Fluoxetine with Phenytoin Interaction Details

Brand Names Associated with Fluoxetine

Brand Names Associated with Phenytoin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 11, 2023

Interaction Effect

An increased risk of phenytoin toxicity (ataxia, hyperreflexia, nystagmus, tremor)

Interaction Summary

Patients receiving stable doses of phenytoin have developed elevated phenytoin plasma concentrations and clinical toxicity following initiation of concomitant FLUoxetine; alternatively, patients stabilized on FLUoxetine and phenytoin therapy may experience subtherapeutic concentrations of phenytoin and loss of seizure control when concurrent FLUoxetine is discontinued . During concurrent use, measure baseline phenytoin serum levels and monitor periodically to assure stability; lower phenytoin dosage may be required during coadministration. Serum levels of phenytoin should also be monitored following the discontinuation of FLUoxetine; however, because of the long half-life of FLUoxetine, decreases in phenytoin levels may not be clinically significant for a few weeks.

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Patients receiving stable doses of phenytoin have developed elevated phenytoin plasma concentrations and clinical toxicity following initiation of concomitant FLUoxetine, and alternatively, patients stabilized on FLUoxetine and phenytoin therapy may experience subtherapeutic concentrations of phenytoin and loss of seizure control when concurrent FLUoxetine is discontinued . During concurrent use, measure baseline phenytoin serum levels and monitor periodically to assure stability; lower phenytoin dosage may be required during coadministration. Serum levels of phenytoin should also be monitored following the discontinuation of FLUoxetine; however, because of the long half-life of FLUoxetine, decreases in phenytoin levels may not be clinically significant for a few weeks.

Mechanism Of Interaction

Reduced phenytoin metabolism

Literature Reports

A) A 42-year-old man receiving phenytoin 200 mg daily and carbamazepine 600 mg daily for grand mal seizures remained symptomatic with a phenytoin level of 2 nanograms/milliliter (ng/mL; 7.9 nanomol/L). Phenytoin was subsequently increased to 400 mg daily, FLUoxetine 20 mg daily was added for aggression, and the patient experienced resolution of his behavioral problems and a cessation of his seizure activity. The phenytoin level ranged between 10.9 ng/mL and 15.7 ng/mL (43.21 nanomol/L and 62.23 nanomol/L) during FLUoxetine therapy. However, the patient discontinued FLUoxetine on his own and after a month experienced a recurrence of problems. Phenytoin concentration was measured at 6.6 ng/mL (26.2 nanomol/L) 6 weeks after the discontinuation of FLUoxetine, despite no change in his phenytoin dose. This case report illustrates the need for close monitoring of phenytoin levels when FLUoxetine is initiated and discontinued, since subtherapeutic levels of phenytoin may result if doses of phenytoin are not readjusted following the cessation of FLUoxetine .

B) During an in vitro study, the inhibitory effects of FLUoxetine on CYP2C9 were evaluated using p-hydroxylation of phenytoin as an established index reaction reflecting CYP2C9 activity. In vivo, p-hydroxylation of phenytoin depends on the formation of 5-(p-hydroxy-phenyl)-5-phenylhydantoin (HPPH). FLUoxetine, specifically the R-enantiomer, impaired the formation of HPPH, which can lead to an increase in steady-state phenytoin levels .

C) Twenty-three reported cases of FLUoxetine-phenytoin interactions have resulted in large increases in serum phenytoin levels and/or symptoms of phenytoin toxicity. On the average, the adverse effects began within 2 weeks after FLUoxetine was added to existing phenytoin therapy. The average increase in plasma levels in 9 evaluable cases was 161% (range 75 to 309%) and the maximum phenytoin serum concentration in 16 evaluable cases ranged from 22 to 53.5 mcg/mL (87.21 to 212.07 mcmol/L; therapeutic level, 10 to 20 mcg/mL [39.6 to 79.3 mcmol/L]) .

D) An 84-year-old woman experienced phenytoin toxicity within 5 days of adding FLUoxetine to stabilized phenytoin therapy. After 2 months of phenytoin 300 mg/day, FLUoxetine 20 mg daily was added and increased to 40 mg daily after 10 days. Within five days of starting FLUoxetine, she developed vertigo, gait ataxia, diplopia, and altered mental status; her phenytoin serum level had increased from 15 to 35 mcg/mL (59.5 to 138.7 mcmol/L). Both phenytoin and FLUoxetine were gradually reduced and the signs and symptoms of toxicity abated. Four weeks later she was rechallenged with the same dose of FLUoxetine without a return of toxicity .

E) A 57-year-old woman experienced phenytoin toxicity within 10 days of adding FLUoxetine to stabilized phenytoin therapy. After phenytoin 400 mg daily for a year (serum level, 11.5 mcg/mL [45.59 mcmol/L]), FLUoxetine 20 mg daily was added. Ten days later she developed vomiting, vertigo, trunk ataxia, limb dysmetria, and multidirectional nystagmus, and the phenytoin serum level was 47 mcg/mL (186.3 mcmol/L). FLUoxetine was discontinued and all signs and symptoms of toxicity disappeared over a 3-week period. At 4 weeks post-FLUoxetine, the phenytoin serum level was 20 mcg/mL (79.3 mcmol/L) .

F) Patients on stable doses of phenytoin have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant FLUoxetine treatment .

Fluoxetine Overview

• Fluoxetine is used to treat depression, obsessive-compulsive disorder (bothersome thoughts that won't go away and the need to perform certain actions over and over), some eating disorders, and panic attacks (sudden, unexpected attacks of extreme fear and worry about these attacks). Fluoxetine is also used to relieve the symptoms of premenstrual dysphoric disorder, including mood swings, irritability, bloating, and breast tenderness. It is also used along with olanzapine (Zyprexa) to treat depression that did not respond to other medications and episodes of depression in people with bipolar I disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Fluoxetine is in a class of medications called selective serotonin reuptake inhibitors (SSRIs). It works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance.

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.