Vigabatrin

γ-vinyl-GABA

UK-SmPC: (1) monotherapy in the treatment of infantile spasms and (2) treatment in combination with other anti-epileptic drugs for patients with resistant partial epilepsy with or without secondary generalisation, where all other appropriate drug combinations have proved inadequate or have not been tolerated.

FDA-PI: not yet licensed, but expected soon.

• initial treatment of choice for infantile (epileptic) spasms
• used cautiously in the treatment of patients with intractable focal seizures that have failed to respond to all other appropriate AED combinations and surgical procedures.1,2

Adults: start treatment with 500 mg/day and titrate in increments of 500 mg/day every week. Typical adult maintenance dose is 1000–3000 mg/day given in two equally divided doses.

Because the excretion is mainly renal, the dose should be reduced in patients with renal insufficiency and creatinine clearance

Children with infantile spasms: start treatment with 50 mg/kg/day and adjust according to the response over 7 days, up to a total of 150–200 mg/kg/day.

Dosing: despite its short half-life (5–7 hours), vigabatrin may be given once or twice daily, because inhibition of GABA-T results in a relatively long duration of action, and GABA levels in the CSF can remain elevated for up to 120 hours after a single oral dose.

TDM: unnecessary; useful only to check compliance.18,19

Reference range: 6–278 μmol/l, which is irrelevant in clinical practice.

• Visual field defects 9,16
  • high prevalence of visual field defects occurring in around one-third of patients (adults and children)16 treated with vigabatrin
  • also produces retinal electrophysiological changes in nearly all patients.4,5,17
  • Visual field loss resulting from vigabatrin is not usually reversible. However, visual acuity, colour vision and the loss of amplitude on the electroretinogram may be reversible in patients with minimal or no visual field loss. There is some evidence that visual field defects remain stable with continuous treatment. It is, therefore, feasible to continue treatment with vigabatrin in these cases, provided visual field monitoring is performed regularly.15
  • In one study involving 24 children treated with vigabatrin, visual field constriction or abnormal ocular electrophysiological studies were seen in over 50% of cases.16
  • The mechanism of vigabatrin-induced visual field defects are probably due to reversible oedema of the myelin in the optic nerves, retinal cone system dysfunction or both.
• Other ADRs include sedation, dizziness, headache, ataxia, paraesthesiae, memory, cognitive and behavioural disturbances, weight gain and tremor
• There is no evidence of idiosyncratic ADRs.

The anti-epileptic activity of vigabatrin is by selective and irreversible inhibition of GABA-T, thus preventing the breakdown of GABA. Vigabatrin produces dose-dependent increases in GABA concentrations in the CSF and decreases in GABA-T activity. Raised brain GABA levels inhibit the propagation of abnormal hypersynchronous seizure discharges.

Vigabatrin may also cause a decrease in excitationrelated amino acids.

• Oral bioavailability: 80–100%
• Protein binding: none
• Metabolism: it is not metabolised and 70% is excreted unchanged in the urine. It is eliminated by the kidneys by glomerular filtration
• Elimination half-life: 5–8 hours (not clinically important).

There are no drug interactions of any clinical significance, except for lowering the concentration of phenytoin.

• Pregnancy: category C
• Breastfeeding: only small amounts of the drug are excreted in breast milk
• Interactions with hormonal contraception: none.

• Visual field defects have virtually eliminated vigabatrin from common clinical practice except for infantile spasms
• Aggravation of seizures: vigabatrin is a pro-absence agent which aggravates absence seizures and provokes absence status epilepticus.14 This alone would prohibit use of vigabatrin in IGEs with absences.

Vigabatrin, in addition to its aggravation effect on typical absence seizures, may also exaggerate atypical absences (such as those occurring in Lennox–Gastaut syndrome) and myoclonic seizures (such as those occurring in progressive or non-progressive myoclonic epilepsies).

Visual field defects may not be clinically detectable. Therefore, patients should be monitored with perimetry prior to and every 6 months during vigabatrin treatment. Electrophysiological testing is considered to be more accurate than perimetry for the direct vigabatrin effect on the outer retina.17The manufacturers provide a procedure for testing children.

Numerous RCTs failed to detect common and serious visual field defects Vigabatrin was used as and adjunctive medication in the treatment of focal epilepsies from 1989, when it was first licensed in Europe. Concern over neuropathological findings of microvacuolisation of white matter in animals caused trials of vigabatrin to be halted in 1983, but trials were resumed when a lack of evidence (including visualevoked responses) for toxicity in humans was found.

Numerous RCTs (mostly of class I and II in the ratings of ‘therapeutic articles’)3-10 were all consistent in their conclusion that vigabatrin was a ‘relatively safe drug with a relatively benign adverse-effect profile’. They all failed to identify vigabatrin-associated irreversible visual field defects. It was astute clinicians who first reported these serious ADRs,9 but even after this report had been published, a class I RCT found vigabatrin to be ‘less effective but better tolerated than carbamazepine’.10 Results of proper testing for visual field defects are not given; that the patients did not have abnormalities on visual confrontation testing is not reassuring. When such ADRs come to light, good clinical practice mandates that patients are informed and offered the appropriate testing. Visual field testing performed by a protocol amendment post hoc (after termination of another RCT) showed abnormalities in 10% of vigabatrin-treated patients.11

Authorities failed to warn of the pro-absence effects of vigabatrin That vigabatrin is a pro-absence AED should be evident by its action on GABAB receptors. No such warning was given to practising physicians,13 who only discovered this effect when patients with IGEs experienced significant deterioration and absence status epilepticus.4

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