Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the catabolism of GABA, which increases the level of GABA in the synapses.

Vigabatrin is a racemic compound, and its -enantiomer is pharmacologically active.^,

Pharmacokinetics

With most drugs, elimination half-life is a useful predictor of dosing schedules and the time needed to reach steady state concentrations. In the case of vigabatrin, however, it has been found that the half-life of biologic activity is far longer than the elimination half-life.

For vigabatrin, there is no range of target concentrations because researchers found no difference between the serum concentration levels of responders and those of non-responders. Instead, the duration of action is believed to be more a function of the GABA-T resynthesis rate; levels of GABA-T do not usually return to their normal state until six days after stopping the medication.

Uses

Approved/clinically proven

Canada

In Canada, vigabatrin is approved for use as an adjunctive treatment (with other drugs) in treatment resistant epilepsy,complex partial seizures, secondary generalized seizures, and for monotherapy use in infantile spasms in West syndrome.

Mexico

As of 2003, vigabatrin is approved in Mexico for the treatment of epilepsy that is not satisfactorily controlled by conventional therapy (adjunctive or monotherapy) or in recently diagnosed patients who have not tried other agents (monotherapy).

Vigabatrin is also indicated for monotherapy use in secondarily generalized tonic-clonic seizures, partial seizures, and in infantile spasms due to West syndrome.

Unapproved/Investigational

In November of 2001, a team of scientists lead by Peter Zwanzger of the University of Munich reported that vigabatrin reduced cholecystokinin tetrapeptide-induced symptoms of panic disorder, in addition to elevated cortisol and ACTH levels, in healthy volunteers.

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Guideline for prescribing vigabatrin in children has been revised - Brief Article - Statistical Data Included - Letter to the Editor
From British Medical Journal, 5/20/00

EDITOR--In 1998 a paediatric advisory group in the United Kingdom produced a guideline to help clinicians when prescribing vigabatrin in children.[1] The visual field defect reported in association with the drug[2] has now been confirmed in five children treated with it. The paediatric guideline has now been revised and replaced with the one below, which reflects the current opinion of the advisory group.

* The defect is specific--a bilateral and concentric constriction that, within a 30 [degrees] radius from fixation, consists of a nasal loss extending in an annulus over the horizontal midline, with a relative sparing of the temporal field. Its pathogenesis is thought to involve cone and amacrine cell dysfunction in the retina. The prevalence in adults is about 30%[3]; that in children is not established. The relation between the duration of exposure to vigabatrin and the development of the field defect is not known. Neither recovery nor progression of the defect has been confirmed after withdrawal of the drug. Confrontation testing does not reliably identify the defect.

* Children with a cognitive age of [is greater than or equal to] 9 should undergo visual field examination with a Goldmann perimeter (11e or 12e isopter and 14e or V4e isopter) or a Humphrey field analyser (age related, three zone suprathreshold strategy and the 135 point field) before vigabatrin is prescribed and, ideally, every six months, particularly if they continue to take the drug.

* For children aged [is less than] 9 a field specific visual evoked potential technique to assess peripheral vision is being evaluated in children with epilepsy[4] but is not yet routinely available.

* Electroretinography performed according to international standards has shown abnormalities of cone function in adults[5] and may be useful in children.

The continued prescription of vigabatrin remains one of risk versus benefit--the potential risk of the visual field defect developing against the potential benefit of seizure control. One specific risk is the implications of a field defect for driving in a patient with epilepsy who is seizure free.

* Children who have, or are at risk of developing, a visual defect due to other causes (for example, surgery) should be prescribed vigabatrin with caution. Children who are already registered blind, however, will have an altered risk:benefit ratio, possibly in favour of the drug. If the defect is identified the continued use of vigabatrin will depend on the overall clinical situation.

* Children taking vigabatrin whose seizures are well controlled should not automatically have the drug withdrawn. Current evidence suggests that the defect is unlikely to develop if perimetry gives normal results after more than three years of treatment.

* Vigabatrin remains the drug of choice for infantile spasms. Limited data suggest that it could be withdrawn without a relapse in infants who have been spasm free for six months.

* Other therapeutic indications include the treatment of children with partial epilepsy with or without secondary generalisation when other drug combinations have been ineffective or poorly tolerated. Vigabatrin seems to be particularly effective in children with seizures caused by tuberous sclerosis.

* Vigabatrin exacerbates typical absence and myoclonic seizures and should therefore not be prescribed in the idiopathic generalised epilepsies.

Vigabatrin Paediatric Advisory Group

Members of the group are: Richard Appleton, consultant paediatric neurologist, Liverpool (to whom correspondence should be addressed at the Roald Dahl EEG Unit, Alder Hey Children's Hospital, Liverpool L12 2AP); Peter Baxter, consultant paediatric neurologist, Sheffield; David Calver, consultant ophthalmologist, London; Celia Cramp, consultant paediatrician, Shrewsbury; John Gibbs, consultant paediatrician, Chester; Graham Harding, consultant clinical neurophysiologist, Birmingham; John Livingston, consultant paediatric neurologist, Leeds; Richard Robinson, consultant paediatric neurologist, London; Isabelle Russell-Eggitt, consultant paediatric ophthalmologist, London; Sheila Wallace, consultant paediatric neurologist, Cardiff; and John Wild, senior lecturer in vision sciences, Birmingham.

Competing interest: The group is supported by an educational grant from Hoechst Marion Roussel.

[1] Appleton RE. Guideline may help in prescribing vigabatrin. BMJ 1998;317:1322.

[2] Eke T, Talbot JF, Lawden MC. Severe, persistent visual field defect constriction associated with vigabatrin. BMJ 1997;314:180-1.

[3] Wild JM, Martinez C, Reinshagen G, Harding GFA. Characteristics of a unique visual field defect attributed to vigabatrin. Epilepsia 1999;40:1784-94.

[4] Harding GFA, Robertson K, Holliday I, Jones L. Field-specific visual-evoked potentials for assessment of peripheral field defect in a paediatric population. J Physiol 1999;518(P):P171 (abstract).

[5] Krauss GL, Johnson MA, Miller NR. Vigabatrin-associated retinal cone dysfunction. Neurology 1998;50:614-8.

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