INR 8.2 after a course of fluconazole in a stable warfarin patient
A 62-year-old man with atrial fibrillation has been stable on warfarin 5 mg daily for three years, with INR values between 2.4 and 2.9. He develops oral candidiasis and a medical officer at a primary health centre prescribes oral fluconazole 150 mg once daily for 10 days; no INR monitoring is arranged. On day 8 he presents to the district hospital with bleeding gums, dark urine and bruising over both forearms. INR is 8.2 and haemoglobin has fallen from 13.1 to 10.4 g/dL. He is admitted for three days, given vitamin K 5 mg intravenously and two units of fresh frozen plasma; warfarin is withheld for four days and restarted at 3 mg. He also takes amlodipine and atorvastatin, has no liver disease, drinks no alcohol, and reports no change in diet or other medicines. The hospital is a PvPI adverse drug reaction monitoring centre and the pharmacist has been asked to review the case.
1. Explain the mechanism and carry out a causality assessment using Naranjo and WHO-UMC scales, showing your scoring.
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Mechanism. Fluconazole is a potent inhibitor of CYP2C9, and to a lesser extent CYP3A4 and CYP2C19. S-warfarin, the more potent enantiomer, is cleared mainly by CYP2C9, so inhibition reduces its clearance, prolongs the prothrombin time and raises the INR. The effect appears within days and peaks around the first week, exactly matching day 8 here. Protein-binding displacement is a minor contributor.
Naranjo scoring.
| Question | Score |
|---|---|
| Previous conclusive reports? | +1 |
| Appeared after the drug was given? | +2 |
| Improved on withdrawal or antagonist (vitamin K, FFP)? | +1 |
| Reappeared on readministration? | 0 (no rechallenge) |
| Alternative causes ruled out? | +1 (no liver disease, alcohol, diet change, other interacting drugs) |
| Placebo response? | 0 |
| Drug concentration in toxic range? | 0 (INR is pharmacodynamic) |
| Dose-response? | 0 |
| Previous similar reaction? | 0 |
| Confirmed by objective evidence? | +1 (INR 8.2, haemoglobin fall) |
Total 6: Probable.
WHO-UMC. Probable/likely: plausible time relationship, documented response to withdrawal, not explained by other causes, and no rechallenge. Only a positive rechallenge would make it Certain.
Reasoning point. Do not score the vitamin K response as evidence of an alternative cause; vitamin K is an antagonist, and improvement after an antagonist is scored positively.
2. Classify the seriousness of this reaction and set out the reporting obligations of the hospital and of the marketing company.
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Seriousness. Under the CIOMS/WHO criteria a reaction is serious if it causes death, is life-threatening, requires or prolongs hospitalisation, causes persistent disability, is a congenital anomaly, or requires intervention to prevent permanent impairment. This patient was admitted for three days and needed transfusion, so the reaction is serious, even though it is well recognised and treatable.
Hospital (PvPI ADR monitoring centre). Complete the PvPI ADR reporting form with the suspect drug, dose, dates, concomitant drugs, reaction description, laboratory values and outcome, and upload it to the national database through Vigiflow within 30 days of becoming aware. Report even though causality is only 'probable' - the programme wants suspected reactions, not proven ones. Causality and severity fields should be completed honestly; do not upgrade to 'certain'. The centre should also feed the case back to the prescriber and flag it for signal review, since repeated reports of this interaction have labelling implications.
Marketing company. As holder of the authorisation it must maintain pharmacovigilance, capture the case in its safety database, and report serious unexpected adverse reactions to CDSCO on an expedited basis (within 15 days) under the New Drugs and Clinical Trials Rules, 2019, with periodic safety update reports thereafter.
What not to do. Do not file the report only after the episode is fully resolved, and do not omit the fluconazole regimen. The 150 mg daily dose for ten days is itself a questionable choice for oral candidiasis and is part of the signal.
3. What preventive and regulatory actions should follow, and how would you judge the clinical management?
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Clinical management. Appropriate overall: withholding warfarin, 5 mg intravenous vitamin K and fresh frozen plasma for a bleeding patient with INR 8.2, then restarting at a reduced dose. Two criticisms: vitamin K could have been given orally if bleeding had been minor, and the restart should have been guided by a repeat INR rather than a fixed day.
Preventive actions.
- Any patient started on an azole while on warfarin needs an INR check within 3-5 days and again at the end of the course; this should be a written protocol at the health centre.
- Prescribers should prefer an antifungal with no CYP2C9 effect where clinically equivalent.
- Patients on warfarin should carry an alert card listing interacting drug classes.
- The hospital should audit whether high-risk coprescribing generates an automatic interaction alert in its dispensing system.
Regulatory angle. This is a well-documented class interaction, so the realistic outcome is not a new warning but reinforcement: check that the package insert and the prescribing information for fluconazole in India carry the interaction prominently, and that warfarin labelling advises INR monitoring on co-administration. Generate a signal through PvPI if local reports are accumulating.
Judgement on fault. The medical officer's failure to monitor is a clinical governance and training issue, not an offence under the Drugs and Cosmetics Act; the pharmacist's role is to report, educate and improve the system, not to apportion blame.