This supplement provides a comprehensive overview and review of vigabatrin, from mechanism of action to clinical development to benefit–risk considerations. Given the long and storied history of vigabatrin during the last 35 years, it is both important and timely to offer up-to-date reviews of the efficacy and safety of vigabatrin, along with expert opinions about the place of vigabatrin in antiepileptic drug (AED) therapy.
Vigabatrin, a molecule first synthesized in 1974, is an irreversible inhibitor of γ-aminobutyric acid (GABA) transaminase (1–3). Structurally identical to GABA except for the addition of a vinyl group, vigabatrin was designed specifically to increase concentrations of GABA in the brain and thereby inhibit epileptogenic circuits and decrease seizure frequency.
Global development history
Initially licensed in the UK and Ireland in 1989, vigabatrin is available in more than 50 countries (4–7). It was approved for use in the United States as adjunctive therapy for adult patients with refractory complex partial seizures (rCPS) in 2009 for those who have responded inadequately to several alternative treatments and as monotherapy for patients 1 month to 2 years of age with infantile spasms (IS) (8, 9). For both indications, vigabatrin should be considered for those for whom the potential benefits outweigh the risk of vision loss. In Europe, vigabatrin is approved as treatment in combination with other AEDs for patients with resistant partial epilepsy with or without secondary generalization (i.e., when all other appropriate drug combinations have proved inadequate or have not been tolerated) and as monotherapy in the treatment of IS (10). More than two million patients worldwide have received vigabatrin therapy.
After vigabatrin-associated effects on peripheral vision were reported (11), restrictions on the use of vigabatrin were put in place in Europe (10). The current Summary of Product Characteristics (SmPC) indicates (via a special warning) that, because of the risk of visual field defect, “vigabatrin should only be used after a careful assessment of the balance of benefits and risk compared with alternatives” (10). Further, the SmPC states that “vigabatrin is not recommended for use in patients with any pre-existing clinically significant visual field defect” and that “patients should undergo systematic screening examination when starting vigabatrin and at regular intervals for detection of visual field defects” (10).
Clinical development of vigabatrin in the United States began in 1980, but a regulatory delay occurred in 1983 because of the observation of intramyelinic edema in rodents and dogs receiving vigabatrin (4). US clinical trials resumed in 1990 after a review of additional data revealed no evidence of intramyelinic edema in humans. A second regulatory delay occurred after vigabatrin-associated peripheral visual field defects (pVFDs) were reported in 1997 (11). The Food and Drug Administration (FDA) withheld approval of vigabatrin until additional information on pVFDs could be gathered and analyzed (4, 12). Much research has been conducted to characterize vigabatrin-associated pVFDs. In 2009, vigabatrin (brand name Sabril®) was approved by the FDA in conjunction with a comprehensive Risk Evaluation and Mitigation Strategy (REMS) to decrease the risk of vigabatrin-associated vision loss while providing benefit–risk analyses for appropriate patient populations (8, 9).
Vigabatrin was designated as an orphan drug by the US FDA for use in treating IS in 2000. A drug is eligible for orphan drug designation if it is intended to treat a disease or condition that affects <200,000 people in the United States. Ovation Pharmaceuticals, Inc., acquired the North American rights to vigabatrin from Sanofi-Aventis (Paris, France) in 2004, and H Lundbeck A/S (Valby, Denmark) acquired Ovation (now Lundbeck Inc., Deerfield, IL, USA) early in 2009. Sabril® is made available in the United States by Lundbeck Inc.
Epilepsy, refractory complex partial seizures, and infantile spasms
Epilepsy is a common neurologic disorder with a cumulative incidence of more than 3% in the general population (13). The estimated incidence of epilepsy in the developed world is 40–70 per 100,000 persons, and the estimated prevalence is 5–10 per 1,000 persons (14). In the United States, 1 in 26 people will develop epilepsy during his or her lifetime (13).
Approximately 35% of patients with epilepsy experience CPS (15). CPS initiates focally and spreads to other regions within the brain to cause impairment of consciousness. More than 30% of patients with CPS are refractory to treatment (16). rCPS can have devastating consequences, including greater risk of bodily injury, shortened lifespan, and sudden unexpected death in epilepsy (17–19).
Infantile spasms, also known as West syndrome, are a rare subtype of epilepsy with onset during infancy (20, 21). The estimated incidence of IS is 2 to 3.5 per 10,000 live births. Peak age of onset is between 3 and 7 months, and 90% of infants with IS present before age 12 months (21). IS is characterized by flexor, extensor, and mixed flexor–extensor spasms; a distinct electroencephalography pattern of hypsarrhythmia; and psychomotor delay (20, 21). Reported mortality rates for patients with IS range from 5% to 31% (22). Although IS generally does not persist into adulthood, 50% to 70% of patients develop other seizures types. The majority (70–90%) of adults with a history of IS also experience learning difficulties or mental retardation.
Mechanism of action and efficacy
In the first article in the supplement, Ben-Menachem (23) reviews the mechanism of action of vigabatrin and provides a historical perspective on the role of GABA in epilepsy and the development of AEDs. Vigabatrin was rationally designed and has a well-characterized mechanism of action, contrary to the fairly common misperception that the compound’s antiepileptic effects are unknown or non-specific.
Vigabatrin is effective as adjunctive therapy for adult patients with rCPS who have responded inadequately to several alternative treatments. Well-controlled trials in Europe and the United States demonstrated statistically significant decreases in seizure frequency with the addition of vigabatrin 3 or 6 g/day compared with placebo. Response to therapy was generally observed within 12 weeks of starting vigabatrin. European and US trials are reviewed by Ben-Menachem and Sander (24), and by Faught (25), respectively, in this supplement.
Vigabatrin is also effective as monotherapy for patients 1 month to 2 years of age with IS. Well-controlled trials of vigabatrin dosages generally ranging from 100 to 150 mg/kg per day demonstrated efficacy to decrease spasms and eliminate hypsarrhythmic electroencephalography in patients with newly diagnosed IS. Response to therapy generally occurred within 2 weeks of starting vigabatrin. Trials of vigabatrin for IS are reviewed in this supplement by Carmant (26).
Peripheral visual field defects and safety
Despite its efficacy, vigabatrin is associated with the risk of progressive, permanent bilateral concentric pVFDs (27). Sergott and Westall (28) review visual field testing procedures and electroretinography, summarize the clinical characteristics of vigabatrin-associated pVFDs, and provide recommendations for visual field and visual electrophysiology testing for vigabatrin-treated patients.
To delineate the prevalence of pVFDs directly associated with vigabatrin, Plant and Sergott (29) examine the development of pVFDs in both vigabatrin-treated and vigabatrin-naïve patients with epilepsy. The development of pVFDs in vigabatrin-naïve patients is infrequent but suggests that visual loss unrelated to vigabatrin does occur and may be attributed to confounding factors such as background disease, concomitant medications, and method of vision assessment. Drs. Plant and Sergott also review evidence suggesting an association between vigabatrin-associated retinal toxicity and taurine deficiency.
Although pVFDs are the main safety issue for vigabatrin, other adverse events of interest detected during preclinical or clinical development of vigabatrin include intramyelinic edema and neuropsychiatric effects. Walker and Kälviäinen (30) review the non-vision adverse event profile of vigabatrin in rCPS and IS.
Finally, as with all AEDs, the benefit of improved seizure control must be balanced against the potential risks associated with vigabatrin. Pellock (31) reviews the benefit–risk considerations for vigabatrin in the final article in this supplement. As part of the REMS administered through the Lundbeck Inc. Support, Help And Resources for Epilepsy program, all US patients treated with vigabatrin are required to enroll in a patient registry and undergo regular vision monitoring. Because response to treatment typically occurs much more rapidly (i.e., within 12 weeks for rCPS and 1–2 weeks for IS) than the onset of a vigabatrin-associated pVFD, the risk of developing pVFDs may be minimized by discontinuing vigabatrin early during the course of therapy for patients who experience inadequate clinical response. Given the serious consequences of rCPS and uncontrolled IS and the demonstrated efficacy of vigabatrin for these indications, careful consideration of the potential benefits and risks of vigabatrin for individual patients should help guide appropriate treatment decisions.
We hope that readers will find this supplement timely and instructive and that the contents of the supplement will help inform treatment decisions regarding the use of vigabatrin for appropriate patient populations. Vigabatrin is one of the most well-studied AEDs. However, the literature on its relevant issues is quite disperse and spans several decades. The authors, who are among the leading experts on vigabatrin in Europe, Canada, and the United States, have attempted to bring this wealth of knowledge together in one place to provide a comprehensive view of the unique and intricate considerations involved in the use of vigabatrin.