Summary

Fluconazole significantly increases theophylline blood levels by inhibiting CYP1A2 metabolism, potentially leading to theophylline toxicity. This interaction requires careful monitoring and possible dose adjustments when these medications are used together.

Introduction

Theophylline is a methylxanthine bronchodilator commonly used to treat asthma and chronic obstructive pulmonary disease (COPD) by relaxing airway smooth muscles and reducing inflammation. Fluconazole is a triazole antifungal medication used to treat various fungal infections, including candidiasis and cryptococcal infections. Both medications are metabolized by liver enzymes, which creates the potential for clinically significant drug interactions when used concurrently.

Mechanism of Interaction

Fluconazole inhibits the cytochrome P450 enzyme CYP1A2, which is the primary pathway for theophylline metabolism. When fluconazole blocks this enzyme, theophylline clearance is significantly reduced, leading to increased plasma concentrations and prolonged half-life. Studies have shown that fluconazole can increase theophylline levels by 50-100%, with the degree of inhibition being dose-dependent. This pharmacokinetic interaction occurs within 24-48 hours of fluconazole initiation and can persist for several days after discontinuation.

Risks and Symptoms

The primary risk of this interaction is theophylline toxicity, which can manifest as nausea, vomiting, headache, insomnia, tremors, palpitations, and seizures in severe cases. Theophylline has a narrow therapeutic window (10-20 mcg/mL), making patients particularly vulnerable to toxicity when drug levels increase. Elderly patients and those with liver disease are at higher risk for adverse effects. The interaction is considered clinically significant and can lead to serious complications including cardiac arrhythmias, hypotension, and central nervous system toxicity if not properly managed.

Management and Precautions

When concurrent use is necessary, reduce theophylline dose by 25-50% before starting fluconazole and monitor theophylline serum levels closely. Obtain baseline theophylline levels and recheck within 3-5 days of fluconazole initiation, then weekly during concurrent therapy. Monitor patients for signs of theophylline toxicity including GI symptoms, CNS effects, and cardiovascular changes. Consider alternative antifungal agents with less CYP1A2 inhibition if clinically appropriate. When discontinuing fluconazole, gradually increase theophylline dose back to previous levels while monitoring serum concentrations and clinical response.

Theophylline interactions with food and lifestyle

Theophylline has several important food and lifestyle interactions that patients should be aware of. Caffeine consumption should be limited as both theophylline and caffeine are methylxanthines, and concurrent use can increase the risk of side effects such as nervousness, irritability, and rapid heart rate. High-protein, low-carbohydrate diets may increase theophylline clearance and reduce drug levels, while high-carbohydrate, low-protein diets may decrease clearance and increase drug levels. Charcoal-broiled foods may increase theophylline metabolism and reduce effectiveness. Smoking tobacco significantly increases theophylline clearance, requiring higher doses in smokers, and dose adjustments are needed when patients quit smoking. Alcohol consumption should be limited as it may affect theophylline metabolism. Patients should maintain consistent dietary habits and inform their healthcare provider of any significant dietary changes or smoking status changes, as these may require dose adjustments to maintain therapeutic levels.

Fluconazole interactions with food and lifestyle

Fluconazole can be taken with or without food as food does not significantly affect its absorption. However, patients should avoid excessive alcohol consumption while taking fluconazole, as both substances can potentially affect liver function. While moderate alcohol intake is generally considered acceptable, patients with liver conditions or those taking fluconazole for extended periods should discuss alcohol use with their healthcare provider. No specific dietary restrictions are required with fluconazole therapy.