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Drug Interactions between cilastatin / imipenem and Valproate Sodium

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

valproic acid imipenem

Applies to: Valproate Sodium (valproic acid) and cilastatin / imipenem

GENERALLY AVOID: Coadministration with carbapenem antibiotics may substantially decrease the serum concentrations of valproic acid (VPA) and increase the risk of breakthrough seizures. Approximately 50% to 90% reductions have been typically observed. The exact mechanism of interaction is unknown. In vitro and animal studies suggest that carbapenems may increase the metabolism of VPA to VPA glucuronide; inhibit the hydrolysis of VPA glucuronide in the liver; increase the renal clearance of VPA glucuronide; and inhibit the intestinal absorption of VPA. Carbapenems alone have also been associated with reports of seizures, primarily in patients with central nervous system disorders (e.g., brain lesions, history of seizures), bacterial meningitis, and/or compromised renal function. The interaction with VPA has been reported with various carbapenems including doripenem, ertapenem, imipenem, meropenem and panipenem, often resulting in subtherapeutic VPA levels promptly following initiation of the carbapenem and sometimes despite increases in the VPA dosage. Seizures have been reported in several cases. VPA levels typically begin to increase soon after discontinuation of the carbapenem.

MANAGEMENT: Concomitant use of valproic acid with carbapenem antibiotics is generally not recommended. Use of alternative antibiotics should be considered in patients whose seizures are well controlled on valproic acid therapy. If coadministration is required, supplemental anticonvulsant therapy may be advisable, since increasing the valproic acid dose alone may not be sufficient to overcome the interaction. Nevertheless, pharmacologic response and serum valproate levels should be monitored closely following the addition or withdrawal of carbapenem treatment, and the dosage adjusted as necessary.

References

  1. Pieper JA, Miller JH (1984) "Serum protein binding interactions between propranolol and calcium channel blockers." Drug Intell Clin Pharm, 18, p. 492
  2. (2001) "Product Information. Merrem (meropenem)." Astra-Zeneca Pharmaceuticals
  3. DeTurck BJG, Diltoer MW, Cornelis PJWW, Maes V, Spapen HDM, Camu F, Huyghens LP (1998) "Lowering of plasma valproic acid concentrations during concomitant therapy with meropenem and amikacin." J Antimicrob Chemother, 42, p. 563-4
  4. (2001) "Product Information. Invanz (ertapenem)." Merck & Co., Inc
  5. (2003) "Product Information. Primaxin (imipenem-cilastatin)." Merck & Co., Inc
  6. Nagai K, Shimizu T, Togo A, et al. (1997) "Decrease in serum levels of valproic acid during treatment with a new carbapenem/betamipron." J Antimicrob Chemother, 39, p. 295-6
  7. Yamamura N, Imura K, Naganuma H, Nishimura K (1999) "Panipenem, a carbapenem antibiotic, enhances the glucuronidation of intravenously administered valproic acid in rats." Drug Metab Dispos, 27, p. 724-30
  8. Coves-Orts FJ, Borras-Blasco J, Navarro-Ruiz A, Murcia-Lopez A, Palacios-Ortega F (2005) "Acute seizures due to a probable interaction between valproic acid and meropenem." Ann Pharmacother, 39, p. 533-7
  9. Nacarkucuk E, Saglam H, Okan M (2004) "Meropenem decreases serum level of valproic acid." Pediatr Neurol, 31, p. 232-4
  10. Yamagata T, Momoi MY, Murai K, et al. (1998) "Panipenem-betamipron and decreases in serum valproic acid concentration." Ther Drug Monit, 20, p. 396-400
  11. Santucci M, Parmeggiani A, Riva R (2005) "Seizure worsening caused by decreased serum valproate during meropenem therapy." J Child Neurol, 20, p. 456-7
  12. Clause D, Decleire PY, Vanbinst R, Soyer A, Hantson P (2005) "Pharmacokinetic interaction between valproic acid and meropenem." Intensive Care Med, 31, p. 1293-4
  13. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  14. Spriet I, Meersseman W, De Troy E, Wilmer A, Casteels M, Willems L (2007) "Meropenem -valproic acid interaction in patients with cefepime-associated status epilepticus." Am J Health Syst Pharm, 64, p. 54-8
  15. Cabanes Mariscal MA, Sanchez Lopez P, Alvarez Herranz P, Chamorro Merino G (2006) "Pharmacokinetic interaction between valproic acid and ertapenem." Farm Hosp, 30, p. 313-5
  16. Spriet I, Goyens J, Meersseman W, Wilmer A, Willems L, Paesschen WV (2007) "Interaction between valproate and meropenem: a retrospective study." Ann Pharmacother, 41, p. 1130-6
  17. Lunde JL, Nelson RE, Storandt HF (2007) "Acute seizures in a patient receiving divalproex sodium after starting ertapenem therapy." Pharmacotherapy, 27, p. 1202-5
  18. (2007) "Product Information. Doribax (doripenem)." Ortho McNeil Pharmaceutical
  19. Cerner Multum, Inc. "Australian Product Information."
  20. Agencia Española de Medicamentos y Productos Sanitarios Healthcare (2008) Centro de información online de medicamentos de la AEMPS - CIMA. https://cima.aemps.es/cima/publico/home.html
  21. Haroutiunian S, Ratz Y, Rabinovich B, Adam M, Hoffman A (2009) "Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study." J Clin Pharmacol, 49, p. 1363-9
  22. Tobin JK, Golightly LK, Kick SD, Jones MA (2009) "Valproic acid-carbapenem interaction: report of six cases and a review of the literature." Drug Metabol Drug Interact, 24(2-4), p. 153-82
  23. Liao FF, Huang YB, Chen CY (2010) "Decrease in serum valproic acid levels during treatment with ertapenem." Am J Health Syst Pharm, 67, p. 1260-4
  24. Muzyk AJ, Candeloro CL, Christopher EJ (2010) "Drug interaction between carbapenems and extended-release divalproex sodium in a patient with schizoaffective disorder." Gen Hosp Psychiatry, 32, 560.e1-3
  25. Miller AD, Ball AM, Bookstaver PB, Dornblaser EK, Bennett CL (2011) "Epileptogenic potential of carbapenem agents: mechanism of action, seizure rates, and clinical considerations." Pharmacotherapy, 31, p. 408-23
  26. Hellwig TR, Onisk ML, Chapman BA (2011) "Potential interaction between valproic acid and doripenem." Curr Drug Saf, 6, p. 54-8
  27. Park MK, Lim KS, Kim TE, et al. (2012) "Reduced valproic acid serum concentrations due to drug interactions with carbapenem antibiotics: overview of 6 cases." Ther Drug Monit, 34, p. 599-603
  28. Taha FA, Hammond DN, Sheth RD (2013) "Seizures from valproate-carbapenem interaction." Pediatr Neurol, 49, p. 279-81
  29. Yoon H, Kim DH (2013) "Unusual drug reaction between valproate sodium and meropenem." Int J Clin Pharm, 35, p. 316-8
  30. Miranda Herrero MC, Alcaraz Romero AJ, Escudero Vilaplana V, et al. (2015) "Pharmacological interaction between valproic acid and carbapenem: what about levels in pediatrics?" Eur J Paediatr Neurol, 19, p. 155-61
  31. Molnar GP, Stephens KJ, George LV, Stewart JT (2015) "A critical interaction between ertapenem and valproic acid." J Clin Psychopharmacol, 35, p. 348-50
  32. (2017) "Product Information. Vabomere (meropenem-vaborbactam)." The Medicines Company
View all 32 references

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Drug and food interactions

Moderate

valproic acid food

Applies to: Valproate Sodium (valproic acid)

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References

  1. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc
View all 4 references

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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