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====== Vigabatrin ====== | ====== Vigabatrin ====== | ||
- | γ-vinyl-GABA | + | Vigabatrin (γ-vinyl-GABA) an AED is a structural analogue of GABA, but does not bind to GABA receptors. |
===== Authorised indications ===== | ===== Authorised indications ===== | ||
**UK-SmPC: | **UK-SmPC: | ||
- | **FDA-PI**: | + | **FDA-PI**: |
===== Clinical applications ===== | ===== Clinical applications ===== | ||
* initial treatment of choice for infantile (epileptic) spasms | * 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 | + | * 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[(: |
===== Dosage and titration ===== | ===== Dosage and titration ===== | ||
- | **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. | + | **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 |
- | + | ||
- | 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. | **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. | + | **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; | **TDM:** unnecessary; | ||
- | Reference range: 6–278 μmol/l, which is irrelevant in clinical practice. | + | **Reference range:** 6–278 μmol/l, which is irrelevant in clinical practice. |
===== Adverse drug reactions ===== | ===== Adverse drug reactions ===== | ||
- | * **Visual field defects** | + | * **Visual field defects** |
- | * high prevalence of visual field defects occurring in around one-third of patients (adults and children)16 treated with vigabatrin | + | * high prevalence of visual field defects occurring in around one-third of patients (adults and children) treated with vigabatrin[(: |
- | * also produces retinal electrophysiological changes in nearly all patients.4,5,17 | + | * also produces retinal electrophysiological changes in nearly all patients.[(: |
- | * Visual field loss resulting from vigabatrin is not usually reversible. However, | + | * Visual field loss resulting from vigabatrin is not usually reversible |
- | * 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 | + | * visual acuity, colour vision and the loss of amplitude on the electroretinogram may be reversible in patients with minimal or no visual field loss |
- | * 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. | + | * 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[(: |
+ | * 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, | * Other ADRs include sedation, dizziness, headache, ataxia, paraesthesiae, | ||
- | * There is no evidence of idiosyncratic ADRs. | + | * there is no evidence of idiosyncratic ADRs |
+ | * movement disorders including dystonia, dyskinesia, and hypertonia have been reported in patients treated for infantile spasms. | ||
- | ===== Main mechanisms | + | ===== Mechanism |
- | The anti-epileptic activity | + | * prevents breakdown |
- | + | * produces dose-dependent increases in GABA concentrations in the CSF and decreases in GABA-T activity | |
- | Vigabatrin may also cause a decrease in excitationrelated | + | * Raised brain GABA levels inhibit the propagation of abnormal hypersynchronous seizure discharges |
+ | | ||
==== Pharmacokinetics ==== | ==== Pharmacokinetics ==== | ||
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==== Drug interactions ==== | ==== Drug interactions ==== | ||
- | There are no drug interactions of any clinical significance, | + | * no drug interactions of any clinical significance, |
==== Considerations in women ==== | ==== Considerations in women ==== | ||
- | * Pregnancy: category C | + | * Pregnancy: category C[(categoryc> |
* Breastfeeding: | * Breastfeeding: | ||
* Interactions with hormonal contraception: | * Interactions with hormonal contraception: | ||
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==== Main disadvantages ==== | ==== Main disadvantages ==== | ||
* Visual field defects have virtually eliminated vigabatrin from common clinical practice except for infantile spasms | * 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. | + | |
- | + | * Electrophysiological testing is considered to be more accurate than perimetry for the direct vigabatrin effect on the outer retina[(: | |
- | 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 | + | ==== Safety of Vigabatrin ==== |
+ | * 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’)[(: | ||
+ | * All these studies[(: | ||
+ | * It was astute clinicians who first reported these serious ADRs[(: | ||
- | Authorities failed to warn of the pro-absence effects of vigabatrin | + | ==== References ==== |
- | That vigabatrin is a pro-absence AED should be evident by its action on GABAB receptors. No such warning was given to practising physicians, | + | |
- | **References** | + | ~~REFNOTES~~ |
- | Kramer G, Wohlrab G. Vigabatrin. In: Shorvon S, Perucca E, Engel JJr, eds. The treatment of epilepsy (3nd edition). Oxford: Willey- Blackwell, 2009: | + | |
- | Willmore LJ, Abelson MB, Ben-Menachem E, Pellock JM, Shields WD. Vigabatrin: 2008 update. Epilepsia 2009; | + | |
- | Browne TR, Mattson RH, Penry JK et al. Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update. Neurology 1991; | + | |
- | Arzimanoglou AA, Dumas C, Ghirardi L. Multicentre clinical evaluation of vigabatrin (Sabril) in mild to moderate partial epilepsies. French Neurologists Sabril Study Group. Seizure 1997; | + | |
- | Mumford JP, Dam M. Meta-analysis of European placebo controlled studies of vigabatrin in drug resistant epilepsy. Br J Clin Pharmacol 1989; | + | |
- | Beran RG, Berkovic SF, Buchanan N et al. A double-blind, | + | |
- | Connelly JF. Vigabatrin. Ann Pharmacother 1993; | + | |
- | French JA, Mosier M, Walker S, Sommerville K, Sussman N. A double-blind, | + | |
- | Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. BMJ 1997; | + | |
- | Chadwick D. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised doubleblind study. Vigabatrin European Monotherapy Study Group. Lancet 1999; | + | |
- | Lindberger M, Alenius M, Frisen L, Johannessen SI, Larsson S, Malmgren K, et al. Gabapentin versus vigabatrin as first add-on for patients with partial seizures that failed to respond to monotherapy: | + | |
- | French JA. Response: efficacy and tolerability of the new antiepileptic drugs. Epilepsia 2004; | + | |
- | Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006; | + | |
- | Panayiotopoulos CP, Agathonikou A, Sharoqi IA, Parker AP. Vigabatrin aggravates absences and absence status. Neurology 1997; | + | |
- | Wild JM, Chiron C, Ahn H et al. Visual field loss in patients with refractory partial epilepsy treated with vigabatrin: final results from an open-label, observational, | + | |
- | Duboc A, Hanoteau N, Simonutti M, Rudolf G, Nehlig A, Sahel JA, et al. Vigabatrin, the GABA-transaminase inhibitor, damages cone photoreceptors in rats. Ann Neurol 2004; | + | |
- | Krauss GL, Johnson MA, Sheth S, Miller NR. A controlled study comparing visual function in patients treated with vigabatrin and tiagabine. J Neurol Neurosurg Psychiatry 2003; | + | |
- | Tomson T, Dahl M, Kimland E. Therapeutic monitoring of antiepileptic drugs for epilepsy. Cochrane Database Syst Rev 2007; | + | |
- | Johannessen SI, Tomson T. Pharmacokinetic variability of newer antiepileptic drugs: when is monitoring needed? Clin Pharmacokinet 2006; | + |