Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Aventis Pharma Limited, 410 Thames Valley Park Drive, Reading, Berkshire. RG6 1PT, UK Trading as: Sanofi, 410 Thames Valley Park Drive, Reading, Berkshire. RG6 1PT, UK
Pharmacotherapeutic group: Antiepileptics
ATC code: N03AG04
Vigabatrin is an antiepileptic medicinal product with a clearly defined mechanism of action. Treatment with vigabatrin leads to an increase in the concentration of GABA (gamma aminobutyric acid), the major inhibitory neurotransmitter in the brain. This is because vigabatrin was designed rationally as a selective irreversible inhibitor of GABAtransaminase, the enzyme responsible for the breakdown of GABA.
Controlled and longterm clinical trials have shown that vigabatrin is an effective anticonvulsant agent when given as addon therapy in patients with epilepsy not controlled satisfactorily by conventional therapy. This efficacy is particularly marked in patients with seizures of partial origin.
Epidemiology of VFD in patients with refractory partial epilepsy was observed in an observational, open-label, multicentre, comparative, parallel group, Phase IV study, including 734 patients, at least 8 years old, with refractory partial epilepsy for at least one year.
Patients were split in three treatment groups: patients currently treated with vigabatrin (group I), patients previously exposed to vigabatrin (group II) and patients never exposed to vigabatrin (group III). The following table presents the main findings at inclusion and the first and last conclusive evaluations in the evaluable population (n=524):
| Children (from 8 to 12 years old) | Adults (>12 years old) | |||||
|---|---|---|---|---|---|---|
| Group I1 | Group II2 | Group III | Group I3 | Group II4 | Group III | |
| N=38 | N=47 | N=41 | N=150 | N=151 | N=97 | |
| Visual field defect with non-identified aetiology | ||||||
| Observed at inclusion | 1 (4.4%) | 3 (8.8%) | 2 (7.1%) | 31 (34.1%) | 20 (19.2%) | 1 (1.4%) |
| Observed at first conclusive evaluation | 4 (10.5%) | 6 (12.8%) | 2 (4.9%) | 59 (39.3%) | 39 (25.8%) | 4 (4.1%) |
| Observed at last conclusive evaluation | 10 (26.3%) | 7 (14.9%) | 3 (7.3%) | 70 (46.7%) | 47 (31.1%) | 5 (5.2%) |
1 Median treatment duration: 44.4 months, mean daily dose 1.48 g
2 Median treatment duration: 20.6 months, mean daily dose 1.39 g
3 Median treatment duration: 48.8 months, mean daily dose 2.10 g
4 Median treatment duration: 23.0 months, mean daily dose 2.18 g
Vigabatrin is a water soluble compound and it is rapidly and completely absorbed from the gastrointestinal tract. Food administration does not alter the extent of vigabatrin absorption. Time to reach maximum plasma concentrations (tmax) is approximately 1 hour.
Vigabatrin is widely distributed with an apparent volume of distribution slightly greater than total body water. Binding to plasma proteins is negligible.Plasma and cerebrospinal fluid concentrations are linearly related to dose over the recommended dose range.
Vigabatrin is not significantly metabolised. No metabolites have been identified in plasma.
Vigabatrin is eliminated via renal excretion with a terminal half-life of 5-8 . Oral clearance (CI/F) of vigabatrin is approximately 7 L/h (i.e. 0.10 L/h.kg). Approximately 70% of a single oral dose was recovered as unchanged drug in the urine in the first 24 hours post-dose.
There is no direct correlation between plasma concentration and efficacy. The duration of the effect of the drug is dependent on the GABA transaminase re-synthesis rate.
Pharmacokinetic properties of vigabatrin have been investigated in groups of six neonates (age 15-26 days), six infants (age 5-22 months) and six children (age 4.6-14.2 years) with refractory epilepsy. After administration of a single 37-50 mg/kg dose of an oral solution vigabatrin tmax was approximately 2.5 hours in neonates and infants, and 1 hour in children. Mean terminal half-life of vigabatrin was about 7.5 hours in neonates, 5.7 hours in infants and 5.5 hours in children. The mean Cl/F of active S-enantiomer of vigabatrin in infants and children was 0.591 L/h/kg and 0.446 L/h/kg, respectively.
Animal safety studies carried out in the rat, mouse, dog and monkey have indicated that vigabatrin has no significant adverse effects on the liver, kidney, lung, heart or gastrointestinal tract.
In the brain, microvacuolation has been observed in white matter tracts of rat, mouse and dog at doses of 30-50mg/kg/day. In the monkey these lesions are minimal or equivocal. This effect is caused by a separation of the outer lamellar sheath of myelinated fibres, a change characteristic of intramyelinic oedema. In both rat and dog the intramyelinic oedema was reversible on stopping vigabatrin treatment and even with continued treatment histologic regression was observed. However, in rodents, minor residual changes consisting of swollen axons (eosinophilic spheroids) and mineralised microbodies have been observed. In the dog, the results of an electrophysiological study indicate that intramyelinic oedema is associated with an increase in the latency of the somatosensory evoked potential which is reversible when the medicinal product is withdrawn.
Vigabatrin-associated retinotoxicity has only been observed in albino rats, but not in pigmented rats, dogs or monkeys. The retinal changes in albino rats were characterised as focal or multifocal disorganisation of the outer nuclear layer with displacement of nuclei into the rod and cone area. The other layers of retina were not affected. These lesions were observed in 80- 100% of animals at the dose of 300mg/kg/day orally. The histologic appearance of these lesions was similar to that found in albino rats following excessive exposure to light. However, the retinal changes may also represent a direct drug-induced effect.
Animal experiments have shown that vigabatrin has no negative influence on fertility or pup development. No teratogenicity was seen in rats in doses up to 150mg/kg (3 times the human dose) or in rabbits in doses up to 100 mg/kg. However, in rabbits, a slight increase in the incidence of cleft palate at doses of 150-200 mg/kg was seen.
Studies with vigabatrin revealed no evidence of mutagenic or carcinogenic effects.
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