorbed after oral administration. However, the bioavailability decreases as the dose increases. T _max is between 4 and 6 h. Food increases the extent of absorption 34%.

Distribution

Binding to plasma protein is 34%, predominantly to albumin (27%). Apparent Vd is 50 L at a dosage of 3,200 mg/day.

Metabolism

Extensively metabolized to inactive metabolites, primarily by carboxylesterase-mediated hydrolysis. Rufinamide is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4.

Elimination

Elimination half-life is 6 to 10 h. Renal elimination accounts for 85% of an administered dose, with less than 2% recovered unchanged.

Special Populations

Pharmacokinetics in patients with severe renal function impairment (CrCl less than 30 mL/min) are similar to those of healthy subjects. Patients undergoing dialysis 3 h postdosing displayed a decrease in AUC and C _max of 29% and 16%, respectively. Consider adjusting dose for drug loss during dialysis.

Pharmacokinetics have not been studied. Use in patients with severe hepatic impairment is not recommended.

No significant age-related differences in the pharmacokinetics of rufinamide were found.

The pharmacokinetics of rufinamide in children are similar to the pharmacokinetics in adults.

Population pharmacokinetic analyses of women show a 6% to 14% lower apparent Cl of rufinamide compared with men.

In a population pharmacokinetic analysis of clinical studies, no difference in Cl or Vd of rufinamide was observed between black and white subjects, after controlling for body size.

Indications and Usage

Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in adults and children 4 y and older.

Contraindications

Familial short QT syndrome.

Dosage and Administration

PO Start with 400 to 800 mg/day in 2 equally divided doses. Increase the dosage by 400 to 800 mg/day every 2 days to a max of 3,200 mg/day given in 2 equally divided doses.

PO Start with approximately 10 mg/kg/day in 2 equally divided doses. Increase the dosage in increments of 10 mg/kg every other day to a target dosage of 45 mg/kg/day or 3,200 mg/day (whichever is less) administered in 2 equally divided doses.

PO Hemodialysis decreases exposure by approximately 30%. Consider adjusting the dose to account for drug loss during hemodialysis.

General Advice

• Administer with food.
• Tablets are scored on both sides and can be cut in half for dosing flexibility. Tablets can be administered whole, as half tablets, or crushed.
• Shake suspension well before each administration. The provided adapter and calibrated oral dosing syringe should be used to administer the suspension. The adapter that is supplied in the product carton should be inserted firmly into the neck of the bottle before use and remain in place for the duration of usage of the bottle. The dosing syringe should be inserted into the adapter and the dose withdrawn from the inverted bottle. The cap fits properly when the adapter is in place.
• Patients on valproate should begin rufinamide at a lower starting dose.
• Gradually withdraw treatment by approximately 25% every 2 days to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus.

Storage/Stability

Store between 59° and 86°F. Protect tablets from moisture.

Drug Interactions

Plasma concentrations may be increased by rufinamide, while rufinamide plasma concentrations may be decreased, especially in children.

Carbamazepine and rufinamide plasma concentrations may be decreased.

Efficacy of hormonal contraceptives may be decreased; consider additional, nonhormonal contraception.

Plasma concentrations may be decreased by rufinamide, especially in children.

Rufinamide plasma concentrations may be decreased, especially in children.

Plasma concentrations may be decreased.

Rufinamide plasma concentrations may be elevated, increasing the pharmacologic effects and adverse reactions. Patients stabilized on rufinamide before starting valproate should begin valproate at a low dosage and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a rufinamide dosage lower than 10 mg/kg/day (children) or 400 mg/day (adults). Effects are greater in children.

Adverse Reactions

CNS

Headache (27%); somnolence (17%); dizziness (19%); fatigue (16%); tremor (6%); ataxia (4%); aggression, anxiety, disturbance in attention, gait disturbances, psychomotor hyperactivity, vertigo (3%).

Dermatologic

Rash (4%); pruritus (3%).

EENT

Diplopia (9%); blurred vision, nystagmus (6%); nasopharyngitis (5%); ear infection (3%).

GI

Vomiting (17%); nausea (12%); decreased appetite (5%); constipation, dyspepsia, upper abdominal pain (3%); increased appetite (at least 1%).

Hematologic-Lymphatic

Leukopenia (4%); anemia (at least 1%).

Respiratory

Bronchitis, sinusitis (3%).

Miscellaneous

Influenza (5%); back pain (3%); pollakiuria (at least 1%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined, but likely to be excreted.

Children

Safety and efficacy not established in children younger than 4 y.

Elderly

Select dose with caution, usually starting at the low end of the dose range, because of the greater frequency of decreased hepatic, renal, or cardiac function, and/or of concomitant disease or other drug therapy.

Hypersensitivity

Multiorgan hypersensitivity syndrome, a serious condition sometimes induced by antiepileptic drugs, has occurred.

Renal Function

Consider dosage adjustment in patients on dialysis.

Hepatic Function

Use with caution in patients with mild to moderate hepatic impairment. Use in patients with severe hepatic impairment is not recommended.

CNS effects

Ataxia, coordination abnormalities, dizziness, fatigue, gait disturbances, and somnolence have been reported.

QT shortening

ECG studies demonstrated QT interval shortening (up to 20 msec). Do not treat patients with familial short QT syndrome.

Status epilepticus

Treatment-emergent status epilepticus has been reported.

Suicide

The risk of suicidal thoughts and behavior is increased.

Overdosage

Symptoms

Experience with overdosage is limited. One patient receiving 7,200 mg/day did not exhibit major signs or symptoms and did not require medical intervention.

Patient Information

• Advise patients to read the Medication Guide before starting therapy and with each refill.
• Advise patients or caregivers to be alert for emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, the emergence of suicidal thoughts or behavior, or thoughts about self-harm, and to immediately report any behaviors of concern to health care provider.
• Instruct patients to take with food.
• Instruct patients to shake the suspension vigorously before every administration and to use the adaptor and oral dosing syringe.
• Advise patients to avoid alcoholic beverages while taking this medication.
• Advise patients that this product may cause somnolence or dizziness and not to drive or operate machinery until they have gained sufficient experience to determine whether the drug adversely affects their mental and/or motor performance.
• Instruct patients to notify health care provider if they experience a rash associated with fever.
• Advise patients using oral/hormonal contraceptive to use a nonhormonal form of contraception during therapy.

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