Valproic Acid with Ertapenem Interaction Details

Brand Names Associated with Valproic Acid

  • Depakene®
  • Depakote®
  • Depakote® ER
  • Depakote® Sprinkle
  • Divalproex sodium
  • Valproate sodium
  • Valproic Acid

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Last updated Nov 08, 2023

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Interaction Effect

Reduced valproic acid exposure and 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 69.1% with ertapenem. Alternative antibiotic therapy should be considered in a patient whose seizures are well-controlled on valproic acid. If concomitant administration is unavoidable, consider supplemental anticonvulsant therapy. Increasing the valproic acid or divalproex sodium dose may not be adequate to achieve desired levels . Consider therapeutic drug monitoring of VPA and free VPA serum concentrations, especially when initiating or discontinuing carbapenems .

Severity

Major

Onset

Unspecified

Evidence

Established

How To Manage Interaction

The concomitant use of ertapenem and valproic acid (VPA) or divalproex sodium is generally not recommended as this may cause decreased VPA plasma concentrations and increase the risk for breakthrough seizures. Increasing the VPA or divalproex sodium dose may not be adequate to achieve desired levels. Consider using an alternative antibiotic (other than a carbapenem) 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

Unknown

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 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) A 41-year-old man maintained on divalproex sodium for seizure prophylaxis experienced recurrent tonic-clonic seizures on day 7 of concomitant ertapenem 1000 mg every 24 hours. Medical history was significant for hypertension controlled with metoprolol, seizure disorder secondary to traumatic brain injury, and chronic cranial osteomyelitis. Approximately 3 months prior to starting ertapenem, the patient's serum VPA concentration was therapeutic at 130 mcg/mL while taking divalproex sodium 2000 mg/day. He was admitted following 3 seizure episodes, the last of which was a witnessed tonic-clonic seizure lasting longer than 1 minute. The serum VPA concentration was 70 mcg/mL. The dose of divalproex sodium was increased to 2750 mg/day and the patient was discharged. He returned 4 days later with recurrent seizures and a serum VPA concentration of 10.7 mcg/mL. Valproic acid 1000 mg IV was administered along with 1 oral dose of divalproex sodium 100 mg, ertapenem was discontinued, and ampicillin-sulbactam 3 grams IV every 6 hours was begun. The following day the patient's serum VPA concentration increased to 55 mcg/mL. Oral divalproex sodium was increased to 4500 mg/day, and 2 days later his level was 88.1 mcg/mL. Five days after ertapenem was discontinued his serum VPA concentration reached 146 mcg/mL, necessitating a decrease in divalproex sodium dose. He subsequently remained seizure-free .

C) An 80-year-old woman, chronically treated with valproic acid solution 1100 mg/day for complex partial seizures secondary to severe cerebrovascular disease, experienced significantly reduced serum valproic acid concentrations beginning 4 days after the initiation of ertapenem 1000 mg every 24 hours. Approximately, 1.5 months prior to ertapenem exposure, her total serum valproic acid concentration was 72 mcg/mL. Admitted to the hospital for aspiration pneumonia, the patient was treated with ertapenem. Four days later serum valproic acid concentration was reported to be 36.4 mcg/mL, and her valproic acid dose was increased to 1600 mg/day. Two days later serum valproic acid measured 18.42 mcg/mL and the drug dose increased to 2000 mg/day. A level of 1.04 mcg/mL was measured 4 days after this dose increase. Ertapenem was discontinued. With intravenous administration of valproic acid (800 mg loading dose followed by 400 mg every 6 hours), the patient's serum concentration gradually returned to therapeutic range over the next 11 days. She was subsequently maintained on oral valproic acid 1400 mg/day .

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.

See More information Regarding Valproic Acid

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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.

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

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.