Summary

Fluconazole significantly increases colchicine blood levels by inhibiting CYP3A4 and P-glycoprotein, leading to potentially serious colchicine toxicity. This interaction requires careful dose adjustment or alternative therapy consideration.

Introduction

Colchicine is an anti-inflammatory medication primarily used to treat gout attacks and prevent gout flares, as well as familial Mediterranean fever. It works by inhibiting microtubule formation and reducing neutrophil migration. Fluconazole is a triazole antifungal medication commonly prescribed for candidiasis, cryptococcal infections, and other fungal infections. It functions by inhibiting fungal cytochrome P450 enzymes, particularly 14α-demethylase, which is essential for ergosterol synthesis in fungal cell membranes.

Mechanism of Interaction

Fluconazole is a potent inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein, both of which are crucial for colchicine metabolism and elimination. Colchicine is primarily metabolized by CYP3A4 in the liver and is also a substrate for P-glycoprotein, an efflux transporter that helps eliminate the drug from cells. When fluconazole inhibits these pathways, colchicine clearance is significantly reduced, leading to increased plasma concentrations and prolonged half-life. This pharmacokinetic interaction can result in colchicine accumulation and enhanced toxicity risk.

Risks and Symptoms

The primary risk of this interaction is colchicine toxicity, which can be life-threatening. Symptoms may include severe gastrointestinal effects (nausea, vomiting, diarrhea), bone marrow suppression leading to cytopenias (thrombocytopenia, leukopenia, anemia), muscle weakness, peripheral neuropathy, and in severe cases, multi-organ failure. Patients with renal or hepatic impairment are at particularly high risk due to reduced drug clearance. The interaction is considered clinically significant and may require dose modifications or alternative therapy selection.

Management and Precautions

When concurrent use is necessary, colchicine dose reduction is essential. For gout treatment, reduce colchicine dose by 50% or consider alternative anti-inflammatory agents. For gout prophylaxis, reduce the dose to 0.3 mg daily or every other day. Monitor patients closely for signs of colchicine toxicity, including complete blood count, liver function tests, and renal function. Educate patients about early toxicity symptoms and advise immediate medical attention if they occur. Consider alternative antifungal agents with less CYP3A4 inhibition potential when clinically appropriate. Always consult current prescribing information and consider individual patient factors when making dosing decisions.

Colchicine interactions with food and lifestyle

Grapefruit juice should be avoided with colchicine as it can significantly increase colchicine blood levels and risk of toxicity. Alcohol consumption should be limited or avoided as it may increase the risk of gastrointestinal side effects and potentially worsen gout symptoms. High-purine foods (such as organ meats, certain seafood, and excessive amounts of red meat) should be limited as they can trigger gout flares, potentially counteracting colchicine's therapeutic effects.

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.