Summary

Fluoxetine can significantly increase phenytoin levels by inhibiting its metabolism, potentially leading to phenytoin toxicity. This interaction requires careful monitoring and possible dose adjustments when these medications are used together.

Introduction

Phenytoin is a widely used antiepileptic drug (AED) belonging to the hydantoin class, primarily prescribed for the treatment of tonic-clonic seizures, partial seizures, and status epilepticus. Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) antidepressant commonly prescribed for major depressive disorder, anxiety disorders, and obsessive-compulsive disorder. Both medications are frequently prescribed and may be used concurrently in patients with comorbid epilepsy and depression.

Mechanism of Interaction

The interaction between phenytoin and fluoxetine occurs through inhibition of hepatic cytochrome P450 enzymes, particularly CYP2C9 and CYP2C19, which are responsible for phenytoin metabolism. Fluoxetine and its active metabolite norfluoxetine are potent inhibitors of these enzymes, leading to decreased phenytoin clearance and subsequent elevation of phenytoin plasma concentrations. This pharmacokinetic interaction can result in a 2-3 fold increase in phenytoin levels, with effects potentially persisting for weeks after fluoxetine discontinuation due to the long half-life of norfluoxetine.

Risks and Symptoms

The primary clinical risk of this interaction is phenytoin toxicity, which can manifest as neurological symptoms including ataxia, diplopia, nystagmus, confusion, slurred speech, and in severe cases, seizures or coma. Elevated phenytoin levels can also cause cardiovascular effects such as arrhythmias and hypotension. The narrow therapeutic index of phenytoin makes this interaction particularly concerning, as small increases in plasma concentration can lead to significant toxicity. Additionally, the delayed onset and prolonged duration of this interaction increase the risk of unrecognized toxicity.

Management and Precautions

When concurrent use of phenytoin and fluoxetine is necessary, close monitoring of phenytoin levels is essential. Baseline phenytoin levels should be obtained before initiating fluoxetine, with follow-up levels checked 1-2 weeks after starting fluoxetine and periodically thereafter. Consider reducing the phenytoin dose by 25-50% when initiating fluoxetine, with further adjustments based on clinical response and serum levels. Monitor patients closely for signs of phenytoin toxicity, including neurological symptoms and changes in seizure control. Alternative antidepressants with less CYP450 inhibition potential, such as sertraline or citalopram, may be considered. If fluoxetine is discontinued, phenytoin levels should be monitored as concentrations may decrease over several weeks.

Phenytoin interactions with food and lifestyle

Phenytoin has several important food and lifestyle interactions that patients should be aware of. Alcohol consumption can significantly affect phenytoin levels - chronic alcohol use may decrease phenytoin effectiveness by increasing metabolism, while acute alcohol intoxication can increase phenytoin levels and toxicity risk. Patients should discuss alcohol use with their healthcare provider. Enteral nutrition (tube feeding) can significantly reduce phenytoin absorption, requiring dosing adjustments and timing considerations. Folic acid supplementation may decrease phenytoin levels, as phenytoin can cause folate deficiency but supplementation can reduce drug effectiveness. Vitamin D supplementation may be necessary as phenytoin can cause vitamin D deficiency and bone problems. Smoking may increase phenytoin metabolism, potentially requiring dose adjustments. Patients should maintain consistent dietary habits and discuss any significant dietary changes with their healthcare provider, as phenytoin levels can be affected by nutritional status.

Fluoxetine interactions with food and lifestyle

Alcohol: Fluoxetine may increase the sedative effects of alcohol and impair cognitive and motor performance. Patients should avoid or limit alcohol consumption while taking fluoxetine. Grapefruit juice: May increase fluoxetine blood levels, though this interaction is generally considered minor. St. John's Wort: Should be avoided as it may increase the risk of serotonin syndrome when combined with fluoxetine.