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Chiron and the STICLO study group report a dramatic improvement in seizure control in children with severe myoclonic epilepsy in infancy or Dravet’s syndrome (DS) when treated with valproate, clobazam, and stiripentol.1 Stiripentol inhibits the metabolism of clobazam and its metabolite norclobazam by P450 cytochromes.
SM, 9 year old girl with DS and severe developmental delay had poor seizure control and frequent status epilepticus despite various combinations of antiepileptic medicines, most recently lamotrigine 35 mg/kg/day and nitrazepam 0.8 mg/kg/day. Careful seizure diaries were kept by her mother CM while lamotrigine and nitrazepam were slowly withdrawn and valproate and clobazam were introduced. Several 14 day courses of miconazole 2% oral gel were given SM for oral thrush. During each course CM observed that SM’s seizure control improved remarkably, and she progressed from being wheelchair bound to standing and displaying more interest in her environment. No unwanted side effects of this treatment were observed. Miconazole is partly absorbed orally, and inhibits P450 cytochromes including isoenzymes 3A4 and 2C9,2 causing interactions with antiepileptic medicines including benzodiazepines.3 We hypothesised that miconazole may have a similar action to stiripentol when given with valproate and clobazam in DS.
With CM’s informed consent, we analysed steady state trough plasma levels of valproate, nitrazepam, clobazam and the metabolites aminonitrazepam and norclobazam while SM was taking these medicines (baseline) and then while taking added miconazole (day 22) or stiripentol (day 50) (see table 1). The analyses were performed by MH, SD, and RB using liquid chromatography–tandem mass spectrometry, except for valproate, where gas chromatography–mass spectrometry was used. The results show markedly increased levels of norclobazam during miconazole or stiripentol treatment compared with baseline, similar to Chiron’s results for stiripentol, which supports our hypothesis.
The safety of long term miconazole use is unknown. Literature searches and correspondence with the distributor of miconazole in New Zealand (Janssen-Cilag Pty Ltd, 4 March 2002) have identified no studies of long term miconazole use in children, nor has this interaction between clobazam and miconazole been reported.4 Miconazole may be a useful medication in DS for trialling the possible benefits of stiripentol when the latter is not readily available, when stiripentol cannot be tolerated,5 or during episodes of fever when children with DS are more likely to develop status epilepticus. Miconazole and stiripentol are also likely to interact with other medicines used in children with DS. This interesting and potentially useful interaction warrants further cautious study.