• Sabril

• Antiepileptic drug (AED)

• Adjunctive therapy for adults and pediatric patients ≥10 years of age 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
• Monotherapy for pediatric patients (1 month-2 years of age) with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss (Solution)   

General Notes: Take with or without food.  Either tablet or powder for oral solution can be used for complex partial seizures. Use powder for oral solution for infantile spasms; do not use tablets

• Refractory complex partial seizures, >16 years:
• 1000 mg/day (500 mg twice daily)
• May increase total daily dose in 500 mg increments at weekly intervals to a recommended dose of 3000 mg/day (1500 mg twice daily)

• Infantile spasms:  
• 50 mg/kg/day given in 2 divided doses
• Subsequent dosing can be titrated by 25-50 mg/kg/day increments every 3 days
• Maximum: 150 mg/kg/day in 2 divided doses
• Refractory complex partial seizures, 10-16 years:  
• 25-60 kg: 500 mg/day (250 mg twice daily)
• May increase weekly to a total maintenance dose of 2000 mg/day (1000 mg twice daily) 
• >60 kg: Dose according to adult recommendations
  

• Mild, ClCr >50-80 mL/min:  
• Decrease dose by 25%
• Moderate, ClCr>30-50 mL/min:  
• Decrease dose by 50%
• Severe, ClCr >10-30 mL/min:  
• Decrease dose by 75%
  

• None

• Tablet:  500 mg
• Powder for Oral Solution:  500 mg/pkt [50S}
  

• Vigabatrin causes permanent bilateral concentric visual field constriction. Because assessing vision may be difficult in infants and children, the frequency and extent of vision loss is poorly characterized in these patients. For this reason, the risk described below is primarily based on the adult experience.
• Based upon adult studies, 30 percent or more of patients can be affected, ranging in severity from mild to severe, including tunnel vision to within 10 degrees of visual fixation, and can result in disability. In some cases, vigabatrin also can damage the central retina and may decrease visual acuity. 
• The onset of vision loss from vigabatrin is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years. 
• Symptoms of vision loss from vigabatrin are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function. 
• The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss. 
• Unless a patient is formally exempted from periodic ophthalmologic assessment as documented in the SHARE program, vision should be assessed to the extent possible at baseline (no later than 4 weeks after starting vigabatrin) and at least every 3 months during therapy. Vision assessment is also required about 3 to 6 months after the discontinuation of vigabatrin therapy. 
• Once detected, vision loss due to vigabatrin is not reversible. It is expected that, even with frequent monitoring, some patients will develop severe vision loss. 
• Drug discontinuation should be considered, balancing benefit and risk, if visual loss is documented. 
• It is possible that vision loss can worsen despite discontinuation of vigabatrin. 
• Because of the risk of visual loss, vigabatrin should be withdrawn from patients with refractory complex partial seizures who fail to show substantial clinical benefit within 3 months of initiation and within 2-4 weeks of initiation for patients with infantile spasms, or sooner if treatment failure becomes obvious. Patient response to and continued need for vigabatrin should be periodically reassessed. 
• Vigabatrin should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks. The interaction of other types of irreversible vision damage with vision damage from vigabatrin has not been well-characterized, but is likely adverse. 
• Vigabatrin should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks. 
• The possibility that vision loss from vigabatrin may be more common, more severe or have more severe functional consequences in infants and children than in adults cannot be excluded. 
• The lowest dose and shortest exposure to vigabatrin consistent with clinical objectives should be used. 
• Because of the risk of permanent vision loss, vigabatrin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SHARE Program

• None

• Coma, unconsciousness, and/or drowsiness common symptoms.  Other symptoms may include:  vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder.  
• Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage.  

• None

• Category C  

• Vigabatrin is excreted in human milk.  A decision should be made whether to discontinue nursing or to discontinue the drug.    

• Scientific Name: Racemate consisting of two enantiomers:  (±)4-amino-5-hexenoic acid.  
• Empirical Formula: C6H11NO2 
• Molecular Weight: 129.16

• Vigabatrin displayed linear pharmacokinetics after administration of single doses ranging from 0.5 g to 4 g, and after administration of repeated doses of 0.5 g and 2.0 g twice daily. Bioequivalence has been established between the oral solution and tablet formulations. The following PK information (Tmax, half-life, and clearance) of vigabatrin was obtained from stand-alone PK studies and population PK analyses.  
• Absorption: Following oral administration, vigabatrin is essentially completely absorbed.  The time to maximum concentration (Tmax) is approximately 1 hour for children (10 years-16 years) and adults, and approximately 2.5 hours for infants (5 months-2 years).  There was little accumulation with multiple dosing in adult and pediatric patients.  A food effect study involving administration of vigabatrin to healthy volunteers under fasting and fed conditions indicated that the Cmax was decreased by 33%, Tmax was increased to 2 hours, and AUC was unchanged under fed conditions.  
• Distribution: Vigabatrin does not bind to plasma proteins. Vigabatrin is widely distributed throughout the body; mean steady-state volume of distribution is 1.1 L/kg (CV = 20%). 
• Metabolism: Vigabatrin is not significantly metabolized.  
• Elimination: Vigabatrin is eliminated primarily through renal excretion. The terminal half-life of vigabatrin is about 5.7 hours for infants (5 months - 2 years), 9.5 hours for children (10 years - 16 years), and 10.5 hours for adults.  Following administration of [14]C-vigabatrin to healthy male volunteers, about 95% of total radioactivity was recovered in the urine over 72 hours with the parent drug representing about 80% of this. Vigabatrin induces CYP2C9, but does not induce other hepatic cytochrome P450 enzyme systems. 
• Special Populations
• Geriatric: The renal clearance of vigabatrin in healthy elderly patients (≥65 years of age) was 36% less than those in healthy younger patients.  This finding is confirmed by an analysis of data from a controlled clinical trial. 
• Pediatric: The clearance of vigabatrin is 2.4 L/hr for infants (5 months-2 years), 5.8 L/hr for children (10 years-16 years) and 7 L/hr for adults.
• Gender: No gender differences were observed for the pharmacokinetic parameters of vigabatrin in patients.  
• Race: No specific study was conducted to investigate the effects of race on vigabatrin pharmacokinetics. A cross study comparison between 23 Caucasian and 7 Japanese patients who received 1, 2, and 4 g of vigabatrin indicated that the AUC, C max, and half-life were similar for the two populations.  However, the mean renal clearance of Caucasians (5.2 L/hr) was about 25% higher than the Japanese (4.0 L/hr).  Inter-subject variability in renal clearance was 20% in Caucasians and was 30% in Japanese.  
• Renal Impairment: Mean AUC increased by 30% and the terminal half-life increased by 55% (8.1 hr vs 12.5 hr) in adult patients with mild renal impairment (ClCr from >50-80 mL/min) in comparison to normal subjects.
• Mean AUC increased by two-fold and the terminal half-life increased by two-fold in adult patients with moderate renal impairment (ClCr from >30-50 mL/min) in comparison to normal subjects. 
• Mean AUC increased by 4.5-fold and the terminal half-life increased by 3.5-fold in adult patients with severe renal impairment (ClCr from >10-30 mL/min) in comparison to normal subjects. 
• Adult patients with renal impairment: Dosage adjustment, including starting at a lower dose, is recommended for adult patients with any degree of renal impairment.  
• Infants with renal impairment: Information about how to adjust the dose in infants with renal impairment is unavailable. 
• Pediatric patients 10 years and older with renal impairment: Although information is unavailable on the effects of renal impairment on vigabatrin clearance in pediatric patients 10 years and older, dosing can be calculated based upon adult data and an established formula 
• Hepatic Impairment: Vigabatrin is not significantly metabolized. The pharmacokinetics of vigabatrin in patients with impaired liver function has not been studied.        

• Vigabatrin (Sabril).  Product Insert.  Lundbeck.  Deerfield, IL.  2013.