Warfarin and Moxifloxacin: Interaction Details

a) Initiation of antibiotics in patients on continuous warfarin therapy resulted in a significantly increased risk of serious bleeding requiring hospitalization according to a nested case-control study of United States Medicare part D beneficiaries aged 65 years and older (n=38,762). Patients on warfarin who received any antibiotic were twice as likely to be hospitalized for bleeding compared with matched controls on warfarin who were not exposed to antibiotics (adjusted odds ratio (aOR), 2.01; 95% CI, 1.62 to 2.5). Additionally, continuous-warfarin users were twice as likely to have a bleeding event that required hospitalization within 60 days of antibiotic exposure compared with non-exposure. Antibiotic exposure greater than 60 days from the index bleed was not significantly associated with increased risk of bleeding. Specific antibiotics with the highest bleeding risk were azole antifungals (aOR, 4.57; 95% CI, 1.9 to 11.03), followed by cotrimoxazole (aOR, 2.7; 95% CI, 1.46 to 5.05), cephalosporins (aOR, 2.45; 95% CI, 1.52 to 3.95), penicillins (aOR, 1.92; 95% CI, 1.21 to 2.07), macrolides (aOR, 1.86; 95% CI, 1.08 to 3.21), and quinolones (aOR, 1.69; 95% CI, 1.09 to 2.62) ⁵.

b) In healthy subjects (n=24), coadministration of oral moxifloxacin 400 mg once daily for 8 days had no significant effect on prothrombin time or the pharmacokinetics of warfarin, which was administered as a single, oral, 25-mg dose on day 5. However, moxifloxacin and other quinolones have been reported to increase the anticoagulant effects of warfarin or its derivatives ¹.

c) A case series described significant and prolonged increases in INR following in-patient moxifloxacin therapy in 5 elderly patients (age range, 63 to 92 years) who were receiving warfarin concurrently for atrial fibrillation. All patients were stabilized on warfarin doses of 2 to 5 mg/day, and INR and hemoglobin values at time of admission ranged from 2.2 to 3.3 and 13.3 to 15.4 g/dL, respectively. In all patients, within 3 to 7 days after oral administration of moxifloxacin 400 mg/day, the INR values increased ranging from 3.4 to 12.8. In 3 of the 5 patients, warfarin was discontinued and vitamin K was administered. In 1 of these 3 patients, a significant decrease in Hb level, with endoscopic evidence of bleeding, also necessitated 2 units each of packed RBCs and fresh frozen plasma. Two of these 3 patients died later from complications of COPD and CHF, respectively. Using the Naranjo probability scale, a moxifloxacin-warfarin interaction was probable cause in these 3 patients. In the remaining 2 patients, warfarin was discontinued in 1 patient while it was continued with a reduced dosage (2 mg/day) in the other patient. As no signs of significant bleeding were evident in these 2 patients, vitamin K was not administered. Using the Naranjo probability scale, a moxifloxacin-warfarin interaction was the possible cause in these 2 patients. The mechanism for this interaction is unknown ².

d) Significant and prolonged increases in INR occurred following in-patient oral moxifloxacin therapy in 3 patients (age range, 50 to 78 years) who were receiving warfarin concurrently. Two of the patients had been stabilized on warfarin 5 mg/day and INR values were within desired range (2.5 to 3.5). Within 1 to 3 days of starting moxifloxacin 400 mg/day in both patients (patients 1 and 2), the INR increased to 3.4 and 6.3, respectively. Despite withholding warfarin in patient 1, the INR rose to 5.7 and 6.2 over the next 2 days, but subsequently dropped down to 1.4 over the next 6 days. Warfarin was re-initiated concurrently with moxifloxacin 400 mg/day and the INR gradually rose from 1.4 to 3.2. One day after discontinuing moxifloxacin after 13 days of treatment, the INR climbed to 4.1 prompting withholding of warfarin. In patient 2, warfarin was withheld and vitamin K 10 mg was given for an INR of 7.3. Moxifloxacin was subsequently discontinued and warfarin was re-initiated at 5 mg/day. At discharge, INR values were 3.9 and 1.5 for patients 1 and 2, respectively. The third patient, who was receiving intravenous levofloxacin and piperacillin-tazobactam for postoperative pneumonia, was initiated on warfarin (titrated to 4 to 5 mg/day) for atrial fibrillation and had stable INR values (1.2 to 1.8). One day after replacing levofloxacin with moxifloxacin 400 mg/day (day 15), the patient's INR rose to 3.3, prompting a decrease in warfarin dosage and subsequent withholding of warfarin. Moxifloxacin was discontinued after 3 doses and INR at discharge (day 19) was 3.8. The mechanism for this interaction is unknown ³.

e) A case series described significant and prolonged increases in INR following in-patient oral moxifloxacin therapy in 3 frail, elderly patients (age range, 76 to 85 years) who were also receiving warfarin. All patients had normal hepatic and renal function but low serum albumin levels (18 to 32 g/L). Two of the patients, who medical history was significant for atrial fibrillation and heart disease, had been stabilized on warfarin (INR range in 1 patient, 2.5 to 4). The third patient, who was admitted for surgical removal of a thrombotic embolus, was initiated on heparin and warfarin. However, after an initial overshoot of INR, heparin was discontinued and warfarin was withheld, which led to an initial downward trend in her INR. In all 3 patients, moxifloxacin 400 mg daily was initiated following development of lower respiratory tract infection while in the hospital, and this resulted in sudden increases in INR to peaks of 7.4 to 10. Despite discontinuation of warfarin in the first 2 patients and no warfarin in the third patient, the INR values remained elevated for 7 to 14 days. The mechanism for this interaction was unknown. While other concurrent medications (allopurinol, amiodarone) in 1 patient may have affected warfarin's metabolism, they were given concurrently with warfarin with no significant changes in INR. Careful monitoring of coagulation parameters is recommended in patients, especially the elderly, receiving concomitant warfarin and fluoroquinolones such as moxifloxacin. Alternative antibiotic therapy may also be considered ⁴.