Clinical evidence,mechanism, importance and management
A woman taking lithium and valproate 3.5 g daily developed fatigue and walking difficulties a day after starting to take erythromycin 250mg four times daily. Within a week she had also developed slurred speech,confusion, difficulty in concentrating and a worsening gait. Her serum valproate levels had risen from 88 mg/L (measured 2 months before) to 260 mg/L. She recovered within 24 hrs of valproate and erythromycin being withdrawn. Her serum lithium levels remained unchanged (See reference number 1). A child taking sodium valproate had a threefold increase in serum valproate levels after taking erythromycin 150mg every 8 hrs and aspirin 250mg every 6 hrs for 3 days (See reference number 2). These case reports contrast with another study in a 10-year-old boy taking valproic acid 375mg twice daily who had only very small and clinically unimportant changes in pharmacokinetics of valproate, consistent with inhibition of cytochrome P450 metabolism, when given erythromycin 250mg four times daily (See reference number 3).
This resolved when patient was given oral vitamin K. It was suggested that effect was because numbers of vitamin-K producing intestinal bacteria were reduced (See reference number 4)
The general relevance of these isolated reports is unclear,but probably small. Further study is needed.
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Cordes I,Buchmann S, Scheffner D. Vitamin K-mangel unter Erythromycin. Beobachtung beieinem mit Valproat behandelten Jungen. Monatsschr Kinderheilkd (1990) 138, 85–7.