Basic Information
ID DDInter1913 and DDInter1157
Interaction Coadministration with carbapenem antibiotics may substantially decrease the serum concentrations of valproic acid (VPA) and increase the risk of breakthrough seizures. The exact mechanism of interaction is unknown.
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.
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Drug Intell Clin Pharm 18 (1984): 492 [6] Muzyk AJ, Candeloro CL, Christopher EJ "Drug interaction between carbapenems and extended-release divalproex sodium in a patient with schizoaffective disorder." Gen Hosp Psychiatry 32 (2010): 560.e1-3 [7] Park MK, Lim KS, Kim TE, et al. "Reduced valproic acid serum concentrations due to drug interactions with carbapenem antibiotics: overview of 6 cases." Ther Drug Monit 34 (2012): 599-603 [8] 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 64 (2007): 54-8 [9] "Product Information. Merrem (meropenem)." Zeneca Pharmaceuticals, Wilmington, DE. [10] 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 39 (2005): 533-7 [11] Santucci M, Parmeggiani A, Riva R "Seizure worsening caused by decreased serum valproate during meropenem therapy." J Child Neurol 20 (2005): 456-7 [12] Lunde JL, Nelson RE, Storandt HF "Acute seizures in a patient receiving divalproex sodium after starting ertapenem therapy." Pharmacotherapy 27 (2007): 1202-5 [13] Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0 [14] "Product Information. Invanz (ertapenem)." Merck & Company Inc, West Point, PA. [15] Hellwig TR, Onisk ML, Chapman BA "Potential interaction between valproic acid and doripenem." Curr Drug Saf 6 (2011): 54-8 [16] Cerner Multum, Inc. "Australian Product Information." O 0 [17] Spriet I, Goyens J, Meersseman W, Wilmer A, Willems L, Paesschen WV "Interaction between valproate and meropenem: a retrospective study." Ann Pharmacother 41 (2007): 1130-6 [18] Yamagata T, Momoi MY, Murai K, et al "Panipenem-betamipron and decreases in serum valproic acid concentration." Ther Drug Monit 20 (1998): 396-400 [19] Clause D, Decleire PY, Vanbinst R, Soyer A, Hantson P "Pharmacokinetic interaction between valproic acid and meropenem." Intensive Care Med 31 (2005): 1293-4 [20] Taha FA, Hammond DN, Sheth RD "Seizures from valproate-carbapenem interaction." Pediatr Neurol 49 (2013): 279-81 [21] "Product Information. Doribax (doripenem)." Ortho McNeil Pharmaceutical, Raritan, NJ. [22] Miranda Herrero MC, Alcaraz Romero AJ, Escudero Vilaplana V, et al. "Pharmacological interaction between valproic acid and carbapenem: what about levels in pediatrics?" Eur J Paediatr Neurol 19 (2015): 155-61 [23] Yoon H, Kim DH "Unusual drug reaction between valproate sodium and meropenem." Int J Clin Pharm 35 (2013): 316-8 [24] "Product Information. Primaxin (imipenem-cilastatin)." Merck & Company Inc, West Point, PA. [25] DeTurck BJG, Diltoer MW, Cornelis PJWW, Maes V, Spapen HDM, Camu F, Huyghens LP "Lowering of plasma valproic acid concentrations during concomitant therapy with meropenem and amikacin." J Antimicrob Chemother 42 (1998): 563-4 [26] Liao FF, Huang YB, Chen CY "Decrease in serum valproic acid levels during treatment with ertapenem." Am J Health Syst Pharm 67 (2010): 1260-4 [27] Cabanes Mariscal MA, Sanchez Lopez P, Alvarez Herranz P, Chamorro Merino G "Pharmacokinetic interaction between valproic acid and ertapenem." Farm Hosp 30 (2006): 313-5 [28] "Product Information. Vabomere (meropenem-vaborbactam)." The Medicines Company, Parsippany, NJ. [29] Nacarkucuk E, Saglam H, Okan M "Meropenem decreases serum level of valproic acid." Pediatr Neurol 31 (2004): 232-4 [30] Nagai K, Shimizu T, Togo A, et al "Decrease in serum levels of valproic acid during treatment with a new carbapenem/betamipron." J Antimicrob Chemother 39 (1997): 295-6 [31] Miller AD, Ball AM, Bookstaver PB, Dornblaser EK, Bennett CL "Epileptogenic potential of carbapenem agents: mechanism of action, seizure rates, and clinical considerations." Pharmacotherapy 31 (2011): 408-23 [32] Haroutiunian S, Ratz Y, Rabinovich B, Adam M, Hoffman A "Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study." J Clin Pharmacol 49 (2009): 1363-9 [33] Warrington SJ, Ankier SI, Turner P "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology 15 (1986): 31-7 [34] "Product Information. Fycompa (perampanel)." Eisai Inc, Teaneck, NJ. [35] Gilman AG, Rall TW, Nies AS, Taylor P, eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 8th ed." New York, NY: Pergamon Press Inc. (1990): [36] "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc, Rockville, MD.
Alternative for Valproic acid N03A
Levetiracetam Paramethadione Ethotoin Stiripentol Vigabatrin Mephenytoin
Ganaxolone Clonazepam Primidone Topiramate Pregabalin
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Alternative for Meropenem J01D
Ceftibuten Loracarbef Cefamandole Ceftaroline fosamil Cefotetan Cefixime
Cefiderocol Cefonicid Cefoperazone Cefprozil Cefradine
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Potential Metabolism Interactions
Substrate-Substrate Interaction：If more than one drug is metabolized by the same CYP, it is possible that its metabolism is inhibited because of the competition between the drugs. That means, it can be useful to lower the dosage of the drugs in the drug-cocktail because they remain longer in the organism than in monotherapy.
Inhibitor-Inhibitor Interaction：Combining two or more inhibitors of one CYP, should be compensated by lowering the dosage of these drugs because the metabolism is reduced and the drugs remain longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.
Inhibitor-Substrate Interaction：Combining drugs that have inhibitory effect and are substrates of one particular CYP, should be compensated by lowering the dosage. They rest longer in the organism than in monotherapy. Not adapting the dosage bears the risk of even more side effects.