Drug-Drug Interaction

VALPROIC ACID/CARBAPENEM ANTIBIOTICS

MECHANISM OF ACTION
The exact mechanism is unknown. Carbapenems may inhibit the absorption of valproic acid from the gastrointestinal tract. (1-3) Meropenem may accelerate the renal excretion of valproate.(4)

DISCUSSION
In a retrospective review of an 18 month period, charts of 39 patients who received concurrent therapy with valproate and meropenem were examined. A pharmacokinetic interaction was observed in all 39 patients, with an average decrease in valproate levels of 66%. The decrease occurred within 24 hours of the initiation of concurrent therapy. Electroclinical deterioration was seen in 55% of patients.(9)

CLINICAL EFFECTS
Concurrent use of carbapenems may result in sub-therapeutic levels of valproic acid(4-16) and seizures.(4-8)

SEVERITY LEVEL
2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

PATIENT MANAGEMENT
Consider the use of alternative antibiotics in patients maintained on valproic acid.(9) If concurrent therapy is warranted, valproic acid levels should be carefully monitored if a carbapenem is initiated or discontinued. The dosage of valproic acid may need to be adjusted.(5,10) Some patients may require the addition of an alternative anti-epileptic agent.(10)

PREDISPOSING FACTORS
None determined.

REFERENCES

  1. Torii M, Takiguchi Y, Izumi M, Fukushima T, Yokota M. Carbapenem .Torii M, Takiguchi Y, Izumi M, Fukushima T, Yokota M. Carbapenem antibiotics inhibit valproic acid transport in Caco-2 cell monolayers. Int J Pharm 2002 Feb 21;233(1-2):253-6.
  2. Nakajima Y, Mizobuchi M, Nakamura M, Takagi H, Inagaki H, Kominami G, .Nakajima Y, Mizobuchi M, Nakamura M, Takagi H, Inagaki H, Kominami G, Koike M, Yamaguchi T. Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats. Drug Metab Dispos 2004 Dec;32(12):1383-91.
  3. Torii M, Takiguchi Y, Saito F, Izumi M, Yokota M. Inhibition by carbapenem .Torii M, Takiguchi Y, Saito F, Izumi M, Yokota M. Inhibition by carbapenem antibiotic imipenem of intestinal absorption of valproic acid in rats. J Pharm Pharmacol 2001 Jun;53(6):823-9.
  4. Santucci M, Parmeggiani A, Riva R. Seizure worsening caused by decreased .Santucci M, Parmeggiani A, Riva R. Seizure worsening caused by decreased serum valproate during meropenem therapy. J Child Neurol 2005 May; 20(5):456-7.
  5. Coves-Orts FJ, Borras-Blasco J, Navarro-Ruiz A, Murcia-Lopez A, .Coves-Orts FJ, Borras-Blasco J, Navarro-Ruiz A, Murcia-Lopez A, Palacios-Ortega F. Acute seizures due to a probable interaction between valproic acid and meropenem. Ann Pharmacother 2005 Mar;39(3):533-7.
  6. Fudio S, Carcas A, Pinana E, Ortega R. Epileptic seizures caused by low .Fudio S, Carcas A, Pinana E, Ortega R. Epileptic seizures caused by low valproic acid levels from an interaction with meropenem. J Clin Pharm Ther 2006 Aug;31(4):393-6.
  7. Spriet I, Meersseman W, De Troy E, Wilmer A, Casteels M, Willems L. .Spriet I, Meersseman W, De Troy E, Wilmer A, Casteels M, Willems L. Meropenem -valproic acid interaction in patients with cefepime-associated status epilepticus. Am J Health Syst Pharm 2007 Jan 1;64(1):54-8.
  8. Lunde JL, Nelson RE, Storandt HF. Acute seizures in a patient receiving .Lunde JL, Nelson RE, Storandt HF. Acute seizures in a patient receiving divalproex sodium after starting ertapenem therapy. Pharmacotherapy 2007 Aug;27(8):1202-5.
  9. Spriet I, Goyens J, Meersseman W, Wilmer A, Willems L, Van Paesschen W. .Spriet I, Goyens J, Meersseman W, Wilmer A, Willems L, Van Paesschen W. Interaction between valproate and meropenem: a retrospective study. Ann Pharmacother 2007 Jul;41(7):1130-6.
  10. De Turck BJ, Diltoer MW, Cornelis PJ, Maes V, Spapen HD, Camu F, Huyghens .De Turck BJ, Diltoer MW, Cornelis PJ, Maes V, Spapen HD, Camu F, Huyghens LP. Lowering of plasma valproic acid concentrations during concomitant therapy with meropenem and amikacin. J Antimicrob Chemother 1998 Oct; 42(4):563-4.
  11. Clause D, Decleire PY, Vanbinst R, Soyer A, Hantson P. Pharmacokinetic .Clause D, Decleire PY, Vanbinst R, Soyer A, Hantson P. Pharmacokinetic interaction between valproic acid and meropenem. Intensive Care Med 2005 Sep;31(9):1293-4.
  12. Nacarkucuk E, Saglam H, Okan M. Meropenem decreases serum level of .Nacarkucuk E, Saglam H, Okan M. Meropenem decreases serum level of valproic acid. Pediatr Neurol 2004 Sep;31(3):232-4.
  13. Sala Pinol F, Padulles Zamora N, Hidalgo Albert E, Clemente Bautista S, .Sala Pinol F, Padulles Zamora N, Hidalgo Albert E, Clemente Bautista S, Cabanas Poy MJ, Oliveras Arenas M, Balcells Ramirez J. Pharmacokinetic interaction between valproic acid and meropenem. An Pediatr (Barc) 2006 Jan;64(1):93-5.
  14. Gu J, Huang Y. Effect of concomitant administration of meropenem and .Gu J, Huang Y. Effect of concomitant administration of meropenem and valproic acid in an elderly chinese patient. Am J Geriatr Pharmacother 2009 Feb;7(1):26-33.
  15. Invanz (ertapenem) US prescribing information. Merck & Co., Inc. March, .Invanz (ertapenem) US prescribing information. Merck & Co., Inc. March, 2010.
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  17. Perea Falomir M, Roura Poch P, Higueruelo Demason S, Garcia Gil VJ. .Perea Falomir M, Roura Poch P, Higueruelo Demason S, Garcia Gil VJ. Pharmacokinetic interaction between valproic acid and imipenem. Farm Hosp 2006 Sep-Oct;30(5):316-7.
  18. Doribax (doripenem) US prescribing information. Ortho-McNeil-Janssen .Doribax (doripenem) US prescribing information. Ortho-McNeil-Janssen Pharmaceuticals, Inc. April, 2009.