RUFINAMIDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for RUFINAMIDE (RUFINAMIDE).
Modulates sodium channels, prolonging the inactive state, thereby stabilizing neuronal membranes and inhibiting repetitive firing. Also enhances the activity of gamma-aminobutyric acid (GABA) at GABA-A receptors.
| Metabolism | Primarily hydrolyzed by carboxylesterases (CES1 and CES2) to inactive metabolite. Minor CYP450 metabolism (CYP2C19, CYP3A4, CYP1A2). |
| Excretion | Renal: 85% as unchanged drug; fecal: 15% as unchanged drug and metabolites. |
| Half-life | Terminal elimination half-life is 6–10 hours in adults, requiring twice-daily dosing for stable trough concentrations. |
| Protein binding | 34% bound to albumin; low binding reduces displacement interactions. |
| Volume of Distribution | 0.5–0.8 L/kg, indicating distribution into total body water without extensive tissue accumulation. |
| Bioavailability | Oral: ~85% (highly bioavailable); food delays absorption but does not reduce extent. |
| Onset of Action | Oral: Clinical effect observed within 1–2 weeks at steady state; no immediate effect. |
| Duration of Action | Duration of action is approximately 12 hours, consistent with twice-daily dosing; trough levels maintained with regular administration. |
Adults: 200-400 mg orally twice daily, with titration from 200 mg twice daily increasing by 200 mg/day every 2 weeks to a maximum of 3200 mg/day divided twice daily.
| Dosage form | SUSPENSION |
| Renal impairment | No specific dose adjustment guidelines; use with caution in severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B: Reduce dose by 25%. Child-Pugh C: Reduce dose by 50%. |
| Pediatric use | Children ≥4 years: 10 mg/kg/day orally divided twice daily, titrating by 10 mg/kg/day every 2 weeks to a maximum of 45 mg/kg/day or 3200 mg/day, whichever is less. |
| Geriatric use | No specific dose adjustment, but start at lower end of dosing range due to potential reduced clearance and increased sensitivity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for RUFINAMIDE (RUFINAMIDE).
| Breastfeeding | No human data on rufinamide excretion in breast milk exist. In animal studies, rufinamide is excreted in rat milk. Due to potential for serious adverse reactions in nursing infants (e.g., sedation, poor feeding, withdrawal), caution is advised. Milk-to-plasma ratio (M/P) is not established in humans. Consider discontinuing breastfeeding or drug, taking into account importance of drug to mother. |
| Teratogenic Risk | Rufinamide is a triazole derivative antiepileptic drug. Data from animal studies indicate developmental toxicity including embryofetal mortality, growth retardation, and structural anomalies at clinically relevant exposures. In humans, there are no adequate well-controlled studies; however, based on animal data and mechanism of action, rufinamide is classified as Pregnancy Category C. Use during pregnancy only if potential benefit justifies potential risk to fetus. First trimester exposure is associated with increased risk of major congenital malformations, particularly neural tube defects and orofacial clefts. Late pregnancy exposure may cause neonatal hemorrhage due to vitamin K deficiency and persistent pulmonary hypertension. Third trimester use may lead to withdrawal symptoms in neonates. |
■ FDA Black Box Warning
None
| Serious Effects |
["Hypersensitivity to rufinamide or any component of the formulation","Familial short QT syndrome"]
| Precautions | ["Suicidal behavior and ideation","Withdrawal-precipitated seizures if discontinued abruptly","Status epilepticus","Dizziness, somnolence, and ataxia","QT interval shortening (clinical significance unknown)","Multiorgan hypersensitivity reactions","Hematologic abnormalities (e.g., leukopenia, eosinophilia)"] |
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| Fetal Monitoring | Monitor maternal serum rufinamide levels every trimester and postpartum to adjust dose for pharmacokinetic changes. Perform fetal ultrasound at 18-20 weeks to assess for structural anomalies. Obtain vitamin K levels in mother in third trimester and administer oral vitamin K 10 mg/day from 36 weeks to prevent neonatal hemorrhage. Monitor neonates for signs of withdrawal (e.g., irritability, feeding difficulties) and coagulation status post-delivery. |
| Fertility Effects | In animal studies, rufinamide had no adverse effects on male or female fertility at doses up to 60 mg/kg/day (approximately 3 times maximum recommended human dose on mg/m² basis). Human data are insufficient to assess fertility effects. Establish pregnancy risk prior to initiating therapy in women of childbearing potential. |