content:vigabatrin

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content:vigabatrin [2020/02/23 18:04] – [Main disadvantages] icnacontent:vigabatrin [2020/02/23 18:46] – [Adverse drug reactions] icna
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 ===== 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; useful only to check compliance.18,19 **TDM:** unnecessary; useful only to check compliance.18,19
  
-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 =====
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     * 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.     * 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   * Other ADRs include sedation, dizziness, headache, ataxia, paraesthesiae, memory, cognitive and behavioural disturbances, weight gain and tremor
-  * 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.
  
 ===== Mechanism of action ===== ===== Mechanism of action =====
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   * Vigabatrin, 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).   * Vigabatrin, 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).
  
- +==== Safety of Vigabatrin ==== 
- +  * Numerous RCTs failed to detect common and serious visual field defects 
-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. 
-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’)[(:cite:2006001>{{pubmed>2006001}})][(:cite:9203252>{{pubmed>9203252}})][(:cite:2667602>{{pubmed>2667602}})][(:cite:8952010>{{pubmed>8952010}})][(:cite:8439699>{{pubmed>8439699}})][(:cite:8559421>{{pubmed>8559421}})][(:cite:9022432>{{pubmed>9022432}})][(:cite:10406359>{{pubmed>10406359}})] 
- +  * All these studies[(:cite:2006001>{{pubmed>2006001}})][(:cite:9203252>{{pubmed>9203252}})][(:cite:2667602>{{pubmed>2667602}})][(:cite:8952010>{{pubmed>8952010}})][(:cite:8439699>{{pubmed>8439699}})][(:cite:8559421>{{pubmed>8559421}})][(:cite:9022432>{{pubmed>9022432}})][(:cite:10406359>{{pubmed>10406359}})] concluded 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.  
-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 +  * It was astute clinicians who first reported these serious ADRs[(:cite:9022432>{{pubmed>9022432}})], but even after this report had been published, a class I RCT found vigabatrin to be ‘less effective but better tolerated than carbamazepine’[(:cite:10406359>{{pubmed>10406359}})].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[(:cite:11051124>{{pubmed>11051124}})].
- +
-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+
  
 ==== References ==== ==== References ====
  
 ~~REFNOTES~~ ~~REFNOTES~~
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