What are the interactions between Levaquin (levofloxacin) and warfarin?

From the Guidelines

Levofloxacin (Levaquin) can increase the anticoagulant effect of warfarin, potentially leading to dangerous bleeding complications, and thus requires close monitoring of INR and potential warfarin dose adjustments. When these medications are used together, closer monitoring of INR is essential, with more frequent blood tests recommended, especially during the first week of combined therapy. Although the provided study 1 does not specifically mention levofloxacin, it discusses the interaction between fluoroquinolones and warfarin, noting that other fluoroquinolones, such as ciprofloxacin, can increase serum R-warfarin concentrations and elevate the INR, increasing the risk of adverse bleeding. Given the similarity in mechanism, it is reasonable to apply this caution to levofloxacin as well. Warfarin dosage may need to be reduced when starting levofloxacin, with adjustments made based on INR results. This interaction occurs because fluoroquinolones, like levofloxacin, can affect the cytochrome P450 enzyme system in the liver that metabolizes warfarin, potentially resulting in higher warfarin blood levels. Patients should be vigilant for signs of excessive anticoagulation such as unusual bruising, nosebleeds, bleeding gums, blood in urine or stool, or prolonged bleeding from cuts. If these medications must be used concurrently, healthcare providers should develop a monitoring plan and patients should report any bleeding symptoms immediately.

Key considerations for managing this interaction include:

• Close monitoring of INR, especially during the initial phase of combined therapy
• Potential reduction in warfarin dosage to mitigate the risk of bleeding complications
• Patient education on recognizing and reporting signs of excessive anticoagulation
• Regular review and adjustment of the anticoagulation plan as necessary to balance the risk of thrombosis against the risk of bleeding, as informed by the most recent and highest quality evidence available 1.

From the FDA Drug Label

1. 2 Warfarin No significant effect of levofloxacin on the peak plasma concentrations, AUC, and other disposition parameters for R- and S-warfarin was detected in a clinical study involving healthy volunteers. Similarly, no apparent effect of warfarin on levofloxacin absorption and disposition was observed However, there have been reports during the postmarketing experience in patients that levofloxacin enhances the effects of warfarin. Elevations of the prothrombin time in the setting of concurrent warfarin and levofloxacin use have been associated with episodes of bleeding Prothrombin time, International Normalized Ratio (INR), or other suitable anticoagulation tests should be closely monitored if levofloxacin is administered concomitantly with warfarin. Patients should also be monitored for evidence of bleeding [see Adverse Reactions (6.3); Patient Counseling Information (17.4)].

Interactions between Levaquin (levofloxacin) and warfarin:

• No significant effect of levofloxacin on warfarin plasma concentrations was detected in a clinical study.
• However, levofloxacin may enhance the effects of warfarin, increasing the risk of bleeding.
• Key monitoring parameters:
  • Prothrombin time
  • International Normalized Ratio (INR)
  • Evidence of bleeding
• Patients should be closely monitored if levofloxacin is administered concomitantly with warfarin 2.

From the Research

Interactions between Levaquin (Levofloxacin) and Warfarin

• The interaction between Levaquin (levofloxacin) and warfarin has been studied in several research papers 3, 4, 5, 6, 7.
• A study published in 2002 reported four cases of hypoprothrombotic response resulting from the addition of levofloxacin therapy to chronic warfarin therapy, with three patients experiencing an increase in international normalized ratio (INR) to 3.5,8.12, and 11.5 3.
• Another study published in 2003 found that the INR values obtained before and after levofloxacin administration did not differ significantly, but the ability to detect a significant difference may be affected by the small number of patients studied 4.
• A literature review published in 2008 found that changes in prothrombin time (PT) and INR values were considerably variable and inconsistent during concomitant warfarin and fluoroquinolone therapy, including levofloxacin 5.
• A retrospective assessment published in 2009 found a significant increase in INR following the addition of levofloxacin to warfarin therapy, and close monitoring of INR is advisable when patients are prescribed this combination of drugs 6.
• A cohort study published in 2014 found that levofloxacin was associated with an increased risk of serious bleeding events in patients taking warfarin, and early INR evaluation may mitigate this risk 7.

Mechanism of Interaction

• The proposed mechanism of the interaction between levofloxacin and warfarin includes displacement of warfarin from protein binding sites, reduction in gut flora producing vitamin K, and decreased warfarin metabolism 3.

Clinical Implications

• The interaction between levofloxacin and warfarin can lead to an increased risk of bleeding events, and close monitoring of INR is necessary when patients are prescribed this combination of drugs 3, 6, 7.
• Early INR evaluation may help mitigate the risk of serious bleeding events in patients taking warfarin and levofloxacin 7.