Drug interactions and medication reconciliation — formative SAQs

1. Mechanism

Tacrolimus is a substrate of the cytochrome P450 3A4 enzyme with a narrow therapeutic window. Fluconazole is a potent CYP3A4 inhibitor, so it reduces the hepatic and intestinal metabolism of tacrolimus, causing the tacrolimus level to rise. The combination of a narrow-therapeutic-index substrate with a powerful inhibitor is one of the highest-risk paediatric interactions, particularly in transplant and oncology patients. ^{[1] [2]}

2. Direction and timing

The direction of inhibition is a rise in substrate concentration, and the onset is fast — within hours to days of starting the inhibitor — because inhibition acts directly on existing enzyme. This is the opposite of enzyme induction, where a drug such as rifampicin increases enzyme protein synthesis and lowers the substrate level over one to two weeks. State both: inhibition is fast and causes toxicity; induction is slow and causes loss of efficacy. ^{[1] [2]}

3. Prevention and management

The interaction should have been anticipated before the prescription was signed. The preferred approach is to avoid the combination by using a non-azole antifungal such as nystatin for oral candidiasis. If an azole is unavoidable, the tacrolimus dose should be reduced preemptively — often by a substantial fraction — and a level checked within a few days with close clinical and renal review. Now that toxicity has occurred, I stop the fluconazole, reduce the tacrolimus dose, check the level, treat the tremor and renal dysfunction supportively, and arrange early transplant-team liaison. Azithromycin is the safer macrolide when a similar inhibition concern arises with antibiotics. ^{[1] [2]}