Drug Interactions of Co-amoxiclav
Co-amoxiclav has clinically significant interactions with warfarin and oral anticoagulants, requires monitoring with oral contraceptives, and interacts with probenecid, but the evidence for warfarin interaction is conflicting and requires careful interpretation.
Anticoagulant Interactions
The most clinically important interaction is with warfarin and other oral anticoagulants, though the evidence is contradictory:
The FDA label warns that abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving amoxicillin and oral anticoagulants, requiring appropriate monitoring when anticoagulants are prescribed concurrently 1
Higher doses of co-amoxiclav (10-12 g/day versus usual doses of 3.6 g/day) increase the risk of elevated INR values (≥4) when combined with warfarin 2
However, a randomized controlled trial found no significant interaction: the mean maximum INR increase was 0.22 ± 0.3 with amoxiclav versus 0.24 ± 0.6 with placebo (P=0.94) in patients on stable warfarin therapy without infection 3
A case report documented elevated INR and microscopic hematuria from warfarin-amoxicillin/clavulanate interaction, with the suspected mechanism being decreased vitamin K-producing gut flora 4
Clinical approach: Monitor INR closely when initiating co-amoxiclav in patients on warfarin, particularly at higher doses, and adjust anticoagulant dosing as needed to maintain therapeutic INR 1
Probenecid Interaction
- Probenecid decreases renal tubular secretion of amoxicillin, resulting in increased and prolonged blood levels of amoxicillin, and coadministration cannot be recommended 1
Oral Contraceptive Interaction
Co-amoxiclav may reduce the efficacy of oral contraceptives, as with other broad-spectrum antibiotics 1
Most broad-spectrum antibiotics (except rifampin) do not significantly affect contraceptive effectiveness of combined oral contraceptives 5
Clinical approach: Counsel patients on oral contraceptives about potential reduced efficacy and consider backup contraception during treatment 1
Allopurinol Interaction
The concurrent administration of allopurinol and ampicillin substantially increases the incidence of rashes compared to ampicillin alone 1
There are no data with co-amoxiclav and allopurinol administered concurrently, but caution is warranted given the ampicillin data 1
Drug-Laboratory Test Interactions
High urine concentrations of amoxicillin may result in false-positive reactions when testing for glucose in urine using CLINITEST®, Benedict's Solution, or Fehling's Solution 1
Use enzymatic glucose oxidase reactions (such as CLINISTIX®) for accurate glucose testing 1
Following ampicillin administration to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted; this effect may also occur with co-amoxiclav 1
Common Pitfalls and Caveats
Key pitfall: The warfarin interaction evidence is contradictory—case reports and FDA warnings suggest risk, but a well-designed RCT found no interaction in stable patients without infection 1, 4, 3. The interaction may be more likely in the presence of infection, fever, or higher antibiotic doses 2, 4
Avoid: Assuming all patients on warfarin will have INR elevation—the interaction appears rare and may be context-dependent, but monitoring remains essential given potential bleeding complications 1, 3