Valproic Acid with Meropenem Interaction Details

Brand Names Associated with Valproic Acid

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 08, 2023

Interaction Effect

Reduced valproic acid exposure and an increased risk of seizures and status epilepticus

Interaction Summary

Significant reductions in serum valproic acid (VPA) levels have been reported in patients receiving carbapenem antibiotics (imipenem/cilastatin, meropenem, or ertapenem) concomitantly with valproic acid which resulted in a significant increase in the risk of seizures and a nonsignificant increase in the risk of status epilepticus in a 10-year retrospective study. Concomitant use of valproic acid and a carbapenem resulted in a subtherapeutic VPA serum level (50 mcg/mL) in 92% of patients. The VPA serum concentration significantly decreased by 65.2% with meropenem. Increasing the valproic acid or divalproex sodium dose may not be adequate to achieve desired levels. Consider alternative antibiotic therapy in a patient whose seizures are well-controlled on valproic acid. If concomitant administration is unavoidable, consider supplemental anticonvulsant therapy  and consider therapeutic drug monitoring of VPA and free VPA serum concentrations, especially when initiating or discontinuing carbapenems .

Severity

Major

Onset

Rapid

Evidence

Established

How To Manage Interaction

Concomitant use of meropenem with valproic acid (VPA) is not recommended as the therapeutic effect of VPA is concentration dependent and decreased VPA plasma concentrations may increase the risk for breakthrough seizures. Increasing the valproic acid or divalproex sodium dose may not be adequate to achieve desired levels. If possible, consider an alternative antibiotic which does not affect VPA serum levels. If concomitant administration is unavoidable, consider supplemental anticonvulsant therapy  and consider therapeutic drug monitoring of VPA and free VPA serum concentrations, especially when initiating or discontinuing carbapenems .

Mechanism Of Interaction

Inhibition of the hydrolysis of valproic acid's glucuronide metabolite (VPA-g) back to valproic acid

Literature Reports

A) In a 10-year retrospective study, concomitant use of valproic acid and a carbapenem (imipenem/cilastatin n=46; meropenem n=68, or ertapenem n=48) resulted in a subtherapeutic valproic acid (VPA) serum level (50 mcg/mL) in 92% of patients. The VPA serum concentration significantly decreased by 69.1% with ertapenem and by 65.2% with meropenem, while a nonsignificant decrease of 11.9% occurred with imipenem/cilastatin. A decrease in VPA serum levels during concomitant therapy was associated with a significant increased risk of seizures (OR, 0.96 [95% CI, 0.95 to 0.98]) and a nonsignificant increase in status epilepticus (OR, 0.98 [95% CI, 0.96 to 1]) .

B) In a retrospective study of 36 patients, mean valproic acid plasma concentrations were reduced within 24 hours of meropenem coadministration and remained reduced for more than 14 days after discontinuation of meropenem, regardless of valproic acid dose. Various valproic acid dose forms were tested at dosages of less than 1000 mg/day (group 1), 1000 to less than 2000 mg/day (group 2), 2000 to less than 3000 mg/day (group 3), and 3000 mg/day or greater (group 4). Following meropenem administration, the mean valproic acid plasma concentration significantly decreased from 50.8 +/- 4.5 mcg/mL to 9.9 +/- 2.1 mcg/mL (p less than 0.001); a mean decrease of 82.1% +/- 2.7%. Valproic acid concentrations remained low (18.6 +/- 3.4 mcg/mL) for 7 days after meropenem discontinuation and then gradually increased to baseline levels (44.7 +/- 5.2 mcg/mL) after 8 to 14 days. The effect on valproic acid concentrations was similar in all dosage groups. In blood samples collected within 24 hours of meropenem administration, the mean valproic acid plasma concentration was 9.9 +/- 3.2 mcg/mL. There was no significant difference in the mean reduction of valproic acid levels with high-dose (83.4% +/- 3.8%) compared with low-dose (81% +/- 4.8%) meropenem. Concomitant use of meropenem with valproic acid is not recommended and an increase in valproic acid dose to 3000 mg or greater during meropenem therapy did not increase valproic acid concentration above 20 mcg/mL .

C) A retrospective study of 39 patients with concurrent treatment with valproic acid and meropenem demonstrated an average decrease of valproic acid levels of 66% within 24 hours. In patients receiving meropenem after the start of valproic acid, the mean plasma concentrations of valproic acid decreased from 64.3 mg/L to 22.5 mg/L. Therapeutic valproic acid plasma concentrations range from 50 to 100 mg/L. Patients receiving valproic acid after meropenem did not achieve therapeutic plasma levels of valproic acid, with mean levels of 11.8 mg/L. Despite additional loading doses and increased maintenance doses, only one patient achieved therapeutic plasma levels after the maintenance dose was increased to 12 grams daily. Due to adverse patient outcomes or incomplete data, 20 patients were evaluated for causality and clinical relevance of the interaction. The interaction was rated probable in 16 and possible in 4 of the 20 patients. Eleven of these patients experienced an increase in seizures, electroencephalogram changes, or both. Valproic acid concentrations achieved therapeutic range approximately 8 days after concurrent use of the two medications ceased, and seizure activity was controlled .

D) The coadministration of meropenem with valproic acid produced a pronounced decline in valproic acid plasma concentrations. In a case report, a 21-year-old woman was administered valproic acid 1920 mg as a continuous IV infusion over 24 hours in an attempt to control recurrent tonic-clonic seizures. A valproic acid serum concentration of 52.5 mcg/mL was attained on treatment day 6, with therapeutic serum concentrations maintained on days 8, 10, and 12. On day 13, the patient developed a fever for which IV meropenem 1 gram 3 times daily was started. Two days later, numerous myoclonic events were observed in the woman's arms and face; valproic acid serum concentration was measured at 42 mcg/mL. Valproic acid dose was increased to 2880 mg (continuous IV infusion over 24 hours), yet tonic-clonic seizures recurred on day 17 in conjunction with a further decline of valproic acid serum concentration to 7 mcg/mL. Valproic acid dose was increased the following day to 3600 mg; however, valproic acid serum concentrations did not exceed 10 mcg/mL. Intravenous ceftazidime and ciprofloxacin were substituted for meropenem on day 19, after which serum concentration of valproic acid increased over the next several days, eventually attaining therapeutic levels, with cessation of seizure activity .

E) As described in a case series, serum concentration levels of VPA were substantially decreased by the concurrent administration of meropenem for the treatment of Acinetobacter infections. A 14-year-old boy with epilepsy had been treated for 2 years with VPA 50 mg/kg/day, prior to receiving meropenem and tobramycin for pneumonia. VPA serum concentrations subsequently declined to subtherapeutic levels (nadir of 15 mcg/mL) despite an increase in VPA dose to 200 mg/kg/day. On day 7 after completing meropenem therapy, valproic acid serum concentrations returned to therapeutic levels (114 mcg/mL). A 7-month-old girl with West syndrome, receiving anticonvulsant treatment with VPA 75 mg/kg/day. Baseline VPA plasma concentrations were within therapeutic range (69 to 90 mcg/mL) prior to receiving concomitant treatment with meropenem and vancomycin for nosocomial pneumonia. VPA was increased to 130 mg/kg/day, yet plasma VPA declined to as low as 18 mcg/mL. The patient continued to receive meropenem for 14 days, without seizure activity, and sustained an increase in plasma VPA concentrations to 81 mcg/mL on the third day after completing meropenem therapy. A 14-month-old girl, was receiving VPA 75 mg/kg/day for anticonvulsant control of West syndrome symptoms. Baseline VPA serum concentrations were 85 mcg/mL. The patient received meropenem therapy for a urinary tract infection; within 3 days of beginning meropenem therapy, VPA plasma concentrations decreased to a nadir of 10 mcg/mL, yet returned to within therapeutic range 3 days after completing the course of meropenem treatment .

F) In 2 patients, substantial reductions occurred in VPA plasma concentrations when meropenem was added to previously stable dose regimens of VPA. The first patient, a 65-year-old woman, received an infusion of VPA 1200 mg IV over 24 hours following shunt placement for management of a subdural hemorrhage. Therapeutic valproic acid concentration levels were maintained with a dose range of 1200 mg to 1600 mg daily. After approximately 23 days, meropenem 1 g IV 3 times daily was administered with amikacin to treat a Gram-negative bacillus infection. On the day following initiation of meropenem, the VPA serum concentration declined from approximately 55 mg/mL to 25 mg/L (per graphic analysis), despite supplementation of VPA dose. In the second case report, a 57-year-old woman was given a prophylactic infusion of valproic acid (dose unspecified) IV along with phenytoin 100 mg 3 times daily administered on postop days 9 to 15. Due to development of a lung infection with Klebsiella and Pseudomonas organisms, IV meropenem and amikacin were administered at an indeterminate point in time during the postoperative course, accompanied by an unspecified supplementation of VPA dose. Despite VPA dose augmentation, serum concentration of VPA declined from 44 mg/L to 5 mg/L within 24 hours of beginning meropenem. For this second patient, the plasma elimination half-life of VPA was found to have declined from an expected mean of 15 hours to only 4 hours .

Valproic Acid Overview

• Valproic acid is used alone or with other medications to treat certain types of seizures. Valproic acid is also used to treat mania (episodes of frenzied, abnormally excited mood) in people with bipolar disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). It is also used to prevent migraine headaches but not to relieve headaches that have already begun. Valproic acid is in a class of medications called anticonvulsants. It works by increasing the amount of a certain natural substance in the brain.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.