Drug-Drug Interaction

VALPROIC ACID DERIVATIVES/TOPIRAMATE

MECHANISM OF ACTION
The exact mechanism is unknown, but a pharmacokinetic interaction does not occur.(1-4) Topiramate may contribute to increased ammonia levels by inhibiting carbonic anhydrase and cerebral glutamine.(5) Concurrent use may exacerbate or unmask existing metabolism defects.(1-4)

DISCUSSION
There have been several reports of hyperammonemia with and without encephalopathy in patients receiving concurrent valproic acid derivatives and topiramate.(1-12) In many of these reports, the patients tolerated the valproic acid derivative alone, but developed hyperammonemia with or without encephalopathy following the addition of topiramate.(1-9) Two clinical trials showed no clinically significant pharmacokinetic interaction between valproic acid and topiramate.(12,13)

CLINICAL EFFECTS
Concurrent use of valproic acid or its derivatives and topiramate may increase the risk of hyperammonemia with or without encephalopathy. Hyperammonemic encephalopathy may present as changes in state of consciousness and/or cognitive function with lethargy and vomiting.(1-4) Concurrent use has also resulted in hypothermia.(1)

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

PATIENT MANAGEMENT
In patients receiving concurrent valproic acid derivatives and topiramate, monitor for unexplained lethargy, vomiting, and/ or changes in mental status. If these symptoms develop, check the patient's ammonia level.(1-4) The valproic acid derivative and/or topiramate may need to be discontinued if hyperammonemia develops.(1-3)

PREDISPOSING FACTORS
The risk of hyperammonemia with or without encephalopathy may be increased in patients with inborn metabolism errors or decreased hepatic mitochondrial activity.(1-4)

REFERENCES

  1. Depakote (divalproex sodium) US prescribing information. Abbott .Depakote (divalproex sodium) US prescribing information. Abbott Laboratories January, 2009.
  2. Depacon (valproate sodium) US prescribing information. Abbott Laboratories .Depacon (valproate sodium) US prescribing information. Abbott Laboratories July 12, 2006.
  3. Depakene (valproic acid) US prescribing information. Abbott Laboratories .Depakene (valproic acid) US prescribing information. Abbott Laboratories January, 2009.
  4. Topamax (topiramate) US prescribing information. Ortho-McNeil .Topamax (topiramate) US prescribing information. Ortho-McNeil Pharmaceutical, Inc. December, 2009.
  5. Hamer HM, Knake S, Schomburg U, Rosenow F. Valproate-induced .Hamer HM, Knake S, Schomburg U, Rosenow F. Valproate-induced hyperammonemic encephalopathy in the presence of topiramate. Neurology 2000 Jan 11;54(1):230-2.
  6. Longin E, Teich M, Koelfen W, Konig S. Topiramate enhances the risk of .Longin E, Teich M, Koelfen W, Konig S. Topiramate enhances the risk of valproate-associated side effects in three children. Epilepsia 2002 Apr; 43(4):451-4.
  7. Ortiz-Saenz de Santa Maria MR, Barriuso-Perez E, Soto-Alvarez MI, .Ortiz-Saenz de Santa Maria MR, Barriuso-Perez E, Soto-Alvarez MI, Moche-Loeri JA. Ring chromosome 20, hypersensitivity to valproate and hyperammonemic encephalopathy. Rev Neurol 2003 Oct 16-31;37(8):733-5.
  8. Cheung E, Wong V, Fung CW. Topiramate-valproate-induced hyperammonemic .Cheung E, Wong V, Fung CW. Topiramate-valproate-induced hyperammonemic encephalopathy syndrome: case report. J Child Neurol 2005 Feb; 20(2):157-60.
  9. Panda S, Radhakrishnan K. Two cases of valproate-induced hyperammonemic .Panda S, Radhakrishnan K. Two cases of valproate-induced hyperammonemic encephalopathy without hepatic failure. J Assoc Physicians India 2004 Sep; 52:746-8.
  10. Rath A, Naryanan TJ, Chowdhary GV, Murthy JM. Valproate-induced .Rath A, Naryanan TJ, Chowdhary GV, Murthy JM. Valproate-induced hyperammonemic encephalopathy with normal liver function. Neurol India 2005 Jun;53(2):226-8.
  11. Latour P, Biraben A, Polard E, Bentue-Ferrer D, Beauplet A, Tribut O, .Latour P, Biraben A, Polard E, Bentue-Ferrer D, Beauplet A, Tribut O, Allain H. Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both?. Hum Psychopharmacol 2004 Apr; 19(3):193-203.
  12. Solomon GE. Valproate-induced hyperammonemic encephalopathy in the .Solomon GE. Valproate-induced hyperammonemic encephalopathy in the presence of topiramate. Neurology 2000 Aug 22;55(4):606.
  13. Rosenfeld WE, Liao S, Kramer LD, Anderson G, Palmer M, Levy RH, Nayak RK. .Rosenfeld WE, Liao S, Kramer LD, Anderson G, Palmer M, Levy RH, Nayak RK. Comparison of the steady-state pharmacokinetics of topiramate and valproate in patients with epilepsy during monotherapy and concomitant therapy. Epilepsia 1997 Mar;38(3):324-33.
  14. Mimrod D, Specchio LM, Britzi M, Perucca E, Specchio N, La Neve A, Soback .Mimrod D, Specchio LM, Britzi M, Perucca E, Specchio N, La Neve A, Soback S, Levy RH, Gatti G, Doose DR, Maryanoff BE, Bialer M. A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy. Epilepsia 2005 Jul;46(7):1046-54.