Warfarin Azithromycin

Eschenauer G, Collins CD, Regal RE. Azithromycin-warfarin interaction ae we fishing with a red herring Pharmacotherapy (2005) 25, 630-1. 

Azithromycin Drugs that may interact with azithromycin include antacids, cyclosporine, HMG-CoA reductase inhibitors, pimozide, tacrolimus, theophyllines, and warfarin. Also consider all drug interactions with erythromycin. 

A retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interactions in patients who were also taking various other drugs, including warfarin (1,45). 

Woldtvedt BR, Cahoon CL, Bradley LA, Miller SJ. Possible increased anticoagulation effect of warfarin induced by azithromycin. Ann Pharmacother 1998 32(2) 269-70. 

Azithromycin can increase the effect of warfarin (183), perhaps by inhibiting its metabolism. Despite only modest effects of macrohdes on serum warfarin concentrations and increases in prothrombin time (119), morbidity caused by hemorrhage may be significant, as illustrated by several case reports (184-188). It is hkely that this interaction is potentiated by other factors, such as old age or dietary restrictions (119). However, a retrospective analysis of 3995 patients treated with azithromycin did not show any pharmacokinetic interaction in patients who were also taking warfarin (127). 

A 71-year old woman, who was taking maintenance warfarin for a prosthetic heart valve, took a 5-day course of azithromycin, and 6 days later her INR rose from 2.5 to 3.5-15 (189). 

Foster DR, Milan NL. Potential interaction between azithromycin and warfarin. Pharmacotherapy 1999 I9(7) 902-8. 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

Clinically important, potentially hazardous interactions with amiodarone, atazanavir, azithromycin, bosentan, ciprofibrate, clarithromycin, clopidogrel, cyclosporine, darunavir, delavirdine, diltiazem, erythromycin, fosamprenavir, fusidic acid, gemfibrozil, grapefruit juice, imatinib, itraconazole, lopinavir, rabeprazole, ranolazine, red rice yeast, ritonavir, roxithromycin, selenium, St John s wort, tacrolimus, telithromycin, tipranavir, verapamil, warfarin... 

There are no studies of the effeet of azithromycin on the pharmacokinetics of coumarins. One pharmacodynamic study and two case series suggest no interaction occurs with warfarin. However, at least 7 published case reports suggest an interaction might occur. These are discussed below. 

The manufacturer notes that a 5-day course of azithromycin (500 mg on day one then 250 mg daily for 4 days) did not affect the prothrombin time response to a single 15-mg dose of warfarin in healthy subjects. - A retrospective study of 26 patients stabilised on warfarin found no evidence that treatment with azithromycin had any effect on their DSTRs. The patients had stable INRs for a least 2 consecutive records before receiving azithromycin, and an INR taken within 14 days (9 patients) or 30 days (17 patients) of starting the azithromycin. The same finding was reported in another similar smaller study in 17 patients. A major disadvantage of these 2 retrospective studies is the small numbers of patients who had an INR value within 7 days of starting azithromycin. 

Erythromycin is a known inhibitor of the cytochrome P450 isoenzyme CYP3A4. However, this isoenzyme has only a minor role in the metabolism of warfarin , (p.358), specifically the less active R-isomer of warfarin. Consequently, only minor increases in the levels of warfarin have been seen in pharmacokinetic studies, which would generally not be expected to be clinically relevant. However, it is possible that even these small changes might be important in a very few patients, particularly those with a low prothrombin complex aetivity. Other macrolides (azithromycin, clarithromycin, dirithromycin, roxithromycin) have less effect on CYP3A4 than erythromycin, and consequently would be expected to have even less effect on the pharmacokinetics of warfarin or acenocoumarol, which is borne out in the few studies available. Nevertheless, cases of interactions have been reported for nearly all these macrolides. Moreover, one cohort study found that clarithromycin increased the risk of an interaction and erythromycin did not. It is possible that there is some other, as yet unidentified, mechanism involved. Alternatively, it is equally possible that the relatively few cases just represent idiosyncratic effects attributable to other factors, and not to any interaction (see also Coumarins -i- Antibacterials , p.365). 

Beckey NP, Parra D, Colon A. Retrospective evaluaticn of a potential interaction between azithromycin and warfarin in patients stabilized on warfaria PhamuKo ien (2000) 20, 1055-9. 

McCall KL, Anderson HG, Jones AD. Determination of the lack of a drug interaction between azithromycin and warfarin. Pharmacolhempy (2004) 24,188-94. 

Shrader SP, Fermo JD, Dzikowski AL. Azithromycin and warfarin interaction. Phamaco-therc (200A)2A, 945-9. 

Rao KB, PaUaki M, Tolbert SR, Homick TR. Enhanced hypoprotiirombinemia witii warfarin due to azithromycin. Am Phamaco ier (2004) 38, 982-5. 

Class 2 (High PermeabiUty, Low Solrrbility) Azathioprine, Azithromycin, Alprazolam, Warfarin, Haloperidol, Glipizide, Griseofulvinum, Danazol, Dapsone, Diclofenac, Indometacin, Itraconzol, Carbamazepine, Carvedilol, Ketoconazole, Lansoprazol, Mebendazole, Mefloqrrine, Nalidixic acid. Nevirapine, Piroxicam, Praziquantel, Ritonavir, Rifampicinirm, Spironolactone, Tamoxifen, Terfenadine, Trimethoprim, Ibnprofen, lopanoic add, Lovastatin, Naproxen, Oxaprozin, Flubiprofen, Cisapride. ... 

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