Valproic Acid with Nortriptyline Interaction Details

Brand Names Associated with Valproic Acid

Brand Names Associated with Nortriptyline

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Dec 03, 2023

Interaction Effect

Increased nortriptyline exposure

Interaction Summary

Coadministration of amitriptyline and valproic acid may significantly increase amitriptyline and nortriptyline (metabolite) exposure. In a retrospective study, the mean sum serum concentration of both amitriptyline and nortriptyline increased by 88% when valproic acid was coadministered with amitriptyline compared with amitriptyline alone. In another study, administration of a single oral 50 mg dose of amitriptyline and valproate 500 mg twice daily resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Increased amitriptyline levels have been reported rarely during postmarketing use of valproate in combination with amitriptyline. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity . If concomitant use is required, dose cautiously . Monitor amitriptyline levels and consider lowering the dose of amitriptyline in the presence of valproate .

Severity

Moderate

Onset

Unspecified

Evidence

Probable

How To Manage Interaction

Coadministration of amitriptyline and valproic acid may significantly increase amitriptyline and nortriptyline (metabolite) exposure. If coadministration is required, dose cautiously. Monitor nortriptyline levels and consider lowering the dose of nortriptyline in the presence of valproate .

Mechanism Of Interaction

Possible inhibition of CYP2D6-mediated metabolism by valproate

Literature Reports

A) Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Increased amitriptyline levels have been reported rarely during postmarketing use of valproate in combination with amitriptyline. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity .

B) Coadministration of valproic acid with amitriptyline compared with matched controls treated with amitriptyline alone significantly increased both amitriptyline and nortriptyline concentrations by 59% (mean, 110.5 vs 69.7 nanograms(ng)/mL) and 123% (mean, 126.6 vs 56.7 ng/mL), respectively, in a retrospective study of therapeutic drug monitoring data. With concomitant valproic acid, the mean sum serum concentration of both amitriptyline and nortriptyline increased by 88% (237.1 vs 126.4 ng/mL). When corrected for dose, the difference in serum levels of amitriptyline, nortriptyline, and the sum of both nortriptyline and amitriptyline were also significantly increased with concomitant valproic acid. The ratio of metabolite to parent drug (nortriptyline/amitriptyline) was lower with concomitant valproic acid use (0.865 vs 1.3), which supports a possible mechanism of inhibition of CYP2D6 by valproic acid .

C) In an open-label study of 15 healthy volunteers, the pharmacokinetic interactions between divalproex sodium and amitriptyline were studied. Subjects were given amitriptyline 50 mg alone and two hours after receiving nine doses of divalproex sodium 500 mg, which was given every 12 hours. Coadministration of amitriptyline with divalproex sodium resulted in a 17% increase in amitriptyline maximum concentration (Cmax) and a 31% increase in the amitriptyline area under the concentration-time curve (AUC). Time to maximum concentration (Tmax) for amitriptyline was unaffected during coadministration with divalproex sodium. For nortriptyline, the metabolite of amitriptyline, AUC was increased by 55%, Cmax was increased by 28%, and Tmax was unaffected. The authors postulated that divalproex sodium significantly alters amitriptyline and nortriptyline disposition, possibly through inhibition of hepatic metabolism .

D) The addition of valpromide to a stable amitriptyline regimen may result in an increase of antidepressant plasma level. Twenty patients with major depressive illness (DSM - III criteria) were divided into two groups, one treated with amitriptyline alone and one treated with both amitriptyline and valpromide. All patients received oral amitriptyline 125 mg once daily in the evening for 20 days. Only benzodiazepines (diazepam, lorazepam, bromazepam, clorazepate dipotassium), 5 to 30 mg/day, were also administered. Ten patients also received 600 mg valpromide daily after 10 days on amitriptyline to avoid relapses and/or to decrease irritability and agitation. No statistically significant difference between amitriptyline and nortriptyline plasma levels were determined on days 10 and 20, respectively in ten patients treated with amitriptyline 125 mg daily. In the 10 patients who received valpromide 600 mg, amitriptyline and nortriptyline plasma levels increased. The mean amitriptyline level increased significantly from 70.5 to 105.5 nanograms(ng)/mL, and the mean nortriptyline level increased significantly from 61 to 100.5 ng/mL. No significant relationship was seen between the percentage increase of amitriptyline levels and the plasma level of valproic acid, the main valpromide metabolite. There was a significant linear relationship between the plasma levels of amitriptyline before and after valpromide (r equal to 0.94) and between the nortriptyline plasma levels before and after valpromide (r equal to 0.87). Tricyclic antidepressant plasma levels may increase above the therapeutic window after addition of valpromide. Monitoring of plasma levels of tricyclic antidepressants is advisable to control this interaction .

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.

Nortriptyline Overview

• Nortriptyline is used to treat depression. Nortriptyline is in a group of medications called tricyclic antidepressants. It works by increasing the amounts of certain natural substances in the brain that are needed to maintain mental balance.

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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.