Valproic Acid with Warfarin Interaction Details

Brand Names Associated with Valproic Acid

Brand Names Associated with Warfarin

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

Interaction Effect

An increased risk of bleeding

Interaction Summary

Concomitant use of valproic acid and warfarin has resulted in supratherapeutic INR levels. Valproic acid (highly protein bound) may displace warfarin and increase the fraction of free warfarin in plasma by up to 32.6% . Additionally, valproic acid is a CYP2C9 inhibitor, which may increase the exposure of both warfarin enantiomers . Coagulation tests should be monitored if valproate therapy is instituted in patients taking warfarin and dosage adjustments of warfarin may be needed . The patient should be closely observed for signs of bleeding, especially around valproic acid dose changes.

Severity

Major

Onset

Rapid

Evidence

Probable

How To Manage Interaction

Concomitant use of valproic acid and warfarin has resulted in supratherapeutic INR levels. Coagulation tests should be monitored if valproate therapy is instituted in patients taking warfarin and dosage adjustments of warfarin may be needed . The patient should be closely observed for signs of bleeding, especially around valproic acid dose changes.

Mechanism Of Interaction

Displacement of warfarin from protein-binding sites and inhibition of CYP2C9-mediated warfarin metabolism

Literature Reports

A) In an in-vitro study, valproate increased the unbound fraction of warfarin by up to 32.6% .

B) Administration of warfarin in a 42-year-old women receiving divalproex 1000 mg/day for bipolar disorder resulted in supratherapeutic INR levels following mitral valve surgery. Her INR on the first postoperative day was 1.11 but after receiving warfarin 2.5 mg, the INR climbed to 6.54 on day 4. Interruption of divalproex therapy resulted in a decrease in INR to 3.23. Divalproex was reinitiated at 250 mg twice daily, but she had difficulties in maintaining therapeutic INR. and had levels increased as high as 8.2 associated with epistaxis. Divalproex was discontinued and alternative therapy was instituted .

C) A case report described doubling of INR without bleeding in a 71-year old woman within 24 hours of the addition of an IV loading dose of valproic acid to warfarin. The patient, who had a history of glioblastoma multiforme (WHO grade 4) treated with radiation and temozolomide and was taking warfarin for a recent right leg DVT, presented to the emergency room with new onset complex partial seizures. The patient was given an IV loading dose of levetiracetam and midazolam 3 mg IV to treat the seizure, and dexamethasone 4 mg IV to treat tumor edema. Home medications included warfarin regimen of 2.5 mg daily on 5 days per week and 5 mg daily on the 2 other days per week had provided a stable INR over the month prior to admission. Head CT showed no hemorrhage, mass effect or midline shift, and INR was 3.01, so the patient received warfarin 2.5 mg on the night of admission. On day 2, a morning INR returned at 3.4, so warfarin 0.75 mg was given, and because seizure activity continued on EEG in the afternoon, levetiracetam was increased to 2.5 g IV twice daily and IV valproic acid was added with a loading dose of 1100 mg followed by 500 mg IV twice daily. The next morning, INR returned at 5.5 and 8 hours later had increased to 7.6. The patient remained asymptomatic and head MRI showed no new hemorrhage in the tumor bed. The patient was treated with oral vitamin K 1 mg and warfarin was held for 2 days, with resumption when INR was 2.5. This case suggests that a more significant acute INR change may occur when an IV loading dose of valproic acid is added to warfarin compared with the addition of oral valproic acid to chronic warfarin therapy .

D) A case report described INR elevation without bleeding in a 68-year-old woman within 24 hours of the addition of oral valproic acid to warfarin. The patient, who had at least a 20-year history of schizophrenia and schizoaffective disorder and a recent 3-week period of medication noncompliance, was admitted for the treatment of left leg DVT. Upon admission, she received IV heparin and oral warfarin, treated to a goal INR of 2.5 to 3.5. On a warfarin regimen of 5 mg daily alternating with 2.5 mg daily, INR ranged between 1.8 and 2.6 over several days. The patient was delusional and paranoid and continued to refuse psychotropic medications until transfer to the psychiatric service, where she agreed to the addition of valproic acid 250 mg twice daily and fluphenazine 5 mg once daily to her warfarin regimen. On the morning after the first dose of valproic acid, the INR increased to 3.9. Over the course of the next 3 weeks, the warfarin regimen was adjusted many times to maintain the desired INR goal. The patient was discharged with improved psychiatric symptoms and a stable INR on warfarin 2.5 mg daily alternating with 5 mg daily, valproic acid 500 mg twice daily, and fluphenazine 5 mg once daily .

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.

Warfarin Overview

• Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin is in a class of medications called anticoagulants ('blood thinners'). It works by decreasing the clotting ability of the blood.

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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.