Drug-Drug Interaction

VALPROIC ACID/SALICYLATES

MECHANISM OF ACTION
Multiple mechanisms appear to be involved. Salicylates may: 1. displace valproic acid from plasma protein binding sites

DISCUSSION
The interaction between salicylates and valproic acid has only been reported clinically during concurrent administration of aspirin and valproic acid. However, this interaction would be expected to occur with other salicylates as well. An average increase of nearly 50% in the free fraction of valproic acid has been reported. Valproate toxicity may occur.

CLINICAL EFFECTS
The unbound fraction of serum valproic acid concentration may be increased resulting in toxicity.

SEVERITY LEVEL
3-Moderate Interaction: Assess the risk to the patient and take action as needed.

PATIENT MANAGEMENT
Observe the patient for signs of valproic acid toxicity (e.g., ataxia, drowsiness, nystagmus, tremor) during combined administration salicylates and valproic acid. Adjust the dose of valproic acid as necessary.

PREDISPOSING FACTORS
None determined.

REFERENCES

  1. Farrell K, Orr JM, Abbott FS, Ferguson S, Sheppard I, Godolphin W, Bruni .Farrell K, Orr JM, Abbott FS, Ferguson S, Sheppard I, Godolphin W, Bruni J. The effect of acetylsalicylic acid on serum free valproate concentrations and valproate clearance in children. J Pediatr 1982 Jul; 101(1):142-4.
  2. Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W. .Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W. Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects. Clin Pharmacol Ther 1982 May; 31(5):642-9.
  3. Rettenmeier AW, Prickett KS, Gordon WP, Bjorge SM, Chang SL, Levy RH, .Rettenmeier AW, Prickett KS, Gordon WP, Bjorge SM, Chang SL, Levy RH, Baillie TA. Studies on the biotransformation in the perfused rat liver of 2-n- propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid. Evidence for the formation of chemically reactive intermediates. Drug Metab Dispos 1985 Jan-Feb;13(1):81-96.
  4. Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic .Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic acid metabolism. Clin Pharmacol Ther 1986 Jul;40(1):94-100.
  5. Goulden KJ, Dooley JM, Camfield PR, Fraser AD. Clinical valproate toxicity .Goulden KJ, Dooley JM, Camfield PR, Fraser AD. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 1987 Aug;37(8):1392-4.