Drug-drug interactions with metronidazole and itraconazole in patients using acenocoumarol

Abstract

Purpose Various population-based cohort studies have shown that antimicrobial agents increase the risk of overanticoagulation in patients using coumarins. In this study, we assessed this association in hospitalized patients. Methods We included all patients hospitalized in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands), who started using an antimicrobial agent during acenocoumarol treatment or vice versa between 1 January 2015 and 1 July 2019. Patients were followed from start of concomitant therapy until 48 h after termination of the concomitant therapy or discharge, whichever came first. We analyzed the association between the antimicrobial agents and the risk of overanticoagulation, defined as an interpolated INR above 6, using Cox regression analysis. We corrected for multiple testing with the Bonferroni correction. Patients who started using acenocoumarol and amoxicillin/clavulanic acid were used as reference group. Results In the study population, sixteen antimicrobial agents were started frequently concomitantly with acenocoumarol treatment. We included 2157 interaction episodes in 1172 patients. Patients who started using the combination of co-trimoxazole (HR 3.76; 95% CI 1.47-9.62; p = 0.006), metronidazole (HR 2.55; 95% CI 1.37-4.76; p = 0.003), or itraconazole (HR 4.11; 95% CI 1.79-9.45; p = 0.001) concomitantly with acenocoumarol treatment had an increased risk of overanticoagulation compared with patients using acenocoumarol and amoxicillin/clavulanic acid concomitantly. The associations for metronidazole (p = 0.045) and itraconazole (p = 0.015) remained statistically significant after correction for multiple testing. Conclusion Co-trimoxazole, metronidazole, and itraconazole increase the risk of overanticoagulation in patients using acenocoumarol. These combinations should be avoided if possible or otherwise acenocoumarol doses should be reduced and INR measured more frequently.

Detect Drug Interactions with Metronidazole

“…the risk of bleeding due to warfarin's anticoagulant action being enhanced and prothrombin time being prolonged. Therefore, patients at increased risk of bleeding may need monitoring of their prothrombin time, INR, and signs or symptoms of bleeding [20,21]. Metronidazole combined with 5-fluorouracil prodrugs such as fluorouracil, capecitabine, doxifluridine, and tegafur may increase 5fluorouracil exposure; therefore, fluorouracil toxicity such as thrombocytopenia, granulocytopenia, anemia, and stomatitis must be monitored [22,23].…”

Formulation, Evaluation and Release Kinetics of Low Viscosity Metronidazole Gel with Varying Amount o f Carbopol

“…Metronidazole grows the risk for over anticoagulation where acenocoumarol used by patients. This fusion must be avoided (5) .…”

Impact of ABCB1 C3435T Polymorphism on Treatment Response of Vitamin K Antagonists: A Systematic Review and Meta-analysis

“…It is necessary for patient safety and personal medication therapy to regularly monitor prothrombin time (PT) or the international normalized ratio (INR). VKAs have a narrow therapeutic range and, therefore, levels outside this range increase the risk of thromboem-bolism or bleeding incidences.VKAs are drugs that interact with various medications and foods [4][5][6] and maintenance doses of VKAs are affected by patient age, 7) body weight, 8) clinical conditions, 9,10) and genetic factors. 8,11) According to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) are known to influence the warfarin dosing algorithm.…”

“…VKAs are drugs that interact with various medications and foods [4][5][6] and maintenance doses of VKAs are affected by patient age, 7) body weight, 8) clinical conditions, 9,10) and genetic factors. 8,11) According to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) are known to influence the warfarin dosing algorithm.…”