Valproate Interaction With Carbapenems: Review and Recommendations

Introduction: Valproic acid is a commonly used antiepileptic drug. Combining valproate derivatives with carbapenem antibiotics is associated with a potential drug interaction that decreases serum concentration of valproate and may expose the patient to uncontrolled seizure risk from valproate subtherapeutic concentration. Raising awareness of this drug interaction among health care providers including emergency department physicians, neurologists, and pharmacists is highly needed. The aim of this article was to review the current literature about the potential drug interaction resulting from combining valproate derivatives with carbapenem antibiotics and to establish therapeutic recommendations regarding their use together. Methods: A review of the literature was conducted using Medline (through PubMed), Ovid, Embase, Cochrane library using the following keywords: valproate, valproic acid, carbapenem, ertapenem, doripenem, meropenem, imipenem, and valproate drug interaction. In addition, a manual search through major journals for articles referenced in PubMed was performed. Related publications from January 1998 till November 2018 were included in the initial search. Relevant publications were reviewed, and data regarding patients, type of carbapenem used, valproic acid dosing and level, interaction severity, and clinical outcome were summarized. Results and Discussion: Few clinical trials and multiple case reports have shown that carbapenem antibiotics including meropenem, ertapenem, imipenem, and doripenem can decrease the serum concentration of valproate derivatives leading to a subtherapeutic serum concentration and seizures in some patients. Valproic acid serum concentration may be significantly decreased with addition of a carbapenem antibiotic but generally return toward normal shortly after discontinuation of the carbapenem antibiotic. Conclusions: Generally, the concurrent use of carbapenem antibiotics with valproate derivatives should be avoided due to the potential of drug-drug interaction that results in subtherapeutic valproate serum concentration. Other antimicrobial agents should be considered as alternatives to carbapenems but if a concurrent carbapenem is necessary, using an additional antiepileptic agent is recommended. Therapeutic drug monitoring of valproate serum concentrations is warranted when a carbapenem-valproic acid combination therapy is unavoidable.