Valproic Acid with Phenobarbital Interaction Details

Brand Names Associated with Valproic Acid

Brand Names Associated with Phenobarbital

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

Interaction Effect

Increased PHENobarbital exposure, an increased risk of PHENobarbital toxicity, reduced valproic acid exposure, reduced efficacy of valproic acid and an increased risk of CNS depression

Interaction Summary

Concurrent administration of valproic acid and PHENobarbital results in decreased PHENobarbital clearance and increased serum concentrations which may increase the risk of PHENobarbital-related adverse reactions. If concomitant use cannot be avoided, closely monitor for adverse reactions and consider titration of the PHENobarbital maintenance dosage accordingly . Concomitant use of PHENobarbital and valproic acid may also result in CNS depression. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Closely monitor for neurological toxicity. Serum PHENobarbital concentrations should be obtained and decrease the PHENobarbital dosage if appropriate . Conversely, valproic acid levels may decrease significantly with concurrent use .

Severity

Major

Onset

Unspecified

Evidence

Probable

How To Manage Interaction

Concomitant use of PHENobarbital (a CYP2C9 substrate) with valproic acid ( a CYP2C9 inhibitor) may increase PHENobarbital exposure, which may increase the risk of PHENobarbital-related adverse reactions. If concomitant use cannot be avoided, closely monitor for adverse reactions and consider titration of the PHENobarbital maintenance dosage accordingly. Concomitant use of PHENobarbital and valproic acid may also result in CNS depression. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Closely monitor for neurological toxicity. Serum PHENobarbital concentrations should be obtained and decrease the PHENobarbital dosage if appropriate . Conversely, valproic acid levels may decrease significantly with concurrent use .

Mechanism Of Interaction

Inhibition of CYP2C9-mediated metabolism of PHENobarbital; decreased PHENobarbital metabolism or increased valproic acid metabolism; additive CNS depression

Literature Reports

A) Elevations in serum PHENobarbital levels have occurred with concurrent sodium valproate administration in epileptics, secondary to inhibition of PHENobarbital metabolism . Conversely, PHENobarbital may shorten the serum half-life of sodium valproate due to the induction of liver enzymes . A 10% increase in clearance of valproic acid has been observed in patients taking PHENobarbital .

B) One hundred patients with epilepsy taking primidone alone or in combination with other anticonvulsants were retrospectively studied . Primidone doses ranged from 1.45 mg per kg to 27.03 mg per kg. All patients had been taking the same dosage for at least three weeks prior to blood sampling. Results showed no significant change in the primidone serum level when given concomitantly with valproate sodium, but there was a significant increase in the derived PHENobarbital serum level.

C) PHENobarbital metabolism is inhibited by valproate. Six subjects received valproate 250 mg twice daily for 14 days with PHENobarbital which resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of PHENobarbital (60 mg single dose). The fraction of PHENobarbital dose excreted unchanged increased by 50% in presence of valproate .

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.

Phenobarbital Overview

• Phenobarbital is used to control seizures. Phenobarbital is also used to relieve anxiety. It is also used to prevent withdrawal symptoms in people who are dependent ('addicted'; feel a need to continue taking the medication) on another barbiturate medication and are going to stop taking the medication. Phenobarbital is in a class of medications called barbiturates. It works by slowing activity 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.