Summary

Phenytoin and itraconazole have a clinically significant drug interaction where itraconazole can increase phenytoin levels, potentially leading to phenytoin toxicity. This interaction occurs through inhibition of phenytoin metabolism and requires careful monitoring and possible dose adjustments.

Introduction

Phenytoin is a widely used anticonvulsant medication belonging to the hydantoin class, primarily prescribed for the treatment and prevention of seizures, including tonic-clonic and focal seizures. Itraconazole is a triazole antifungal agent used to treat various systemic and superficial fungal infections, including aspergillosis, blastomycosis, and histoplasmosis. Both medications are metabolized by the liver's cytochrome P450 enzyme system, which forms the basis of their potential interaction.

Mechanism of Interaction

The interaction between phenytoin and itraconazole occurs primarily through competitive inhibition of the cytochrome P450 enzyme system, particularly CYP3A4 and CYP2C9. Itraconazole is a potent inhibitor of these enzymes, which are responsible for phenytoin metabolism. When itraconazole inhibits these enzymes, phenytoin clearance is reduced, leading to increased plasma concentrations and prolonged half-life of phenytoin. This mechanism can result in elevated phenytoin levels within days of starting concurrent therapy.

Risks and Symptoms

The primary clinical risk of this interaction is phenytoin toxicity, which can manifest as neurological symptoms including ataxia, diplopia, nystagmus, confusion, and drowsiness. Severe toxicity may lead to seizures, coma, or cardiovascular complications. Additionally, elevated phenytoin levels increase the risk of dose-dependent adverse effects such as gingival hyperplasia, hirsutism, and bone marrow suppression. The interaction is considered clinically significant and may occur within 2-7 days of initiating concurrent therapy, with effects potentially persisting for weeks after discontinuation due to the long half-lives of both medications.

Management and Precautions

Close monitoring of phenytoin serum levels is essential when initiating itraconazole therapy in patients taking phenytoin. Baseline phenytoin levels should be obtained before starting itraconazole, with follow-up levels checked within 3-5 days and weekly thereafter until stable. Consider reducing the phenytoin dose by 25-50% when starting itraconazole, with further adjustments based on serum levels and clinical response. Monitor patients closely for signs of phenytoin toxicity, including neurological symptoms and changes in seizure control. Alternative antifungal agents with less CYP450 inhibition potential, such as fluconazole (at lower doses) or terbinafine, may be considered when clinically appropriate. If concurrent use is necessary, maintain therapeutic drug monitoring throughout the treatment course and for several weeks after discontinuing either medication.

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.

Itraconazole interactions with food and lifestyle

Itraconazole should be taken with food to enhance absorption and bioavailability. The capsule formulation requires an acidic environment for optimal absorption, so it should be taken with a full meal or acidic beverage. Avoid taking itraconazole with antacids, H2 blockers, or proton pump inhibitors as these reduce stomach acid and significantly decrease drug absorption. Grapefruit juice should be avoided as it can increase itraconazole levels and risk of side effects. Alcohol should be used with caution as both itraconazole and alcohol can affect liver function.