Update On Moxifloxacin (Avelox): Potential Interaction with Warfarin and Cardiac Rhythm Safety

Special Feature (Part 2 of 3 Part Series)

By Cindy Tat, PharmD Candidate, Jessica C. Song, PharmD

Cindy Tat is a PharmD Candidate at the University of the Pacific, School of Pharmacy, and Jessica C. Song is Pharmacy Residency Coordinator at SCVMC, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA. Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert.

Cindy Tat and Jessica C. Song report no consultant, stockholder, speaker’s bureau, research, or other financial relationship with any company related to this field of study.

Introduction

Adverse drug events (ADES) are unwanted consequences of drug therapy and have important implications for each patient, the treating physician, and the institution itself. When assessing adverse effects, prescribing healthcare workers should pay particular attention to ADEs that interrupt the patient’s therapeutic regimen and hence increase the patient’s length of stay in the hospital. Warfarin is a drug with a narrow therapeutic index that is known to interact with numerous drugs, including fluoroquinolones such as ciprofloxacin and levofloxacin.1-3 Recently, several cases of warfarin-moxifloxacin interaction have been reported in the literature, some of which resulted in hemorrhagic events or interruption of warfarin therapy.1-3 In view of the fact that excessive QTc interval prolongation may lead to adverse cardiac events, clinicians should be educated on the comparative propensity of commonly prescribed fluoroquinolones (levofloxacin, moxifloxacin) to cause QTc interval prolongation. This article will: 1) review the published case reports of moxifloxacin-warfarin interaction and 2) review the cardiac rhythm safety profile of moxifloxacin.

Interaction with Warfarin

There have been several case reports of a suspected interaction between warfarin and fluoroquinolones, levofloxacin, moxifloxacin, ofloxacin, norfloxacin and, most frequently, ciprofloxacin, resulting in prolonged prothrombin times.1-3 The mechanism of interaction between warfarin and fluoroquinolones has not been established, but may involve the effect of fluoroquinolones on the inhibition of warfarin metabolism, the displacement of warfarin from protein-binding sites, and the inhibition of vitamin K-producing intestinal flora.2,3

In 2005, 8 cases of elevations in international normalized ratios (INRs) when moxifloxacin was added to patients receiving warfarin were reported in 2 published case report series.2,3 Table 1 summarizes the characteristics of these patients, warfarin dosage prior to admission, INR value prior to moxifloxacin therapy, time to onset of interaction, maximal INR values and corresponding time during therapy, actions taken to reverse the elevation in INRs, and any hemorrhagic complications observed. All patients were on stable oral anticoagulation regimens prior to the initiation of moxifloxacin during hospitalization, with the exception of case 8. The addition of moxifloxacin resulted in a significant increase in INR in all cases, with a decline seen after the discontinuation of moxifloxacin.2,3 Warfarin therapy had to be withheld for an average of 3 days (range, 1-6 days), and discontinued in one case. Four of the 8 patients required the administration of vitamin K, with case 1 requiring a blood transfusion of packed red blood cells and fresh frozen plasma. Although only one patient experienced an adverse clinical event, the elevated INRs placed all patients at an increased risk for bleeding complications, and contributed to the lengthened hospitalization for 3 of the 8 patients.2,3 Of the other medications concurrently taken by these patients, azithromycin has been reported to possibly interact with warfarin. Azithromycin has a long half-life (~57 hours) after multiple-dose administration and may have potentiated the hypoprothrombinemic response observed in cases 3 and 5.3 Allopurinol is known to interact with warfarin, however, the 2 patients that were on allopurinol had been taking it on a regular basis, prior to hospital admission, with a stable, therapeutic INR. Furthermore, it should be noted in case 5 that warfarin was inadvertently ordered at a higher dosage than the patient’s usual regimen, which may have contributed to the increase in INR with or without the addition of moxifloxacin.3 Finally, the Naranjo probability scale was used to assess the moxifloxacin-warfarin interaction in cases 1 through 5. The interaction in cases 1, 2, and 3 was judged as a probable cause for the hypoprothrombinemic response, and the interaction in cases 4 and 5 was judged as a possible cause.3

Although the prescribing information for moxifloxacin states that there is no interaction between moxifloxacin and warfarin, the case reports described here show that a potential interaction does exist in some patients. The premarketing study noted in the prescribing information included 24 healthy volunteers who received oral moxifloxacin 400 mg/day for 8 days, with a single dose of warfarin 25 mg given on day 5.4 No significant elevations in INR were documented in the study. However, the use of warfarin in this study is not consistent with the usual course of warfarin in the clinical setting, where patients are often titrated and maintained on a warfarin dose to achieve an INR within a therapeutic range. The concomitant therapy of warfarin and moxifloxacin, as well as ciprofloxacin or levofloxacin should be administered with caution, and frequent INR monitoring is recommended.

Cardiac Rhythm Safety Profile of Moxifloxacin

As a consequence of its intrinsic potential to block the rapid-component delayed-rectifier (Ikr) potassium channel in the heart,5 moxifloxacin increases the QTc interval by 6 ms,6 a degree of prolongation that is less than the effects associated with either erythromycin (8 to 15 ms) or doxepin (22 ms).7 The Committee for Proprietary Medicinal Products proposed that an increase in the QTc of greater than 60 ms and a QTc exceeding 500 ms "raises clear concern about the potential risk for arrhythmias".8

Morganroth and colleagues conducted a prospective, double-blind, multicenter, noninferiority study (n = 387) that compared the cardiac rhythm safety of moxifloxacin (400 mg/d sequential IV/oral) with that of levofloxacin (500 mg/d sequential IV/oral) in elderly patients with community-acquired pneumonia.9 The primary end point was the composite of fatal/nonfatal cardiac arrest, sustained monomorphic or polymorphic ventricular tachycardia without cardiac arrest, and nonsustained monomorphic or polymorphic ventricular tachycardia, based on Holter monitoring. In addition, pre-treatment and post-third dose 12-lead electrocardiograms were obtained from 117 patients to assess the incidences of QTc prolongation in excess of 30 ms and 60 ms, along with the mean QTc changes for moxifloxacin- and levofloxacin-treated patients.

Of note, the study population was comprised of quite aged and less healthy patients, as two-thirds of the patients were 75 years and older, and nearly 75% of the subjects had a history of cardiac disease. The null hypothesis presented in this study stated that the incidence rate of ventricular arrhythmias seen during levofloxacin treatment would be at least 10% lower than the rate reported with moxifloxacin. The prespecified upper and lower limits of a 2-sided 95% confidence interval (CI) were < 10% and < 0, respectively. Moxifloxacin was shown to be noninferior to levofloxacin, as 8.3% of moxifloxacin-treated patients and 5.1% of the levofloxacin-treated patients experienced the primary end point (95% CI, -1.8 to 8.2, P = 0.49). A QTc prolongation of 30 to 60 ms, using the Bazett formula, was observed in 15.5% of moxifloxacin-treated patients and in 6.8% of levofloxacin-treated patients (P = 0.58). When the investigators used Fridericia’s formula, QTc prolongation of 30 to 60 ms was observed in 10.3% and in 6.8% of moxifloxacin-and levofloxacin-treated patients, respectively (P = 1.0). One patient from each treatment group experienced a QTc increase in excess of 60 ms. The mean QTc changes on day 3 using Bazett’s formula and Fridericia’s formula were 5.3 ± 23.7 ms and 6.4 ± 23.2 ms, respectively, for the moxifloxacin treatment group. The levofloxacin-treated subjects showed a mean QTc change of -5.1 ± 25.8 ms with the Bazett correction, and a mean QTc change of -2.5 ± 22.9 ms with Fridericia’s correction.

To date, no study has compared the cardiac rhythm safety profiles of moxifloxacin (400 mg/d) with that of higher-dose levofloxacin (750 mg/d). However, Noel and colleagues evaluated the effects of levofloxacin (500 mg, 1000 mg, 1500 mg) administered as single doses to 48 healthy volunteers in a 4-way crossover, double-blind, randomized, placebo-controlled study.10 Increases in QTc intervals after a single dose of levofloxacin 1000 mg, ranged from 1.55 8.48 ms to 3.93 7.13 ms with the Bazett correction. Increases in QTc intervals (using Bazett’s formula), following a single dose of levofloxacin 1500 mg, ranged from 6.40 ± 9.63 ms to 7.73 ± 7.92 ms.

Conclusion

At present, the prescribing information for moxifloxacin states that there is no interaction between this drug and warfarin; the case reports described here refute this claim. Consequently, concomitant therapy of warfarin and moxifloxacin (or ciprofloxacin, levofloxacin) should prompt clinicians to monitor INRs more frequently during a treatment course. In addition, moxifloxacin appears to have a comparable cardiac rhythm safety profile to levofloxacin, as both drugs are equally likely to induce an increase in the QTc in excess of 60 ms.

References

  1. Jolson HM, et al. Adverse Reaction Reporting of Interaction Between Warfarin and Fluoroquinolones. Arch Intern Med. 1991;151:1003-1004.
  2. Arnold LM, et al. Moxifloxacin and Warfarin: Additional Evidence for a Clinically Relevant Interaction. Pharmacotherapy. 2005;25:904-907.
  3. Elbe DH, Chang SW. Moxifloxacin-Warfarin Interaction: A Series of Five Case Reports. Ann Pharmacother. 2005;39:361-364.
  4. Moxifloxacin (Avelox®) prescribing information. West Haven, CT: Bayer Pharmaceuticals; December 2005.
  5. Kang J, et al. Interactions of a Series of Fluoroquinolone Antibacterial Drugs with the Human Cardiac K+ Channel HERG. Mol Pharmacol. 2001;59:122-126.
  6. White CM, et al. Moxifloxacin Does Increase the Corrected QT Interval. Clin Infect Dis. 2001;33:1441-1444.
  7. Martin SJ, et al. A Risk-Benefit Assessment of Levofloxacin in Respiratory, Skin and Skin Structure, and Urinary Tract Infections. Drug Saf. 2001;24:199-222.
  8. Owens RC Jr. Risk Assessment for Antimicrobial Agent-Induced QTc Interval Prolongation and Torsades de Pointes. Pharmacotherapy. 2001;21:301-319.
  9. Morganroth J, et al. A Randomized Trial Comparing the Cardiac Rhythm Safety of Moxifloxacin vs Levofloxacin in Elderly Patients Hospitalized with Community-Acquired Pneumonia. Chest. 2005;128:3398-3406.
  10. Noel GJ, et al. Measuring the Effects of Supratherapeutic Doses of Levofloxacin on Healthy Volunteers Using Four Methods of QT Correction and Periodic and Continuous ECG Recordings. J Clin Pharmacol. 2004;44:464-473.