SABRIL (vigabatrin)

SABRIL® (vigabatrin)

SABRIL (vigabatrin)

SABRIL (vigabatrin) is an oral antiepileptic drug and is available as white film-coated 500 mg tablets and as a white to off-white granular powder for oral solution in packets of 500 mg.

The chemical name of vigabatrin, a racemate consisting of two enantiomers, is (±) 4-amino-5-hexenoic acid. The molecular formula is C6H11NO2 and the molecular weight is 129.16.

Each SABRIL tablet contains 500 mg of vigabatrin. The inactive ingredients are hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycols, povidone, sodium starch glycolate, and titanium dioxide.

SABRIL for oral solution is available as a white to off-white granular powder. Each packet contains 500 mg of vigabatrin. The inactive ingredient is povidone.

INDICATIONS AND USAGE

Refractory Complex Partial Seizures (CPS)

SABRIL is indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss. SABRIL is not indicated as a first line agent for complex partial seizures.

Infantile Spasms (IS)

SABRIL is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss.

Mechanism of Action

The precise mechanism of vigabatrin’s anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system.

No direct correlation between plasma concentration and efficacy has been established. The duration of drug effect is presumed to be dependent on the rate of enzyme re-synthesis rather than on the rate of elimination of the drug from the systemic circulation.

DOSAGE AND ADMINISTRATION

Use the lowest dosage and shortest exposure to SABRIL consistent with clinical objectives.

SABRIL is given orally with or without food.

SABRIL for oral solution should be mixed with water prior to administration. A calibrated measuring device is recommended to measure and deliver the prescribed dose accurately. A household teaspoon or tablespoon is not an adequate measuring device.

If a decision is made to discontinue SABRIL, the dose should be gradually reduced

Refractory Complex Partial Seizures

Adults (Patients 17 Years of Age and Older): Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals, depending on response. The recommended dose of SABRIL in adults is 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events.

Pediatric (Patients 2 to 16 Years of Age):

Body Weight [kg]Total Daily* Starting Dose [mg/day]Total Daily* Maintenance Dose† [mg/day]
10 kg to 15 kg350 mg1050 mg
Greater than 15 kg to 20 kg450 mg1300 mg
Greater than 20 kg to 25 kg500 mg1500 mg
Greater than 25 kg to 60 kg500 mg2000 mg

* Administered in two divided doses

† Maintenance dose is based on 3000 mg/day adult-equivalent dose

†† Patients weighing more than 60 kg should be dosed according to adult recommendations

Infantile Spasms: The initial daily dosing is 50 mg/kg/day given in two divided doses (25 mg/kg twice daily); subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days, up to a maximum of 150 mg/kg/day given in 2 divided doses (75 mg/kg twice daily).

WeightStarting DoseMaximum Dose
[kg]50 mg/kg/day150 mg/kg/day
31.5 mL twice daily4.5 mL twice daily
42 mL twice daily6 mL twice daily
52.5 mL twice daily7.5 mL twice daily
63 mL twice daily9 mL twice daily
73.5 mL twice daily10.5 mL twice daily
84 mL twice daily12 mL twice daily
94.5 mL twice daily13.5 mL twice daily
105 mL twice daily15 mL twice daily
115.5 mL twice daily16.5 mL twice daily
126 mL twice daily18 mL twice daily
136.5 mL twice daily19.5 mL twice daily
147 mL twice daily21 mL twice daily
157.5 mL twice daily22.5 mL twice daily
168 mL twice daily24 mL twice daily

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

  • SABRIL can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, SABRIL may also decrease visual acuity.
  • Risk increases with increasing dose and cumulative exposure, but there is no dose or exposure to SABRIL known to be free of risk of vision loss.
  • Risk of new and worsening vision loss continues as long as SABRIL is used, and possibly after discontinuing SABRIL.
  • Baseline and periodic vision assessment is recommended for patients on SABRIL. However, this assessment cannot always prevent vision damage.
  • SABRIL is available only through a restricted program called the Vigabatrin REMS Program
  • SABRIL can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, SABRIL may also decrease visual acuity.
  • Risk increases with increasing dose and cumulative exposure, but there is no dose or exposure to SABRIL known to be free of risk of vision loss.
  • Risk of new and worsening vision loss continues as long as SABRIL is used, and possibly after discontinuing SABRIL.
  • Baseline and periodic vision assessment is recommended for patients on SABRIL. However, this assessment cannot always prevent vision damage.
  • SABRIL is available only through a restricted program called the Vigabatrin REMS Progra

ADVERSE REACTIONS

Birth Defects: Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes

Ear Disorders: Deafness

Endocrine Disorders: Delayed puberty

Gastrointestinal Disorders: Gastrointestinal hemorrhage, esophagitis

General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure

Hepatobiliary Disorders: Cholestasis

Nervous System Disorders: Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia

Psychiatric Disorders: Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder

Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor

Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), alopecia.

DRUG INTERACTIONS

Phenytoin: Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since SABRIL may cause a moderate reduction in total phenytoin plasma levels.

Clonazepam: SABRIL may moderately increase the Cmax of clonazepam resulting in an increase of clonazepam-associated adverse reactions.

Other AEDs: There are no clinically significant pharmacokinetic interactions between SABRIL and either phenobarbital or sodium valproate. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin.

Oral Contraceptives

SABRIL is unlikely to affect the efficacy of steroid oral contraceptives.

Drug-Laboratory Test Interactions

SABRIL decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by SABRIL may preclude the use of these markers, especially ALT, to detect early hepatic injury.

SABRIL may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).

USE IN SPECIFIC POPULATIONS

Pregnancy: There are no adequate data on the developmental risk associated with the use of SABRIL in pregnant women. Limited available data from case reports and cohort studies pertaining to SABRIL use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, based on animal data, SABRIL use in pregnant women may result in fetal harm.

Lactation: Vigabatrin is excreted in human milk. The effects of SABRIL on the breastfed infant and on milk production are unknown. Because of the potential for serious adverse reactions from vigabatrin in nursing infants, breastfeeding is not recommended. If exposing a breastfed infant to SABRIL, observe for any potential adverse effects.

Pediatric Use: The safety and effectiveness of SABRIL as adjunctive treatment of refractory complex partial seizures in pediatric patients 2 to 16 years of age have been established and is supported by three double-blind, placebo-controlled studies in patients 3 to 16 years of age, adequate and well-controlled studies in adult patients, pharmacokinetic data from patients 2 years of age and older, and additional safety information in patients 2 years of age.

Safety and effectiveness as adjunctive treatment of refractory complex partial seizures in pediatric patients below the age of 2 and as monotherapy for the treatment of infantile spasms in pediatric patients below the age of 1 month have not been established.

Renal Impairment: Dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 2 years of age and older and adults with mild (creatinine clearance >50 to 80 mL/min), moderate (creatinine clearance >30 to 50 mL/min) and severe (creatinine clearance >10 to 30 mL/min) renal impairment.

OVERDOSAGE

Signs, Symptoms, and Laboratory Findings of Overdosage

Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g. Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine.

Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care.

Management of Overdosage

There is no specific antidote for SABRIL overdose. Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage. Supportive measures should be employed, including monitoring of vital signs and observation of the clinical status of the patient.

In an in vitro study, activated charcoal did not significantly adsorb vigabatrin.

The effectiveness of hemodialysis in the treatment of SABRIL overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40% to 60%.

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