Valproic Acid with Topiramate Interaction Details

Brand Names Associated with Valproic Acid

Brand Names Associated with Topiramate

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 13, 2023

Interaction Effect

Reduced topiramate or valproic acid exposure and an increased risk of hyperammonemia, encephalopathy, and hypothermia

Interaction Summary

Controlled, clinical pharmacokinetic studies in patients with epilepsy showed an 11% decrease in the concentration of valproic acid when topiramate was added. However, when topiramate was given alone, the concentration of topiramate decreased by 14% when valproic acid was added. In two controlled studies involving a total of seven epileptic patients already receiving valproic acid, the addition of topiramate did not significantly change the serum concentration of valproic acid or valproic acid trough concentrations . The coadministration of valproic acid and topiramate has also been implicated in the development of hyperammonemic encephalopathy . As described in a series of case reports, stuporous encephalopathy developed in 5 patients with drug-resistant epilepsy, shortly after beginning a combination anticonvulsant regimen comprising topiramate and valproic acid. Symptoms largely resolved after either drug was reduced in dose or completely withdrawn . Although not studied, concomitant use of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible patients. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy and hypothermia (with or without hyperammonemia). If concomitant use of topiramate with valproic acid is required, monitor for hyperammonemia, encephalopathy, and hypothermia. Assessment of plasma ammonia levels and discontinuation of either drug may be warranted .

Severity

Major

Onset

Unspecified

Evidence

Probable

How To Manage Interaction

Concomitant use of topiramate and valproic acid may result in hyperammonemia, encephalopathy, and hypothermia. It may also result in decreased plasma concentrations of one or both drugs. Upon the coadministration of topiramate and valproic acid, dosing adjustments may be required for either or both drugs. Consider monitoring patients for seizure control and excessive adverse effects. Assess blood ammonia levels if patient develops hypothermia; if confirmed, discontinuation of topiramate or valproic acid may be warranted.

Mechanism Of Interaction

Unknown

Literature Reports

A) In a controlled study, interactions with topiramate were assessed in six patients with epilepsy already taking phenytoin and three patients with epilepsy already taking valproic acid. The patients were given topiramate 100 mg every morning, which was increased to the maximum tolerated dose (no greater than 1200 mg per day). Plasma concentration-time profiles were then observed over the next eight weeks. No apparent changes were observed in either phenytoin or valproic acid area under the concentration-time curve (AUC) profiles or trough plasma concentrations .

B) Stuporous encephalopathy developed in 5 patients with drug-resistant epilepsy, shortly after beginning combination anticonvulsant regimens comprising topiramate (TPM) and valproic acid (VPA). Hyperammonemia was observed in 4 of the patients (age ranging from 29 to 41 years). Blood ammonia levels ranged from 62 to 146 mcmol/L. After a reduction in dose or withdrawal of TPM or VPA, blood ammonia levels returned to normal. In the 5th case report, a 17-year-old boy developed impaired consciousness, 10 days after VPA 1500 mg/day was added to a stable dose regimen comprising TPM 300 mg/day, phenytoin (PHT) 300 mg/day, and carbamazepine 6 mg/day. Blood ammonia concentrations were within normal limits; however, elevations were observed in plasma concentrations of gamma glutamyl-transferase and alkaline phosphatase. The patient's cognitive status returned to baseline after TPM was tapered and withdrawn, in conjunction with a reduction of PHT dose .

C) A 32-year-old male with centrotemporal epilepsy was controlled on phenobarbital 200 mg daily and topiramate 600 mg daily when valproic acid was added to his regimen. Two days prior to hospital admission, valproic acid was increased to 1500 mg daily and the patient became drowsy with nausea and slurred speech. The phenobarbital concentration was 35 mcg/mL (150 mcmol/L; therapeutic range 15 mcg/mL to 40 mcg/mL (65 mcmol/L to 170 mcmol/L)) and the valproic acid level was 38 mcg/mL (260 mcmol/L; therapeutic range 50 mcg/mL to 100 mcg/mL (350 mcmol/L to 700 mcmol/L)) at hospital admission. The ammonia concentration was elevated at 116 mcmol/L (normal 15 mcmol/L to 60 mcmol/L), as was the gamma glutamyl transpeptidase (GGT) level. Acute valproic acid encephalopathy was suspected, and valproic acid was discontinued. The patient recovered within the next three days and the ammonia concentration decreased to within normal limits .

D) A 37-year-old female with focal epilepsy was receiving topiramate 400 mg daily, carbamazepine 1000 mg daily, and lamotrigine 150 mg daily with little effect on her seizure frequency. Valproic acid 1200 mg daily was slowly substituted for lamotrigine, and the patient became somnolent and dysarthric within three weeks. Laboratory results showed a valproic acid level of 47 mcg/mL (330 mcmol/L; therapeutic range 50 mcg/mL to 100 mcg/mL (350 mcmol/L to 700 mcmol/L)) and a carbamazepine level of 5.2 mcg/mL (22 mcmol/L; therapeutic range 8 mcg/mL to 12 mcg/mL (30 mcmol/L to 51 mcmol/L)). The ammonia level was increased to 88 mmol/L and valproate-induced hyperammonemic encephalopathy was suspected. Topiramate was slowly discontinued over a seven-day period, and the patient completely recovered, although the ammonia level remained elevated. Valproic acid was then also discontinued, and the ammonia concentration returned to a normal range .

E) Controlled, clinical pharmacokinetic studies in patients with epilepsy showed an 11% decrease in the concentration of valproic acid when topiramate was added. However, when topiramate was given alone, the concentration of topiramate decreased by 14% when valproic acid was added .

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.

Topiramate Overview

• Topiramate is used alone or with other medications to treat certain types of seizures including primary generalized tonic-clonic seizures (formerly known as a grand mal seizure; seizure that involves the entire body) and partial onset seizures (seizures that involve only one part of the brain). Topiramate is also used with other medications to control seizures in people who have Lennox-Gastaut syndrome (a disorder that causes seizures and developmental delays). Topiramate is also used to prevent migraine headaches but not to relieve the pain of migraine headaches when they occur. Topiramate is in a class of medications called anticonvulsants. It works by decreasing abnormal excitement 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.