A 58-year-old man with atrial fibrillation on warfarin (INR target 2–3) presents to the clinic. He was recently started on fluconazole 400 mg daily for oral candidiasis. His INR measured today is 8.2 (previously 2.5 one week ago). He is asymptomatic with no signs of bleeding. What is the most appropriate immediate next step?

Explanation

## Clinical Context This is a classic example of a **CYP2C9 inhibitor–warfarin interaction**. Fluconazole inhibits the metabolism of warfarin, leading to supratherapeutic INR and elevated bleeding risk. ## Mechanism of Interaction **Key Point:** Fluconazole is a potent inhibitor of **CYP2C9**, the primary enzyme responsible for the metabolism of S-warfarin (the more pharmacologically active enantiomer). This decreases warfarin clearance, prolongs its half-life, and elevates INR significantly. While fluconazole also inhibits CYP3A4, the dominant mechanism for the warfarin interaction is **CYP2C9 inhibition**. (KD Tripathi 8e, Ch 12; Harrison's Principles of Internal Medicine) ## Management Algorithm for Supratherapeutic INR (No Bleeding) ```mermaid flowchart TD A[INR > 4, asymptomatic]:::outcome --> B{INR level?}:::decision B -->|4-10, no bleeding| C[Reduce dose by 25-50%]:::action B -->|4-10, no bleeding| D[Recheck INR in 3-5 days]:::action B -->|> 10, no bleeding| E[Hold warfarin, give vitamin K1 2.5-5 mg PO]:::action C --> D E --> F[Recheck INR next day]:::action B -->|Any level + bleeding| G[Hold warfarin, give FFP + vitamin K1 10 mg IV]:::urgent D --> H[Adjust dose based on new INR]:::action F --> H ``` **High-Yield:** For INR 4–10 without active bleeding, the standard approach is **dose reduction (25–50%) + close monitoring**, NOT discontinuation or FFP (which is reserved for INR > 10 or active bleeding). ## Why This Patient Needs Dose Reduction 1. **INR is 8.2** — supratherapeutic but not extreme (< 10); no signs of bleeding 2. **Asymptomatic** — no haemorrhage, bruising, haematuria, or neurological symptoms 3. **Fluconazole interaction** — the ongoing CYP2C9 inhibition will continue to suppress warfarin clearance; dose reduction is necessary to bring INR back into the therapeutic range (2–3) 4. **FFP is NOT indicated** — FFP is reserved for active bleeding or INR > 10 requiring urgent reversal 5. **Switching to heparin is NOT indicated** — there is no clinical reason to change the anticoagulant class in an asymptomatic patient with a drug interaction **Clinical Pearl:** Always counsel the patient on bleeding precautions (avoid NSAIDs, contact sports, trauma) and ensure close follow-up INR monitoring every 3–5 days until stable. Consider switching fluconazole to a non-interacting antifungal (e.g., nystatin) if clinically appropriate to minimise ongoing interaction. ## Counselling Points - Avoid NSAIDs, aspirin, and other anticoagulants - Report any signs of bleeding (blood in urine/stool, gum bleeding, bruising, severe headache) - Keep all follow-up appointments for INR checks - Do not stop warfarin without medical advice [cite: KD Tripathi 8e Ch 12; Harrison's Principles of Internal Medicine, 21e]