Carbamazepine with Phenytoin Interaction Details

Brand Names Associated with Carbamazepine

Brand Names Associated with Phenytoin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 25, 2023

Interaction Effect

Decreased phenytoin and/or carbamazepine concentrations

Interaction Summary

Concomitant use of carbamazepine (inducer of CYP2C9/19, CYP3A4; substrate of CYP3A4) and phenytoin (inducer of CYP3A4; substrate of CYP2C9/19) may decrease exposure of both drugs. However, the effect of carbamazepine on phenytoin in an individual is unpredictable, and some patients may have no change in phenytoin exposure , while in other cases simultaneous use has resulted in increased phenytoin exposure . Carbamazepine has been shown to induce its own metabolism for up to 30 days after the initiation of therapy . If concomitant use of carbamazepine and phenytoin is required, monitor concentrations of both agents and consider dosage adjustments as indicated , particularly during initiation or discontinuation of either agent, following dosage adjustments, and periodically thereafter.

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of carbamazepine (inducer of CYP2C9/19, CYP3A4; substrate of CYP3A4) and phenytoin (inducer of CYP3A4; substrate of CYP2C9/19) may decrease exposure of both drugs. However, the effect of carbamazepine on phenytoin in an individual is unpredictable, and some patients may have no change in phenytoin exposure , while in other cases simultaneous use has resulted in increased phenytoin exposure . If concomitant use of carbamazepine and phenytoin is required, monitor concentrations of both agents and consider dosage adjustments as indicated , particularly during initiation or discontinuation of either agent, following dosage adjustments, and periodically thereafter.

Mechanism Of Interaction

Induction of CYP2C9 and CYP2C19-mediated phenytoin metabolism by carbamazepine; induction of CYP3A4-mediated carbamazepine metabolism by phenytoin

Literature Reports

A) Twenty-four epileptic patients who were stabilized on phenytoin and had carbamazepine added to their drug regimen were studied. The mean phenytoin level increased from 13.89 +/- 4.68 to 19 +/- 4.75 (35.9% increase). The effect of carbamazepine on phenytoin in an individual is unpredictable; 12 of the subjects showed no change in phenytoin levels while the other 12 patients showed an average increase of 81.3% in phenytoin concentration. Five of the patients with increased levels had symptoms of acute phenytoin toxicity .

B) Concomitant administration of carbamazepine and phenytoin has been reported to result in a dual interaction, with simultaneous effects of inhibition of phenytoin metabolism by carbamazepine and induction of carbamazepine metabolism by phenytoin. The result is potential phenytoin intoxication and significant reductions of carbamazepine plasma concentrations to subtherapeutic levels. These dual effects appear to be especially significant when phenytoin plasma levels approach a change from linear to saturation kinetics. It is suggested that the interaction may be avoided or minimized by adjusting phenytoin plasma levels to approximately 13 mcg/mL prior to the addition of carbamazepine to the regimen or increasing carbamazepine doses .

C) Factors influencing simultaneous plasma concentrations of carbamazepine and its epoxide metabolite were studied  and it was found that plasma carbamazepine concentrations were significantly lower in patients taking carbamazepine and phenytoin than those taking carbamazepine alone. In contrast to another study, carbamazepine epoxide levels were unaltered . Other researchers studied carbamazepine plasma concentrations in four groups of epileptic patients on a variety of anticonvulsants . Their results suggest that the administration of phenytoin or phenobarbital to patients receiving carbamazepine results in a significant decrease in carbamazepine plasma concentration when compared to patients receiving carbamazepine alone. It should be noted, however, that some subjects in the trial were treated with carbamazepine for only one week prior to the initiation of phenytoin. Carbamazepine has been shown to induce its own metabolism for up to 30 days after the initiation of therapy, thus lowering carbamazepine plasma concentration . This may account for some of the fall in carbamazepine plasma concentration in subjects also receiving phenytoin.

D) A prospective controlled study of the effects of reduction and discontinuation of phenytoin and carbamazepine upon the levels of concomitant antiepileptic drugs was conducted . Phenytoin discontinuation led to a mean 48% increase in total carbamazepine concentration and a 30% increase in free carbamazepine concentration with no change in carbamazepine epoxide concentrations. The authors suggest that phenytoin is a strong inducer of hepatic enzymes metabolizing carbamazepine to carbamazepine epoxide, but has less of an effect on the epoxide hydroxylase enzyme. This results in elevations in carbamazepine-epoxide/carbamazepine ratios in patients on concomitant therapy. Conversely, when carbamazepine was discontinued, phenytoin concentrations decreased by a mean of 26% with no change in free fraction. The authors propose that this may result from inhibition of phenytoin metabolism by carbamazepine. There appeared to be no impact on protein binding of either drug. Similar results were noted by other researchers in 49 patients on concomitant phenytoin and carbamazepine therapy .

Carbamazepine Overview

• Carbamazepine is used alone or in combination with other medications to control certain types of seizures in people with epilepsy. It is also used to treat trigeminal neuralgia (a condition that causes facial nerve pain). Carbamazepine extended-release capsules (Equetro brand only) are also used to treat episodes of mania (frenzied, abnormally excited or irritated mood) or mixed episodes (symptoms of mania and depression that happen at the same time) in patients with bipolar I disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Carbamazepine is in a class of medications called anticonvulsants. It works by reducing abnormal electrical activity in the brain.

Phenytoin Overview

• Phenytoin is used to control certain type of seizures, and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Phenytoin 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:

• 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.