General Information

Sabril (vigabatrin) is a selective, irreversible enzyme-activated GABA

transaminase inhibitor. GABA (gamma-aminobutyric acid) is a neurotransmitter in the brain that inhibits the release of dopamine. GABA is broken down by GABA transaminase (GABA-T).

Vigabatrin works by inhibiting GABA-T and consequently increasing the level of the inhibitory neurotransmitter GABA.
Sabril is specifically indicated 1) in a tablet formulation as adjunctive therapy for adult patients 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 and 2) in an oral solution in pediatrics (1 month to 2 years) as monotherapy for infantile spasms for whom the potential benefits outweigh the potential risk of vision loss.

Sabril is supplied as a powder for reconstitution into an oral solution and as a 500 mg tablet. The recommended initial dose is as follows:

Adults with partial seizures:

3 g/day (1.5 g twice daily) oral administration with or without food. Therapy should be initiated at 1 g/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals depending on response. A 6 g/day dose has not been shown to confer additional benefit. Considerations: In patients with mild renal impairment the dose should be decreased by 25%; in patients with moderate renal impairment, the dose should be decreased by 50%; and in patients with severe renal impairment, the dose should be decreased by 75%. Sabril should be withdrawn gradually.

Infantile Spasms:

50 mg/kg/day given in two divided doses (twice daily) oral administration with or without food. Dosing can be titrated by 25-50 mg/kg/day increments every 3 days up to a maximum of 150 mg/kg/day.
Clinical Results

FDA Approval

The FDA approval of Sabril for the treatment of refractory complex partial seizures (CPS) was based on two clinical studies in patients with CPS, with or without secondary generalization, who were on an adequate and stable dose of an anticonvulsant, and had a history of failure on an adequate regimen of carbamazepine or phenytoin. Efficacy was based on the reduction in mean monthly frequency of complex partial seizures plus partial seizures secondarily generalized at end of study compared to baseline.

Study One
This randomized, double-blind, placebo-controlled, dose response study enrolled 174 subjects and consisted of an 8-week baseline period followed by an 18-week treatment period. The subjects were randomized to receive placebo or 1, 3, or 6 g/day vigabatrin administered twice daily. During the first 6 weeks following randomization, the dose was titrated upward beginning with 1 g/day and increasing by 0.5 g/day on days 1 and 5 of each subsequent week in the 3 g/day and 6 g/day groups, until the assigned dose was reached. The 3 g/day and 6 g/day dose groups were statistically significantly superior to placebo (P<0.05). The 6 g/day dose was not superior to the 3 g/day dose.

Study Two
This randomized, double-blind, placebo-controlled, parallel study enrolled 183 subjects and consisted of consisting of an 8-week baseline period and a 16-week treatment period. During the first 4 weeks following randomization, the dose of vigabatrin was titrated upward beginning with 1 g/day and increased by 0.5 g/day on a weekly basis to the maintenance dose of 3 g/day. Vigabatrin 3 g/day was statistically significantly superior to placebo in reducing seizure frequency (P<0.05).
The FDA approval of Sabril for the treatment of infantile spasms was based on two studies.

Study One
This multicenter, randomized, low-dose high-dose, parallel group, partially-blinded study enrolled 221 subjects with new-onset Infantile Spasms. The study was comprised of two phases. The first phase was a 14 to 21 day partially-blind phase in which patients were randomized to receive either low- dose (18-36 mg/kg/day) or high-dose (100-148 mg/kg/day) vigabatrin. Study drug was titrated over 7 days, followed by a constant dose for 7 days. If the patient became spasm-free on or before day 14, another 7 days of constant dose was administered. The primary efficacy endpoint was the proportion of patients who were spasm-free for 7 consecutive days beginning within the first 14 days of vigabatrin therapy. In the high dose group, 17 patients achieved spasm freedom compared with 8 patients in the low dose group. This difference was statistically significant (p=0.0375).

Study Two
This multicenter, randomized, double-blind, placebo-controlled, parallel group study enrolled 40 subjects and consisted of a pre-treatment (baseline) period of 2-3 days, followed by a 5-day double-blind treatment phase during which patients were treated with vigabatrin (initial dose of 50 mg/kg/day with titration allowed to 150 mg/kg/day) or placebo. The primary efficacy endpoint was the average percent change in daily spasm frequency, assessed during a pre-defined and consistent 2- hour window of evaluation, comparing baseline to the final 2 days of the 5-day double-blind treatment phase. No statistically significant differences were observed in the average frequency of spasms using the 2-hour evaluation window. However, a post-hoc alternative efficacy analysis, using a 24-hour clinical evaluation window, found a statistically significant difference in the overall percentage of reductions in spasms between the vigabatrin group (68.9%) and the placebo group (17.0%) (p=0.030).

Final Report Submission: by May 2010

Side Effects

Adverse events associated with the use of Sabril may include, but are not limited to, the following:
• Headache
• Somnolence
• Fatigue
• Dizziness
• Convulsion
• Nasopharyngitis
• Weight increased
• Upper respiratory tract infection

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