Warfarin with Erythromycin Interaction Details

Brand Names Associated with Warfarin

Brand Names Associated with Erythromycin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 07, 2023

Interaction Effect

An increased risk of bleeding

Interaction Summary

Erythromycin is a CYP3A substrate and inhibitor and concomitant use with warfarin (a CYP3A4 substrate) may result in increased INR and thereby increase the risk for bleeding. If erythromycin therapy is required in a patient taking warfarin, more frequent monitoring of INR is recommended, especially when erythromycin is initiated and discontinued . The majority of case reports of the interaction between erythromycin and warfarin have occurred in the elderly . A case report of an increase in INR values following the initiation of ophthalmic erythromycin was reported in an elderly woman . The suspected mechanism of interaction is related to impairment of the hepatic metabolism of warfarin, but may also involve alterations in intestinal flora that synthesize vitamin K. 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, specifically a 4.5-fold increase with azole antifungals including posaconazole .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of erythromycin and warfarin should be approached with caution as this may result in increased INR and thereby increase the risk for bleeding. When possible, substitute erythromycin with an antibiotic with a low-risk profile for bleeding. If concomitant use of erythromycin and warfarin is required, more frequent monitoring of the patient's INR is recommended, especially during initiation and discontinuation of erythromycin . Dose adjustments of one or both agents may also be warranted .

Mechanism Of Interaction

Disruption of vitamin K synthesis; inhibition of CYP3A4-mediated warfarin metabolism

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) A 77-year-old woman had an increase in INR values following the initiation of ophthalmic erythromycin for chronic bacterial conjunctivitis. The patient was receiving a maintenance dose of 14 mg/week warfarin for thromboembolism prophylaxis secondary to atrial fibrillation. She was stable on this dose for over 4 months with INR values ranging from 1.8 to 2.5. Three weeks following the initiation of erythromycin, the patient had an INR value of 8.5. Due to a suspected drug interaction, warfarin was held for 2 days. The patient then returned for another INR measurement. At this time her INR had decreased to 4.7. Warfarin was again held for 2 more doses. A new weekly warfarin maintenance dose of 12 mg/week (a 14% reduction) was initiated and maintained for 5 weeks. Again the patient returned for an INR measurement, which had decreased to 1.5. It was found that erythromycin had been discontinued 5 days prior to INR monitoring. She was given a new warfarin regimen of 16 mg/weekly (a 25% increase). The patient maintained her warfarin dosage regimen for another 5 months, with INR values ranging between 2.9 to 3.4. In subsequent monitoring, she was found to have an INR of 4.2 and determined that erythromycin had been reintroduced 5 days prior. A new warfarin regimen of 13 mg/week (a 19% reduction) was initiated on which she maintained for over the next 3 months with her INRs ranging from 1.8 to 2.4 .

C) Concomitant administration of erythromycin base and warfarin has been reported to decrease warfarin clearance by 14%. This effect was observed to be greatest among patients whose control phase warfarin clearance was slow and least among patients with fast warfarin clearances. This study was based upon a single 1 mg/kg dose of warfarin and further studies are required using inpatients receiving continuous warfarin therapy .

D) An interaction between warfarin and erythromycin stearate was reported in a 77-year-old female patient who had been well-controlled with warfarin 7.5 mg daily. She was placed on erythromycin stearate 500 mg 4 times a day for a right lower lobe infiltrate. Ecchymoses were present on the extremities, buccal mucosa, and abdomen, and the prothrombin time (PT) was 64/11. The patient was given 2 units of fresh frozen plasma, intramuscular phytonadione 10 mg, and intravenous phytonadione 15 mg. The patient was discharged in 2 weeks in good control (PT 22/11) on 5 mg of warfarin daily. Erythromycin was possibly responsible for inhibition of warfarin metabolism .

E) A 59-year-old white female was admitted to the hospital with an APTT of 72 seconds (control 35 seconds) and a prothrombin time (PT) of 120 seconds (control 12 seconds). She had been on maintenance warfarin 4 mg daily for peripheral embolization with a PT that was 2 times normal. Four days prior to admission, erythromycin ethylsuccinate was prescribed for parotitis. The erythromycin was discontinued and the PT returned to normal after the administration of intravenous phytonadione 10 mg .

F) The addition of intravenous erythromycin lactobionate 1 g every 6 hours to warfarin anticoagulation significantly potentiated the anticoagulant effects, resulting in hemorrhage in a 63-year-old man with Legionella pneumonia. The patient had severe anorexia on admission with concomitant reduction in vitamin K intake for 3 weeks prior to the bleeding episode; this contributed further to the increased warfarin sensitivity. The mechanism was postulated to be inhibition of warfarin metabolism by erythromycin, resulting in reduced warfarin clearance .

G) An enhanced anticoagulant response to warfarin and hemorrhaging was reported in a 32-year-old patient with DVT given erythromycin for treatment of cellulitis in the right foot. Withdrawal of the antibiotic resulted in a normal hypoprothrombinemic response to warfarin. Although the patient was not rechallenged, the authors felt the timing of the events and lack of other drugs being taken concurrently strongly suggested interaction between erythromycin and warfarin .

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.

Erythromycin Overview

• Erythromycin is used to treat certain infections caused by bacteria, such as infections of the respiratory tract, including bronchitis, pneumonia, Legionnaires' disease (a type of lung infection), and pertussis (whooping cough; a serious infection that can cause severe coughing); diphtheria (a serious infection in the throat); sexually transmitted diseases (STD), including syphilis; and ear, intestine, gynecological, urinary tract, and skin infections. It also is used to prevent recurrent rheumatic fever. Erythromycin is in a class of medications called macrolide antibiotics. It works by stopping the growth of bacteria.

• Antibiotics such as erythromycin will not work for colds, flu, or other viral infections. Taking antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.

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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.