Vigabatrin

Sabril (SAB-reel) is the brand name used in the United States and some other countries for the seizure medicine vigabatrin (vi-GAB-a-trin). In the United States, the Food and Drug Administration (FDA) approved vigabatrin in 2009 to be used as a seizure medicine in adults and children with uncontrolled complex partial seizures and children with infantile spasms. In 2013, it was approved or use in children 10 years of age or older with refractory complex partial seizures. Sabril has been available in many countries for decades. The medicine carries warnings about serious visual loss, so it is not a drug of first choice for complex partial seizures.

Vigabatrin has been available around the world for nearly 2 decades. It was approved by the U.S. Federal Drug Administration in 2009 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.

Sabril
Tablet
Sabril Tablets

500-mg (white, film-coated, oval, biconvex, scored on one side, and labeled OV 111)

Liquid Solution
Sabril Packet

For use in babies or children, Sabril comes as 500 mg powder packets to be mixed in 10 ml of water. This makes a solution of 50 mg per ml, which can be given to a child with a syringe without a needle. Pediatric dosage should be initiated at 50 mg/kg/day divided into two daily doses, increasing total daily dose per instructions (for example, by 25-50 mg/kg/day each week) to a maximum of 150 mg/kg/day.

Indications

Sabril (vigabatrin) tablets are indicated as adjunctive (add-on) therapy in the treatment of complex partial seizures (previously called temporal lobe seizures, psychomotor seizures or limbic seizures) in adults, generally taken as 18 years old or older. The medication may be used in complex partial seizures with or without secondary generalization to tonic-clonic seizures. In should only be used after other safer medicines have been found not to work. Usually, Sabril is added when another seizure medicine is not controlling seizures, rather than being used by itself; however, an experienced physician may choose to try Sabril as a single agent in some circumstances. Sabril (vigabatrin) oral solution (mixed from the powder and water) is indicated for children with infantile spasms. Infantile spasms are a type of seizure disorder beginning between 1 month and 2 years of life. The babies have spasms of the limb and neck muscles resulting in sudden flexion or extension of the arms or legs. The seizures are brief, but may cluster. Some episodes are so subtle as to not be recognized as seizures; others are stronger and more obvious. Infantile spasms can be associated with developmental delay (previously called mental retardation) and a characteristic EEG (brainwave) abnormality called hypsarrhythmia. When these three go together, the condition is known as West’s syndrome. Infantile spasms can be of unknown cause or they can be a symptom of another neurological condition, for example, tuberous sclerosis.  Infantile spasms are difficult to treat. Another FDA approved therapy is ACTH ( adrenocorticotropic hormone). This injection has considerable side effects if used for more than a few weeks, and it is increasingly hard to obtain. Other medications have been tried, but evidence of benefit is strongest for vigabatrin, especially when infantile spasms result from tuberous sclerosis.

Forms

Sabril is available in 2 forms: A 500 milligram tablet or a powder meant to be dissolved to create an oral solution.

Sabril is marketed in the United States by Lundbeck. Because of the possibility of sometimes permanent vision loss, the drug can only be prescribed by licensed health care providers who have pre-enrolled in a program to use Sabril (Sabril REMS Program) by calling 1-888-457-4273. The drug can only be obtained through certain specialized and inpatient pharmacies. Information about obtaining the drug and for insurance and reimbursement-related issues can be obtained by contacting the SHAREPlus Program at 1-888-457-4273. If you take a Sabril prescription into a regular pharmacy, it will NOT be filled.

Dosing

Adults with refractory complex partial seizures- the typical starting dose is 500 milligram tablet taken twice a day. The typical recommended dose to stop seizures is 1500 milligrams taken twice a day.

In kids ( ages 10- 16 years of age) with refractory complex partial seizures, the typical starting dose is 250 milligrams twice day. The typical recommended dose is 1000 milligrams twice a day. Treatment dose will depend on the child's weight.

In babies with Infantile spasms, treatment is started at 50 milligrams per kilogram of weight  and the totla daily dose is divided in 2. The total daily dose can be increased to a maximum of 150 milligrams per kilogram per day divided in 2 doses in a day.

How to take and store Vigabatrin?
Missed Doses

See package insert.

Mechanisms of actions of Vigabatrin

See package insert.

Clinical Pharmacology of Vigabatrin

See package insert.

Efficacy of Vigabatrin

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

Common side effects of Vigabatrin

See package insert.

Serious Side effects of Vigabatrin

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 a 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), formal ophthalmologic assessment within 4 weeks of starting Sabril and 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 using specialized and some inpatient pharmacies. Licensed health care providers who prescribe the drug must be enrolled with the Sabril REMS Program. 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.

Vigabatrin Contraindications

See package insert.

Impact of Vigabatrin on bone health

See package insert.

Vigabatrin Interactions with other medications

See package insert.

Vigabatrin effects on Children

See package insert.

Vigabatrin and Pregnancy

See package insert.

Vigabatrin effects on Seniors

See package insert.

Vigabatrin Dosing and titration

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.

Vigabatrin Package insert

"In the United States, companies that manufacture medicines are required to publish certain kinds of information about each product. This document is commonly known as a “package insert” because it is usually included with each package of the medicine. You can also read these documents (also called ""prescribing information"") online. The U.S. package insert for Sabril is found at:

To learn how to read and understand a package insert, see "How to read a package insert"

Vigabatrin References for Professionals

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