Miconazole Warfarin

Anon. Miconazole-warfarin interaction increasedlNR CanMedAssocJ(200 ) 165, 81. 

Antimicrobials. Aztreonam, cefamandole, chloramphenicol, ciprofloxacin, co-trimoxazole, erythromycin, fluconazole, itraconazole, ketoconazole, metronidazole, miconazole, ofloxacin and sulphonamides (including co-trimoxazole) increase anticoagulant effect by mechanisms that include interference with warfarin or vitamin K metabolism. Rifampicin and griseofulvin accelerate warfarin metabolism (enzyme induction) and reduce its effect. Intensive broad-spectrum antimicrobials, e.g. eradication regimens for Helicobacter pylori (see p. 630), may increase sensitivity to warfarin by reducing the intestinal flora that produce vitamin K. 

Colquhoun MC, Daly M, Stewart P, Beeley L. Interaction between warfarin and miconazole oral gel. Lancet 1987 l(8534) 695-6. 

Acetaminophen, aldrin, alfentanil, amiodarone, aminopyrine, amitriptyline, amprenavir, androstenedione,antipyrine, astemizole, benzphetamine, budesonide, carbamazepine, celecoxib, chlorpromazine, chlorzoxazone, cisapride, clarithromycin, clozapine, cocaine, codeine, cortisol, cyclophosphamide,cyclosporin, dapsone, delavirdine, dextromethorphan, digitoxin, diltiazem, diazepam, erythromycin, 17j3-estradiol, ethinylestradiol, etoposide, felbamate, fentanyl, flutamide, hydroxyarginine, ifosphamide, imipramine, indinavir, ketoconazole, lansoprazole, loratidine, losartan, lovastatin, (iS)"mephen3d in, methadone, mianserin, miconazole, mifepristone, nelfinavir, nevirapine, nicardipine, nifedipine, odansetron, omeprazole, orphenadrine, proguanil, propafenone, quinidine, quinine, rapamycin, retinoic acid, ritonavir, saquinavir, selegiline, serindole, sufentanil, sulfinpyrazone, tacrolimus, tamoxifen, tamsulosin, taxol, teniposide, terfenadine, tetrahydrocannabinol, theophylline, toremifene, triazolam, trimethadone, trimethoprim, troleandomycin, verapamil, warfarin, zatosetron, Zolpidem, zonisamide... 

Some imidazoles (miconazole, fluconazole) are known to interact with oral hypogly-caemic drugs (Chapter 6) by enhancing their activity and they may increase the risk of myopathy with lipid-lowering drugs statins (Chapter 4). Some imidazoles enhance the anticoagulant properties of warfarin. 

Miconazole is a potent inhibitor of CYP2C9. Because this azole is generally used topically as pessaries, skin cream, or an oral gel, it is less likely to cause interactions, although it should be noted that interactions with warfarin , (p.388), have been reported, particularly for the oral gel. 

Based on this information the risk of a clinically relevant drug interaction with systemically administered drugs and these topical azoles would seem to be very small. However, for a case report of raised INR in a man taking warfarin while using miconazole cream for a groin infection, see Coumarins and related drugs + Azoles Miconazole , p.388. 

In rate, ketoconazole potentiated the anticoagulant eflect of acenocoumarol, but at much higher doses than miconazole , (p.388). It is now known that ketoconazole is an inhibitor of the cytochrome P450 isoenzyme CYP3A4, but this isoenzyme has only a minor role in the metabolism of warfarin (p.358), specifically the less active R-isomer. 

In one early report, a patient with a prosthetic heart valve and stabilised on warfarin developed blood blisters and bruised easily 12 days after starting miconazole gel 250 g four times a day for a presumed fungal mouth... 

In a study in 6 healthy subjects, miconazole 125 mg daily for 18 days (in the form of tablets) caused a very marked fivefold increase in prothrombin time response to a single dose of warfarin given on day 3. In addition, there was a threefold inerease in the AUC of warfarin, with S-warfarin most affected (fourfold), and R-warfarin increased 1.7-fold. In one early case report with warfarin, one patient with a prosthetic heart valve and stabilised on warfarin was found to have a prothrombin time ratio of 23.4 within 10 days of starting miconazole tablets 250 mg four times a day for a suspected fungal diarrhoea. He developed two haematomas soon after both drugs were withdrawn, and was subsequently lestabilised, in the absence of miconazole, on his former dose of warfarin. ... 

There is evidence that miconazole is a very potent inhibitor of the metabolism of S-warfarin by the cytochrome P450 isoenzyme CYP2C9, and that it also inhibits the metabolism ofR-warfarin to a lesser extent." Even low oral doses of miconazole (125 mg daily) markedly inhibit warfarin metabolism, so it is not surprising that prescription doses of miconazole oral gel (480 to 960 mg daily) interact, since this is swallowed after retaining in the mouth. Very unusually, absorption of miconazole from the vagina (see also comments below) and even exceptionally through the skin, can result in increased anticoagulant effects. 

Bailey GM, Magee P, Hickey FM, Beeley L Miconazole and warfarin intemctioa PharmJ (1989)242,183... 

Shenfield GM, Page M Potentiation of warfarin actic by miconazole oral gel. AustNZJ Me[Pg.389]

Pillans P, Woods DJ Interaction between miconazole oral gel (Daktarin) and warfarin. NZ Me[Pg.389]

Ariyaratnam, Thakker NS, Sloan P, Thornhill MH Potentiatiai of warfarin anticoagulant activity by miconazole oral gel. BW 99T) 314,349... 

O Reilly RA, GoulartDA, Kunze KL, Neal J, Gibaldi M, Eddy AC, Trager WF. Mechanisms of the stereoselective interaction between miconazole and racemic warfarin in human subjects. Clin Pharmacol Ther 9SC) 51,656-67. 

Drug-drug interactions A 71-year-old woman taking 400 mg per day miconazole oral gel four times daily was admitted to hospital because of massive proteinuria (10 g per day) and systemic oedema [20 ]. She received oral prednisolone, cyclosporine (150 mg per day) and was also treated with warfarin (2-2.5 mg per day). Increased oral bioavailability of warfarin and cyclosporine were suggested her INR had increased to 7.25 and cyclosporine trough concentration had increased from 132.9 to 1296.5 ng/ml. Also, a significant miconazole plasma concentration (0.35 ng/ml) was measured. Miconazole was discontinued, amphotericin B was started and cyclosporine A dose was adjusted to 125 mg per day. 

T ima-Okubo R, Tsuruoka S, Moriyama N, Kaneda T, Yamagata K. Interaction of miconazole oral gel with warfarin and cyclosporine in a patient with nephrotic syndrome. CEN Case Rep 2012 1 55-7. 

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