Digoxin with Azithromycin Interaction Details

Brand Names Associated with Digoxin

Brand Names Associated with Azithromycin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Mar 04, 2024

Interaction Effect

Digoxin toxicity (vomiting, cardiac arrhythmias)

Interaction Summary

The mechanism behind the interaction between azithromycin and digoxin is not completely understood[1]. Reduced colonies of the gut microbe Eubacterium lentum, which normally metabolizes digoxin to several pharmacodynamically less active metabolites, may be caused by antibacterial use. This may in turn decrease the presystemic metabolism of digoxin, increase systemic absorption and increase serum digoxin levels. Interference with renal and intestinal P-glycoprotein activity may also contribute to the altered disposition of digoxin [2]. A nested case-control study revealed a strong association between digoxin toxicity and recent macrolide use (clarithromycin, erythromycin and azithromycin); however, clarithromycin imparted the highest risk [3]. Measure the digoxin serum level prior to concurrent use. Continue to monitor digoxin levels throughout the coadministration period and reduce the digoxin dose, if necessary [4].

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Coadministration of azithromycin and digoxin may increase digoxin plasma concentrations. Measure digoxin concentrations prior to initiation of concurrent use. Reduce the digoxin dose by approximately 15% to 30% or by modify the dosing frequency as necessary. Continue monitoring digoxin plasma concentration[4][5].

Mechanism Of Interaction

Unknown

Literature Reports

A) An in vitro study evaluated the impact of macrolide antibiotics on the P-gp mediated efflux of digoxin. Erythromycin had no effect on the P-gp transport of digoxin, although it did reduce the efflux ratio of dihydrodigoxin and digoxigenin (relatively inactive metabolites) by 34% and 43%. Erythromycin demonstrated only partial P-gp inhibition with the use of a known P-gp substrate. In comparison, clarithromycin almost completely inhibited P-gp efflux of digoxin and azithromycin had minimal influence on P-gp mediated digoxin transport. The authors concluded the mechanism behind the clinical cases of erythromycin-induced digoxin toxicity is multifactorial [1].

B) A 15-year, population-based, nested case-control study revealed a strong association between digoxin toxicity and recent treatment with macrolides (clarithromycin, erythromycin and azithromycin), with clarithromycin imparting the highest risk. Patients who received at least 1 prescription a macrolide antibiotic during digoxin treatment and who were hospitalized for digoxin toxicity within 14 days of starting the antibiotic (n=1659; median age, 80 years (yr), interquartile range (IQR), 75 to 85 yr; 34% male) were matched with controls (n=6439; median age 80 yr; IQR, 75 to 85 yr). Analysis revealed a strong correlation between digoxin toxicity and recent treatment with clarithromycin (adjusted odds ratio (OR), 14.83; 95% CI, 7.89 to 27.86), as well as erythromycin (adjusted OR, 3.69; 95% CI, 1.72 to 7.9) and azithromycin (adjusted OR, 3.71; 95% CI, 1.1 to 12.52) compared with no antibiotic treatment. The risk of digoxin toxicity was 4 times greater following treatment with clarithromycin compared with erythromycin (OR, 4.02; 95% CI, 1.49 to 10.81) and azithromycin (OR, 4; 95% CI, 1.06 to 15.73). No difference in risk of digoxin toxicity was observed between erythromycin and azithromycin (OR, 0.99; 95% CI, 0.24 to 4.18). Based on the proposed mechanism for the macrolide-digoxin interaction (inhibition of p-glycoprotein-mediated digoxin transport), as expected, there was no correlation with cefuroxime (no effect on p-glycoprotein) use and hospitalization for digoxin toxicity (adjusted OR, 0.85; 95% CI, 0.21 to 3.41) [3].

C) A case report describes a 31-month-old who developed symptoms of digoxin toxicity after initiation of treatment with azithromycin. After several days of concomitant therapy with digoxin and azithromycin the boy developed progressive worsening of his congestive heart failure, including atrioventricular block, and signs of digoxin toxicity. On the third day of azithromycin therapy his serum digoxin level was 2.37 mcg/L. Digoxin was discontinued after the fourth day of therapy and 26 hours after administration of the last dose of digoxin his serum digoxin levels decreased to 1.81 mcg/L and his atrioventricular block resolved spontaneously [2].

References

1 ) Hughes J & Crowe A: Inhibition of P-glycoprotein-mediated efflux of digoxin and its metabolites by macrolide antibiotics. J Pharmacol Sci 2010; 113(4):315-324.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

2 ) Ten Eick A, Sallee D, Preminger T, et al: Possible drug interaction between digoxin and azithromycin in a young child. Clin Drug Invest 2000; 20(1):61-64.

3 ) Gomes T, Mamdani MM, Juurlink DN, et al: Macrolide-induced digoxin toxicity: a population-based study . Clin Pharmacol Ther 2009; 86(4):383-386.PubMed Abstract: http://www.ncbi.nlm.nih.gov/...

4 ) Product Information: LANOXIN(R) oral tablets, digoxin oral tablets. Covis Pharmaceuticals, Inc. (per FDA), Cary, NC, 2013.

5 ) Product Information: digoxin oral solution, digoxin oral solution. Roxane Laboratories, Inc. (per manufacturer), Columbus, OH, 2012.

Digoxin Overview

• Digoxin is used to treat heart failure and abnormal heart rhythms (arrhythmias). It helps the heart work better and it helps control your heart rate.

Azithromycin Overview

• Azithromycin is used to treat certain bacterial infections, such as bronchitis; pneumonia; sexually transmitted diseases (STD); and infections of the ears, lungs, sinuses, skin, throat, and reproductive organs. Azithromycin also is used to treat or prevent disseminated Mycobacterium avium complex (MAC) infection [a type of lung infection that often affects people with human immunodeficiency virus (HIV)]. Azithromycin is in a class of medications called macrolide antibiotics. It works by stopping the growth of bacteria.

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

Return To Our Drug Interaction Homepage

Feedback, Question Or Comment About This Information?

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.