Few experiences match the drama of a convulsive seizure. A person having a severe seizure may cry out, fall to the floor unconscious, twitch or move uncontrollably, drool, or even lose bladder control. Within minutes, the"...
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.
Effects on Electrocardiogram
There is no indication of a QT/QTc prolonging effect of SABRIL (vigabatrin oral solution) in single doses up to 6.0 g. In a randomized, placebo-controlled, crossover study, 58 healthy subjects were administered a single oral dose of SABRIL (vigabatrin oral solution) (3 g and 6 g) and placebo. Peak concentrations for 6.0 g SABRIL (vigabatrin oral solution) were approximately 2-fold higher than the peak concentrations following the 3.0 g single oral dose.
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 with a half-life of about 7.5 hours. Bioequivalence has been established between the oral solution and tablet formulations.
Following oral administration, vigabatrin is essentially completely absorbed. Time to maximum concentration (tmax) is approximately 1 hour following single and multiple doses. There was little accumulation with multiple dosing. 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 [see DOSAGE AND ADMINISTRATION].
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 and Elimination
Vigabatrin is not significantly metabolized; it is eliminated primarily through renal excretion. The half-life of vigabatrin is about 7.5 hours. Following administration of 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.
Pharmacokinetics in Special Populations
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.
No gender differences were observed for the pharmacokinetic parameters of vigabatrin in patients.
No specific study was conducted to investigate the effects of race on SABRIL (vigabatrin oral solution) 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, Cmax, 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.
Mean AUC increased by 30% and the terminal half-life increased by 55% (8.1 hr vs 12.5 hr) in 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 twofold in 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 patients with severe renal impairment (CLcr from > 10-30 mL/min) in comparison to normal subjects.
Dosage adjustment, including starting at a lower dose, is recommended for patients with any degree of renal impairment [see Use In Specific Populations, Renal Impairment and DOSAGE AND ADMINISTRATION, Patients with Renal Impairment].
Vigabatrin is not significantly metabolized. The pharmacokinetics of vigabatrin in patients with impaired liver function have not been studied.
A 16% to 20% average reduction in total phenytoin plasma levels was reported in controlled clinical studies. In vitro drug metabolism studies indicate that decreased phenytoin concentrations upon addition of vigabatrin therapy are likely to be the result of induction of cytochrome P450 2C enzymes in some patients. Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated.
When co-administered with vigabatrin, phenobarbital concentration (from phenobarbital or primidone) was reduced by an average of 8% to 16%, and sodium valproate plasma concentrations were reduced by an average of 8%. These reductions did not appear to be clinically relevant. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin.
In a study of 12 healthy volunteers, clonazepam (0.5 mg) co-administration had no effect on SABRIL (vigabatrin oral solution) (1.5 g twice daily) concentrations. SABRIL (vigabatrin oral solution) increases the mean Cmax of clonazepam by 30% and decreases the mean tmax by 45%.
Co-administration of ethanol (0.6 g/kg) with vigabatrin (1.5 g twice daily) indicated that neither drug influences the pharmacokinetics of the other.
In a double-blind, placebo-controlled study using a combination oral contraceptive containing 30 µg ethinyl estradiol and 150 µg levonorgestrel, vigabatrin (3 g/day) did not interfere significantly with the cytochrome P450 isoenzyme (CYPSA)-mediated metabolism of the contraceptive tested. Based on this study, vigabatrin is unlikely to affect the efficacy of steroid oral contraceptives. Additionally, no significant difference in pharmacokinetic parameters (elimination half-life, AUC, Cmax, apparent oral clearance, time to peak, and apparent volume of distribution) of vigabatrin were found after treatment with ethinyl estradiol and levonorgestrel.
Complex Partial Seizures in Adults
The effectiveness of SABRIL (vigabatrin oral solution) as adjunctive therapy in adult patients with CPS was established in two U.S. multicenter, double-blind, placebo-controlled, parallel-group clinical studies. A total of 357 adults (age 18 to 60 years) with CPS, with or without secondary generalization were enrolled (Studies 1 and 2). Patients were required to be on an adequate and stable dose of an anticonvulsant, and have a history of failure on an adequate regimen of carbamazepine or phenytoin. Patients had a history of about 8 seizures per month (median) for about 20 years (median) prior to entrance into the study. These studies were not capable by design of demonstrating direct superiority of SABRIL (vigabatrin oral solution) over any other anticonvulsant added to a regimen to which the patient had not adequately responded. Further, in these studies patients had previously been treated with a limited range of anticonvulsants.
The primary measure of efficacy was the patient's reduction in mean monthly frequency of complex partial seizures plus partial seizures secondarily generalized at end of study compared to baseline.
Study 1 (N=174) was a randomized, double-blind, placebo-controlled, dose-response study consisting of an 8-week baseline period followed by an 18-week treatment period. Patients 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.
Results for the primary measure of effectiveness, reduction in mean monthly frequency of Complex Partial Seizures, are shown in Table 4. The 3 g/day and 6 g/day dose groups were statistically significantly superior to placebo, but the 6 g/day dose was not superior to the 3 g/day dose.
Table 4. Median Monthly Frequency of Complex Partial Seizures+
|1 g/day SABRIL||45||8.5||7.7|
|3 g/day SABRIL||41||8.5||3.7*|
|6 g/day SABRIL||43||8.5||4.5*|
| *P < 0.05 compared to placebo
+lncluding one patient with simple partial seizures with secondary generalization only
Figure 1 presents the percentage of patients (X-axis) with a percent reduction in seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in complex partial seizure frequency was consistently higher for the SABRIL (vigabatrin oral solution) 3 and 6 g/day groups compared to the placebo group. For example, 51% of patients randomized to SABRIL (vigabatrin oral solution) 3 g/day and 53% of patients randomized to Sabril (vigabatrin oral solution) 6 g/day experienced a 50% or greater reduction in seizure frequency, compared to 9% of patients randomized to placebo. Patients with an increase in seizure frequency > 100% are represented on the Y-axis as equal to or greater than -100%.
Figure 1. Percent Reduction from Baseline in Seizure Frequency
Study 2 (N=183 randomized, 182 evaluated for efficacy) was a randomized, double-blind, placebo-controlled, parallel study 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.
Table 5. Median Monthly Frequency of Complex Partial Seizures
|3 g/day SABRIL||92||8.3||5.5*|
|*P < 0.05 compared to placebo|
Results for the primary measure of effectiveness, reduction in mean monthly complex partial seizure frequency, are shown in Table 5. Vigabatrin 3 g/day was statistically significantly superior to placebo in reducing seizure frequency.
Figure 2 presents the percentage of patients (X-axis) with a percent reduction in seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the SABRIL (vigabatrin oral solution) 3 g/day group compared to the placebo group. For example, 39% of patients randomized to SABRIL (vigabatrin oral solution) (3 g/day) experienced a 50% or greater reduction in complex partial seizure frequency, compared to 21% of patients randomized to placebo. Patients with an increase in seizure frequency > 100% are represented on the Y-axis as equal to or greater than -100%.
Figure 2. Percent Reduction from Baseline in Seizure Frequency
For both studies, there was no difference in the effectiveness of vigabatrin between male and female patients. Analyses of age and race were not possible as nearly all patients were between the ages of 18 to 65 and Caucasian.
Last reviewed on RxList: 3/7/2011
This monograph has been modified to include the generic and brand name in many instances.
Additional Sabril Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find tips and treatments to control seizures.