Is there a drug interaction between Itraconazole and Metformin?

Itraconazole and Metformin Drug Interaction

Yes, there is a clinically significant pharmacokinetic drug interaction between itraconazole and metformin that results in elevated metformin levels and reduced renal clearance, requiring dose adjustment and monitoring when these medications are coadministered.

Mechanism of Interaction

• Itraconazole competitively inhibits metformin metabolism via hepatic and intestinal CYP3A enzymes, leading to significantly increased metformin plasma concentrations 1
• The interaction is bidirectional—metformin also inhibits itraconazole metabolism through the same CYP3A pathway, though the clinical impact on itraconazole levels is less concerning 1
• When administered together (either intravenously or orally), the area under the plasma concentration-time curve (AUC) for metformin increases by approximately 65%, with a corresponding 37% decrease in renal clearance 1, 2

Clinical Consequences

• Elevated metformin levels increase the risk of lactic acidosis, metformin's most serious adverse effect, particularly in patients with renal impairment or other risk factors 1
• Patients may experience increased gastrointestinal side effects (nausea, diarrhea, abdominal discomfort) due to higher metformin concentrations 1
• The interaction occurs through both hepatic CYP3A inhibition and intestinal metabolism blockade, making it unavoidable regardless of administration route 1

Management Algorithm

Before Initiating Combination Therapy

• Assess baseline renal function (serum creatinine, eGFR) as impaired renal clearance combined with this interaction substantially increases lactic acidosis risk 1
• Review all current medications for additional CYP3A4 interactions that could compound the effect 3
• Document the clinical necessity for itraconazole use and consider whether alternative antifungal agents without CYP3A4 interactions (such as echinocandins) are appropriate 3

During Coadministration

• Reduce metformin dose by 30-40% when initiating itraconazole to account for the decreased clearance 1, 2
• Monitor for signs of metformin toxicity including gastrointestinal symptoms, muscle pain, respiratory distress, or altered mental status (early signs of lactic acidosis) 1
• Check serum lactate levels if any concerning symptoms develop 1
• Consider therapeutic drug monitoring for itraconazole to ensure adequate antifungal levels while minimizing the magnitude of CYP3A4 inhibition 3

Monitoring Schedule

• Obtain itraconazole serum concentrations after 2 weeks (once steady-state is reached) to ensure levels are therapeutic (≥1.0 mg/mL) but not excessive (≤10 mg/mL) 3
• Monitor hepatic enzyme levels at baseline, then at 1,2, and 4 weeks, and every 3 months during therapy as itraconazole may be hepatotoxic 3
• Reassess renal function within 1-2 weeks of starting combination therapy and monthly thereafter 1

Evidence Quality and Context

• The primary evidence for this interaction comes from a well-designed 2010 pharmacokinetic study in rats that demonstrated the mechanism and magnitude of interaction through both hepatic and intestinal CYP3A pathways 1
• A 2022 human study confirmed that metformin exposure increases significantly (GMR 1.654) with decreased renal clearance (GMR 0.633) when coadministered with CYP3A4 inhibitors 2
• Clinical experience from 1999 postmarketing surveillance in diabetic patients showed that itraconazole can be used safely with metformin, though this predates recognition of the specific CYP3A-mediated interaction and did not involve systematic dose adjustment 4
• Importantly, metformin is not primarily metabolized by CYP3A4 in humans (it is largely excreted unchanged renally), but the interaction still occurs through inhibition of renal transporters (OCT1, OCT2, MATE1, MATE2-K) that itraconazole affects 2

Common Pitfalls to Avoid

• Failing to reduce metformin dose prophylactically when starting itraconazole—waiting for symptoms of toxicity puts patients at unnecessary risk 1, 2
• Overlooking the duration of interaction, which persists for several days after itraconazole discontinuation due to its long half-life (approximately 24 hours) 3
• Not recognizing that the interaction magnitude may be greater in patients with baseline renal impairment, as they have reduced capacity to clear metformin even without drug interactions 1, 2
• Assuming the interaction is negligible because older literature suggested metformin has minimal CYP-mediated metabolism—the interaction occurs primarily through transporter inhibition rather than metabolic inhibition 4, 2
• Using itraconazole capsules in patients taking proton pump inhibitors or H2 blockers, which dramatically reduces itraconazole absorption and may lead to subtherapeutic levels; the oral solution should be used instead 3