An isolated report describes a very marked increase in anticoagulant effects of warfarin, accompanied by bruising and bleeding, in a patient given itraconazole. Limited evidence suggeststhat itraconazole may increase risk of over-anticoagulationwith acenocoumarol or phenprocoumon.
A woman stabilised on warfarin 5mg daily and also taking ipratropium bromide, salbutamol, budesonide, quinine sulfate and omeprazole, was given itraconazole 200mg twice daily for oral candidiasis caused by inhaled steroid. Within 4 days she developed generalised bleeding and recurrent nosebleeds. Her INR had risen to more than 8. The warfarin and itraconazole were stopped,but next day she had to be admitted to hospital for intractable bleeding and increased bruising, for which she was treated with fresh frozen plasma. Two days later when bleeding had stopped, and her INR had returned to 2.4,she was restarted on warfarin and later restabilised on her original dosage (See reference number 1).
In one cohort study in patients taking acenocoumarol or phenprocoumon, itraconazole significantly increased risk of over-anticoagulation (INR greater than 6: relative risk of 13.9,range 1.7 to 115). However, authors say this figure should be interpreted cautiously since it was based on just one case (See reference number 2).
Itraconazole is a known potent inhibitor of cytochrome P450 isoenzyme CYP3A4, but this isoenzyme is involved only in metabolism of less potent R-warfarin, and therefore inhibition would not be expected to have a marked effect on warfarin metabolism, . However,there appear to be no pharmacological studies to confirm this. Omeprazole
may also have had some minor part to play in case described (See reference number 1)
A minor to modest pharmacokinetic interaction would be predicted,but as yet there appear to be no studies to confirm this. The case report and cohort study suggest that this interaction might be clinically important in some individuals. Therefore,it would be prudent to increase monitoring of anticoagulant control when any patient on a coumarin anticoagulant is given itraconazole. Further study is needed.
Yeh J,Soo S-C, Summerton C, Richardson C. Potentiation of action of warfarin by itraconazole. BMJ (1990) 301, 669.
Visser LE,Penning-van Beest FJA, Kasbergen AAH, De Smet PAGM, Vulto AG, Hofman A,Stricker BHC. Overanticoagulation associated with combined use of antifungal agents andcoumarin anticoagulants. Clin Pharmacol Ther (2002) 71, 496–502.