Risperidone with Valproic Acid Interaction Details

Brand Names Associated with Risperidone

Brand Names Associated with Valproic Acid

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

Interaction Effect

Increased plasma valproic acid concentrations

Interaction Summary

The addition of risperiDONE to valproic acid produces a significant increase in the peak plasma concentration (Cmax) of valproic acid as well as marked increases in ammonia levels . The high protein capacity of risperiDONE could lead to a competition for protein-binding with the high protein-binding capacity of valproic acid, leading to displacement of valproic acid from plasma protein-binding sites . However, Valproic acid can be added safely to a treatment regimen consisting of risperiDONE . Monitoring of ammonia levels may be warranted in patients who exhibited new or increased manic behavior when taking valproic acid and risperiDONE, especially in patients vulnerable to valproic acid-induced hyperammonemia, including the young, on valproate polytherapy, severely handicapped, or suffering from malnutrition, protein load, and decreased free serum carnitine . In patients prescribed this combination of drugs, monitoring of plasma risperiDONE or 9-OH-risperiDONE concentrations does not appear to be warranted.

Severity

Moderate

Onset

Unspecified

Evidence

Probable

How To Manage Interaction

Monitor for increased ammonia levels and plasma valproic acid concentrations with the addition of risperiDONE to drug therapy or changes in risperiDONE dose.

Mechanism Of Interaction

Unknown

Literature Reports

A) In 2 case reports of 11 year-old boys, there were marked exacerbations in manic behavior and a 2 to 4-fold increase in serum ammonia levels when risperiDONE and valproic acid were concomitantly administered. The first patient, who had a history of Asperger's disorder, attention-deficit/hyperactivity disorder (ADHD), psychosis, and manic symptoms, was admitted for increasing aggressive behavior. Chlorpromazine was added as needed and risperiDONE was added to replace his aripiprazole. Following the initiation of valproic acid 250 mg twice daily, the patient experienced a qualitative exacerbation of manic behavior. The risperiDONE dosage was eventually adjusted to 2 mg/day and valproic acid to 625 mg/day. The patient's valproate level ranged from 87 to 90 and ammonia level was 213. When valproic acid was discontinued, and the ammonia level fell to 55, his manic behavior stopped. The second patient, with a history of absence epilepsy and ADHD, was on stable doses of valproic acid. Because of his psychotic symptoms, risperiDONE was started and increased to 1.125 mg/day over 5 weeks. The patients exhibited markedly pronounced manic behavior and had a serum ammonia level of 113, despite a normal valproic acid level of 71. Upon discontinuation of risperiDONE and valproic acid, the ammonia level normalized to 55 and the manic behavior resolved. One month later when the patient was rechallenged with risperiDONE (in the absence of valproic acid), there was no return of either mania or hyperammonemia .

B) A study was performed to evaluate the pharmacokinetic interaction between risperiDONE and valproic acid. Steady state plasma concentrations of risperiDONE and 9-hydroxyrisperidone (9-OH risperiDONE) were compared in patients treated with risperiDONE alone or in patients comedicated with valproic acid. Thirty-three patients with a DSM-IV diagnosis of schizophrenia, schizoaffective disorder or bipolar disorder, were stabilized with risperiDONE alone or in combination with valproic acid. The results demonstrate that valproic acid given at doses up to 1200-1500 mg/day had clinically insignificant effects on plasma concentrations of risperiDONE and its active metabolite. Valproic acid can be added safely to a treatment regimen consisting of risperiDONE. In patients prescribed this combination of drugs, monitoring of plasma risperiDONE or 9-OH-risperiDONE concentrations does not appear to be warranted .

C) The combination of valproic acid and risperiDONE led to significantly increased levels of valproic acid in one case . A 10-year-old male suffered from mood swings and increasingly aggressive behavior. Valproic acid treatment was initiated and titrated up to 1750 mg/day. Valproate serum levels were in the therapeutic range. After 10 days of treatment, risperiDONE 2 mg/day was added, which was increased to 3 mg/day on day 4. On day 5 after risperiDONE was started, the patients symptoms improved but valproic acid levels were above the therapeutic range at 191 mg/L. Valproic acid was decreased to 1000 mg/day and the level normalized to 108 mg/L within 3 days and subsequently stabilized. The author concludes that the high-protein-binding capacity of risperiDONE could lead to a competition for protein-binding with the high protein-binding capacity of valproic acid, leading to displacement of valproic acid from plasma protein-binding sites .

D) In 21 patients, repeated oral doses of risperiDONE 4 mg daily did not affect the pre-dose or average plasma concentrations or exposure (area under the concentration-time curve) of valproate 1000 mg daily compared to placebo. There was, however, a 20% increase in valproate maximum plasma concentration (Cmax) after risperiDONE coadministration .

Risperidone Overview

• Risperidone is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) in adults and teenagers 13 years of age and older. It is also used to treat episodes of mania (frenzied, abnormally excited, or irritated mood) or mixed episodes (symptoms of mania and depression that happen together) in adults and in teenagers and children 10 years of age and older with bipolar disorder (manic depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Risperidone is also used to treat behavior problems such as aggression, self-injury, and sudden mood changes in teenagers and children 5 to 16 years of age who have autism (a condition that causes repetitive behavior, difficulty interacting with others, and problems with communication). Risperidone is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.

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.

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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.