Valproic Acid with Fosphenytoin Interaction Details
Brand Names Associated with Valproic Acid
- Depakene®
- Depakote®
- Depakote® ER
- Depakote® Sprinkle
- Divalproex sodium
- Valproate sodium
- Valproic Acid
Brand Names Associated with Fosphenytoin
- Cerebyx®
- Fosphenytoin Injection
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 08, 2023
Interaction Effect
Altered valproate levels or altered phenytoin levels
Interaction Summary
Concomitant use of phenytoin and valproate may either increase or decrease phenytoin serum levels and may also increase the risk of hyperammonemia. Additionally, valproic acid serum levels are unpredictable with coadministration. The addition or withdrawal of valproate in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Monitor for signs and symptoms of hyperammonemia. Concomitant administration of phenytoin (an enzyme-inducing antiepileptic drug) with valproic acid can increase valproate clearance and may also alter the levels of phenytoin by inhibiting the metabolism and protein binding displacement of phenytoin. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing drugs are introduced or withdrawn . Valproate may initially reduce total phenytoin level by displacing phenytoin from protein binding sites . Displaced phenytoin re-equilibrates with the large capacity of tissue compartment such that unbound concentration remains unchanged . Valproate may also inhibit phenytoin metabolism .
Severity
Major
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Concomitant use of phenytoin and valproate may either increase or decrease phenytoin serum levels and may also increase the risk of hyperammonemia. Additionally, valproic acid serum levels are unpredictable with coadministration. The addition or withdrawal of valproate in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome. Monitor for signs and symptoms of hyperammonemia. Concomitant administration of phenytoin (an enzyme-inducing antiepileptic drug) with valproic acid can increase valproate clearance and may also alter the levels of phenytoin by inhibiting the metabolism and protein binding displacement of phenytoin. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing drugs are introduced or withdrawn .
Mechanism Of Interaction
Altered clearance and protein binding of both drugs
Literature Reports
A) If phenytoin or carbamazepine (or any prodrugs) is used in pregnant women, there is a substantially increased risk of teratogenicity with many combinations of other anticonvulsants. The teratogenicity of these drugs is largely or wholly related to the levels of the reactive epoxide metabolites . The epoxide/parent drug ratio is generally increased when phenytoin or carbamazepine is combined with each other, any other drugs that induce cytochrome P450 enzymes (3A4, 2C9, 2C19), or drugs which inhibit epoxide hydrolase, such as valproic acid, progabide, and lamotrigine . Such combinations increase the risk of major birth defects 3- to 4-fold over monotherapy and about 10-fold over background rates.
Valproic Acid Overview
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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.
Fosphenytoin Overview
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Fosphenytoin injection is used to treat primary generalized tonic-clonic seizures (formerly known as a grand mal seizure; seizure that involves the entire body) and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Fosphenytoin injection may also be used to control certain type of seizures in people who cannot take oral phenytoin. Fosphenytoin is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical 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:
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.