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Vigabatrin - What Makes This Drug Different

Complex Partial Seizure - Display

Vigabatrin has been available around the world for nearly 2 decades. It was approved by the U.S. Federal Drug Administration in 2010 for the specific indications of infantile spasms in children as well as refractory partial epilepsy in adults where all other options have failed. 


Vigabatrin’s exact mechanism of action is unknown; however, it is believed that it exerts its anti-seizure effect as a result of its action as an irreversible inhibitor of g-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. There is no direct correlation between the serum concentration of the drug and the effectiveness of the drug. The duration of the drug effect is unique because it is actually dependent on the rate of the individual’s enzyme resynthesis rather than on the rate of elimination of the drug from the systemic circulation. This makes the drug quite different from other agents in that monitoring serum levels are rendered almost obsolete, because the drug is individually tailored to the patient’s physiology based on one’s GABA receptors. 


Effectiveness


VGB is approved for use for 2 particular indications in the United States; complex partial seizures in adults and the other is for infantile spasms in children. 


Infantile Spasms


The effectiveness of vigabatrin in monotherapy for infantile spasms has been established in 2 multi-centered, controlled studies. Both studies were similar in terms of the population studied and seizure characteristics of enrolled patients. In the first study, a multi-centered, randomized, low-dose, high-dose, parallel group, partially blinded, caregivers knew the actual dose, but not whether their child was classified as high- or low-dose; the EEG reader was blinded, but investigators were not blinded; study to evaluate the safety and efficacy of vigabatrin in patients less than 2 years of age with new onset infantile spasms. The total number of children studied was 221. The primary efficacy endpoint of the study was to proportion the patients who were spasm free for 7 consecutive days, beginning within the first 14 days of vigabatrin therapy. Patients with both symptomatic and cryptogenic etiologies were studied with infantile spasms. The study comprised of 2 phases. The first phase was a 14-21 day partially blind phase in which patients were randomized to either receive a low dose, 18-36 mg/kg/day, or a high dose, 100-148 mg/kg/day, of vigabatrin. The 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. Seventeen patients in the high-dose group achieved spasm freedom compared to 8 patients in the low-dose group, which was statistically significant at p=0.0375. 


The second study was a multi-centered, randomized, double-blind, placebo-controlled, parallel group study consisting of a pre-treatment baseline period of 2 to 3 days followed by a 5-day, double-blind, treatment phase during which patients were treated with vigabatrin initial dose of 15 mg/kg/day with a titration allowed to 150 mg/kg/day. The total number of children studied was 40. In the second study, no statistically significant differences were observed in the average frequency of spasms using a 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 of 68.9% and the placebo group of 17% (p=0.030). Based on these 2 studies, the drug was approved for the indication of infantile spasms.


Complex Partial Seizures in Adults


The effectiveness of several as add-on therapy in adult patients with complex partial seizures was established in 2 U.S. multi-centered, double-blind, placebo-controlled, parallel-group clinical studies. A total of 357 adults, age 18 to 60 years, with complex partial seizures with or without secondary generalization were enrolled. 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 either carbamazepine or phenytoin. Patients had a history of about 8 seizures per month for about 20 years prior to entrance into the study.


In the first study, a randomized, double-blind, placebo-controlled dose response study consisting of an 8-week baseline followed by an 18-week treatment period, patients were randomized to receive placebo or 1, 3, or 6 g of vigabatrin per day 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 group and 6 g/day group until the assigned dose was reached. The 3 g/day and 6 g/day dose groups were statistically significantly superior to placebo, but the 6 g/day was not superior to the 3 g/day group. The proportion of patients achieving any particular level of reduction in complex partial seizures was consistently higher for the sample of 3 and 6 g/day group compared to the placebo group. For example, 51% of patients randomized in the sample 3 g/day and 53% of patients randomized in sample 6 g/day experienced a 50% or greater reduction in seizure frequency compared to 9% of patients randomized to placebo.


The second study consisted of 183 randomized patients who were placed in 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. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the sample 3 g/day group compared to the placebo group. For example, 39% of patients randomized in sample 3 g/day (50%) had a greater reduction in complex partial seizures compared to 21% of patients randomized to placebo. 


Adverse Effects


VGB has serious potential adverse effects and carries an FDA black box warning. The drug may cause permanent, bilateral concentric visual field constriction in 30% or more of patients that ranges in severity from mild to severe, including tunnel vision to within 10 degrees of visual fixation and can result in disability. In some cases, VGB may damage the central retina decreasing visual acuity. The onset of visual loss is unpredictable and can occur within weeks of starting treatment or sooner or anytime during treatment, even after months or years. The risk of visual loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of visual loss. Unless the patient is formally exempted from periodic ophthalmologic assessment as documented in a special post-marketing program to tightly assess the adverse effects related to this drug entitled “Share Program,” a formal ophthalmologic assessment every 3 months during therapy is required for adults. Visual assessment is also required about 3-6 months after the discontinuation of therapy. 


Once detected, visual loss is irreversible. It is expected that even with frequent monitoring, some patients could develop severe visual loss. It is possible that visual loss could worsen despite discontinuation of the drug. Because of this risk of permanent visual loss, the drug is available only through a restricted distribution program with a central pharmacy. Physicians who prescribe the drug need to take special educational classes in order to appropriately handle these issues and counsel patients. As a result, because of this risk and because vigabatrin, when it is effective, provides an observable symptomatic benefit, a patient who fails to show substantial benefit within 3 months of initiation of treatment should be withdrawn from the drug. If it is in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time. Patient response to and continued need for treatment should be periodically assessed. This is true for both children and adults. The diagnostic approach to assess and monitor vision has been outlined by the pharmaceutical company. Perimetry is recommended, preferably by automated threshold visual field testing. Additional testing may also include electroretinography, retinal imaging, and other methods, depending on the physician’s choice. In patients exempted from visual testing, the treatment may continue according to clinical judgment with appropriate patient counseling.


Outside of the visual adverse effects, other important adverse effects that need to be considered include the presence of somnolence and fatigue, symptoms of peripheral neuropathy, edema and weigt gain. The average weight gained is 3.5 kilograms and this has been reported in 17% of patients.


Dosing


With regards to dosing, for refractory partial epilepsy, 500 mg of the drug is started as twice-daily oral administration with or without food. The total daily dose may be increased in 500 mg increments at weekly intervals depending on the response. The recommended daily dose of vigabatrin is 3 g/day. It is not approved for higher doses.


In children 1 month to 2 years of age with infantile spasms, the drug can be given as a twice-daily oral administration. The initial daily dose of 15 mg/kg/day given in 2 divided doses and can be titrated by 25-50 mg/kg/day in increments every 3 days up to a maximum of 150 mg/day. 


Summary
Given the risks of visual loss and the fact that the drug has a very tightly controlled central distribution for this agent, this drug can only really be prescribed by a neurologist. It is often now left as a last option choice for adults who have refractory partial epilepsy. In children with infantile spasms, the drug is often utilized much earlier in terms of choices available as the only alternative choice of drug is an oral ACTH gel and therefore vigabatrin has been very beneficial in providing another option for individuals with this devastating epilepsy type.
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