Amoxicillin; Clavulanate with Warfarin Interaction Details

Brand Names Associated with Warfarin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 15, 2023

Interaction Effect

An increased risk of bleeding

Interaction Summary

Concomitant use of amoxicillin with oral anticoagulants has resulted in rare cases of abnormal prolongation of bleeding time (increased INR). In a nested case-control study of continuous warfarin users aged 65 years or older, there was a 2-fold increase in risk of bleeding requiring hospitalization with exposure to any antibiotic therapy, including penicillins. The suggested mechanism of interaction is alteration in intestinal flora that synthesize vitamin K . Case reports have also described an increase in INR following concomitant use of amoxicillin or amoxicillin clavulanate with warfarin . However, in a prospective, double-blind, 2-phase crossover study (n=12) in patients on stable warfarin therapy, addition of amoxicillin/clavulanate did not significantly increase the INR compared with placebo. It was suggested that previous case reports of an INR increase with amoxicillin may not be due to a drug-drug interaction and that the infection itself may be the factor altering the INR . When possible, substitute amoxicillin with an antibiotic with a low-risk profile for bleeding. If concomitant use is deemed necessary, more frequent monitoring of INR is recommended , especially during initiation and discontinuation of amoxicillin . It may also be necessary to adjust the warfarin dose in order to maintain the desired anticoagulation level .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Concomitant use of amoxicillin and warfarin should be approached with caution as this may result in increased INR and thereby increase the risk for bleeding. When possible, substitute amoxicillin for an antibiotic with a low-risk profile for bleeding. If concomitant use of amoxicillin and warfarin is required, more frequent monitoring of the patient's INR is recommended, especially during initiation and discontinuation of the antibiotic . In addition, adjust the warfarin dose as needed to maintain the desired anticoagulation level .

Mechanism Of Interaction

Disruption of vitamin K synthesis

Literature Reports

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) .

B) In a prospective, double-blind, two-phase crossover study in patients (n=12; mean age 41.3 years; range, 22 to 68 years) on stable warfarin therapy, addition of amoxicillin/clavulanate did not significantly increase the INR compared with placebo. Patients who had received warfarin for at least 1 month with a stable INR (3 consecutive values over a minimum of 5 days) and had no recent infection or inflammatory disease were randomized to receive a 7-day course of either oral amoxicillin 1000 mg/clavulanate 125 mg twice daily or matching placebo during each 10 day period; warfarin doses remained stable during each period. Mean maximal INR elevations from baseline to day 10 were similar between the amoxicillin/clavulanate and placebo groups (0.22 +/- 0.3 and 0.24 +/- 0.6, respectively; p=0.94); correspondingly, the mean maximum INR was not significantly different between the groups (2.57 +/- 0.4 vs 2.67 +/- 0.5; p=0.64). Warfarin plasma concentrations (factor II, R(-) and S(-)) were also comparable between either treatment period and between days 1 and 7. The study was only powered to detect significant differences in INR (increase of 1.1). It was suggested that previous case reports of an INR increase with concomitant amoxicillin may not be due to a drug-drug interaction and that the infection itself may be the factor altering the INR .

C) A case report described an elevated INR and hematuria in a 58-year-old woman following concomitant use of amoxicillin/clavulanate with warfarin. The patient, whose medical history included atrial fibrillation, hypertension, rheumatoid arthritis, and hysterectomy, was admitted to the emergency room (ER) with a diagnosis of warfarin toxicity. She had been taking warfarin 7.5 mg/day for greater than 1 year for stroke prophylaxis. Her INRs during that time had been in the therapeutic range of 2 to 3. Her INR in the ER was 6.2. One month before the current events, she was prescribed amoxicillin 500 mg/clavulanate potassium 125 mg for 7 days for an ear infection. An INR drawn 3 weeks prior to initiation of the antibiotic was 3.2. The dose of warfarin was not changed. The patient was also taking lisinopril/hydrochlorothiazide, zolpidem, verapamil, loratadine, gabapentin, and acetaminophen/oxycodone. An INR drawn 4 days after completion of antibiotic therapy was 2.55. Two and a half weeks after the course of amoxicillin/clavulanate potassium was completed the patient's INR was 6.2. A repeat INR was 8.7, and microscopic hematuria was noted. She was treated with 2 units of fresh frozen plasma and 1 subQ dose of vitamin K in the ER. The next day, her INR was 3.43. An additional dose of oral vitamin K 2.5 mg was given on hospital day 2 and the patient was discharged home without warfarin. The patient's INR on follow-up was 1.9 and she was restarted on warfarin 5 mg/day alternating with 7.5 mg/day, and later on stabilized on a maintenance dose of 6.5 mg/day .

D) A case report described an increase in INR and the subsequent death of an 85-year-old woman following coadministration of amoxicillin/clavulanate with warfarin. The patient had been on long-term warfarin anticoagulation for a DVT. Amoxicillin/clavulanate was prescribed for one week for a chest infection while she maintained her other medications of warfarin, digoxin, and furosemide. The patient was found collapsed at home and was admitted to the emergency room with oral and rectal bleeding. Hemoglobin was 6.6 g/dL and her INR was greater than 10. The patient died and postmortem evidence of profuse bleeding throughout her body was documented .

E) A case report described an increased INR in a 65-year-old man following coadministration of amoxicillin and warfarin. The patient had 6 lower anterior teeth extracted and was given amoxicillin 3 g orally one hour before the extractions. One week later, the patient's INR was 9.1. He was admitted to the hospital and given 4 units of fresh frozen plasma, 2 units of blood over several days and vitamin K. Warfarin was stopped and his INR fell to 4.3 after 24 hours. His warfarin regimen was eventually reestablished to allow his INR to be within the therapeutic range .

F) A case report described an increase in INR in a 54-year-old woman who was already taking warfarin and was prescribed amoxicillin. Amoxicillin 3 g was prescribed as prophylactic cover before routine dental treatment. She had been taking warfarin for several years with a stable INR in the range of 2.8 to 3.1. Five days after receiving a single dose of amoxicillin, her INR was 6.4. Warfarin was stopped for 2 days. She then received her usual maintenance dose of 10 mg daily. Her INR returned to the therapeutic range .

Warfarin Overview

• Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels. It is prescribed for people with certain types of irregular heartbeat, people with prosthetic (replacement or mechanical) heart valves, and people who have suffered a heart attack. Warfarin is also used to treat or prevent venous thrombosis (swelling and blood clot in a vein) and pulmonary embolism (a blood clot in the lung). Warfarin is in a class of medications called anticoagulants ('blood thinners'). It works by decreasing the clotting ability of the blood.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.