Lithium and Fluconazole Interaction
There is no clinically significant documented interaction between lithium and fluconazole based on available evidence.
Mechanism Analysis
Fluconazole's primary interaction profile involves inhibition of CYP2C9, CYP2C19, and moderate inhibition of CYP3A4 enzymes 1, 2, 3. However, lithium is not metabolized by cytochrome P450 enzymes—it is eliminated unchanged primarily through renal excretion 4. This fundamental difference in elimination pathways means fluconazole's enzyme inhibition effects do not impact lithium metabolism.
Key Clinical Considerations
Lithium's Known Interaction Profile
- Lithium's therapeutic window is narrow, with toxic levels close to therapeutic dosing 4
- The most serious lithium interactions occur with drugs that reduce renal clearance (NSAIDs, ACE inhibitors, thiazide diuretics) 4
- Psychiatric drug combinations with lithium may enhance therapeutic effects but do not typically cause the dangerous elevations in lithium levels that renal clearance-affecting drugs produce 4
Fluconazole's Interaction Profile
- Fluconazole interactions predominantly involve CYP450-metabolized drugs including warfarin, phenytoin, certain antiepileptics, and drugs metabolized via CYP2C9/CYP3A4 pathways 1, 3
- Common interacting medications include calcium channel blockers, statins, benzodiazepines, and oral contraceptives 5
- Lithium does not appear in any major fluconazole interaction databases or guidelines reviewed 1
Clinical Management Algorithm
When prescribing fluconazole to patients on lithium:
- Continue both medications without dose adjustment based on the interaction profile alone
- Monitor lithium levels according to standard clinical practice (not specifically because of fluconazole)
- Watch for lithium toxicity signs (tremor, confusion, ataxia, polyuria) as you would with any patient on lithium therapy 4
- Review the complete medication list for drugs that genuinely affect lithium clearance (diuretics, NSAIDs, ACE inhibitors) 4
Important Caveats
- While fluconazole does not interact with lithium through metabolic pathways, always verify renal function since both drugs have renal considerations—fluconazole is renally eliminated and lithium toxicity risk increases with renal impairment 6, 4
- If using high-dose fluconazole (≥400 mg/day), the increased risk is for interactions with CYP450-metabolized drugs, not lithium 1, 3
- The absence of documented interaction does not eliminate the need for routine lithium monitoring given its narrow therapeutic index 4