Sabril - Drug Monograph

Introduction

Sabril (vigabatrin) is an antiepileptic medication approved for the treatment of refractory complex partial seizures in adults and pediatric patients 2 years and older, and for infantile spasms in infants 1 month to 2 years of age. As an irreversible inhibitor of GABA transaminase, it represents a unique mechanism among antiepileptic drugs. Sabril carries a boxed warning for permanent vision loss, requiring careful patient selection and monitoring.

Mechanism of Action

Vigabatrin works as an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for GABA catabolism. By inhibiting GABA-T, Sabril increases GABA concentrations in the central nervous system. GABA is the primary inhibitory neurotransmitter in the brain, and enhanced GABAergic activity reduces neuronal excitability, thereby suppressing seizure activity.

Indications

• FDA-approved indications:

- Monotherapy for infantile spasms (IS) in patients 1 month to 2 years of age - Adjunctive therapy for refractory complex partial seizures (CPS) in patients 2 years and older who have responded inadequately to several alternative treatments

• Important note: Sabril should only be used in patients for whom the potential benefits outweigh the risk of vision loss

Dosage and Administration

• Initial dose: 50 mg/kg/day divided twice daily
• May titrate up to 150 mg/kg/day based on clinical response

• Adults: Start with 500 mg twice daily; may increase by 500 mg increments weekly to maximum of 1500 mg twice daily
• Pediatrics (10-16 years): Start with 250 mg twice daily; titrate to maximum of 1000 mg twice daily
• Pediatrics (2-9 years): Start with 250 mg twice daily; titrate to maximum of 1000 mg twice daily

• Administer with or without food
• Tablets should be swallowed whole
• Powder for oral solution should be dissolved in water (approximately 10 mL per 500 mg packet)

• CrCl >50 mL/min: No adjustment needed
• CrCl 30-50 mL/min: Reduce dose by 25%
• CrCl 10-30 mL/min: Reduce dose by 50%
• CrCl <10 mL/min: Reduce dose by 75%

Pharmacokinetics

• Absorption: Rapidly absorbed with bioavailability approximately 60%; food does not significantly affect absorption
• Distribution: Minimal protein binding (<5%); widely distributed throughout body water
• Metabolism: Not significantly metabolized hepatically; does not undergo cytochrome P450 metabolism
• Elimination: Primarily excreted unchanged in urine (80%); elimination half-life approximately 7.5 hours (prolonged in renal impairment)
• Steady state: Reached within 2 days

Contraindications

• Hypersensitivity to vigabatrin or any component of the formulation
• Patients with pre-existing visual field defects (relative contraindication requiring careful risk-benefit assessment)

Warnings and Precautions

• Progressive, bilateral, concentric peripheral visual field constriction that may become severe
• Risk increases with cumulative dose and duration of therapy
• Can occur without symptoms; patients may not notice vision loss until substantial damage has occurred
• Requires baseline and periodic vision assessment

• Neurotoxicity: MRI abnormalities characterized by increased T2 signal and restricted diffusion in thalamus, basal ganglia, brainstem, and cerebellum
• Suicidal behavior and ideation: Antiepileptic drugs increase risk of suicidal thoughts or behavior
• Withdrawal seizures: Abrupt discontinuation may increase seizure frequency; taper gradually
• Hematologic effects: Anemia requiring periodic monitoring
• Sedation and fatigue: May impair ability to drive or operate machinery

Drug Interactions

• Minimal CYP450 interactions: Unlike many antiepileptics, vigabatrin does not induce or inhibit cytochrome P450 enzymes
• Clonazepam: May increase risk of sedation when co-administered
• Phenytoin: Vigabatrin may decrease phenytoin concentrations by approximately 20%
• Other CNS depressants: Additive sedative effects with alcohol, benzodiazepines, opioids, and other sedating medications
• Drugs affecting renal function: Altered vigabatrin clearance with medications affecting renal function

Adverse Effects

• Fatigue/sedation (20-40%)
• Dizziness (15-30%)
• Headache (20-25%)
• Weight gain (10-15%)
• Tremor (10-15%)
• Vision blurring (10-15%)
• Memory impairment (10-12%)

• Permanent vision loss (30-40% of patients after prolonged use)
• MRI abnormalities (22-32% of infants with infantile spasms)
• Suicidal behavior and ideation
• Peripheral neuropathy
• Depression and psychosis
• Status epilepticus

Monitoring Parameters

• Comprehensive ophthalmologic examination including visual field testing
• Neurologic examination
• Renal function (serum creatinine, BUN)
• Complete blood count
• MRI (consider baseline in infants)

• Ophthalmologic evaluation every 3 months during therapy
• Visual field testing at least every 6 months
• Seizure frequency and response
• Neurologic status including assessment for depression/suicidal ideation
• Weight and nutritional status
• Complete blood count every 6 months
• Renal function in patients with renal impairment

• Developmental assessment
• Head circumference measurement
• Regular neurologic examination

Patient Education

• Vision risks: Understand that permanent vision loss may occur and report any vision changes immediately
• Compliance: Take medication exactly as prescribed; do not stop abruptly
• Monitoring: Keep all scheduled eye appointments even if vision seems normal
• Pregnancy/breastfeeding: Discuss family planning with healthcare provider; vigabatrin is excreted in breast milk
• Activities: Medication may cause drowsiness or dizziness; avoid driving or hazardous activities until effects are known
• Administration: Take with or without food; tablets must be swallowed whole
• Symptom reporting: Report any thoughts of self-harm, depression, or unusual behavioral changes
• Storage: Store at room temperature; protect from moisture

References

1. FDA Prescribing Information: Sabril (vigabatrin) tablets and powder. Revised 2020. 2. Wheless JW, Ramsay RE, Collins SD. Vigabatrin. Neurotherapeutics. 2007;4(1):163-172. 3. Maguire MJ, Hemming K, Wild JM, et al. Prevalence of visual field loss following exposure to vigabatrin therapy: A systematic review. Epilepsia. 2010;51(12):2423-2431. 4. Wild JM, Ahn HS, Baulac M, et al. Vigabatrin and epilepsy: lessons learned. Epilepsia. 2007;48(8):1478-1486. 5. Pearl PL, Vezina LG, Saneto RP, et al. Cerebral MRI abnormalities associated with vigabatrin therapy. Epilepsia. 2009;50(2):184-194. 6. Willmore LJ, Abelson MB, Ben-Menachem E, et al. Vigabatrin: 2008 update. Epilepsia. 2009;50(2):163-173. 7. ClinicalTrials.gov: Vigabatrin studies in refractory complex partial seizures and infantile spasms.