Clarithromycin with Digoxin Interaction Details

Brand Names Associated with Clarithromycin

Brand Names Associated with Digoxin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Jan 08, 2024

Interaction Effect

Increased risk of digoxin toxicity

Interaction Summary

Concomitant use of clarithromycin (a P-gp inhibitor) with digoxin (a P-gp substrate) may increase digoxin exposure and risk for toxicity, including potentially fatal arrhythmias. Coadministration of clarithromycin and digoxin increased digoxin AUC by 70% in a pharmacokinetic study. If concomitant use is required, reduce digoxin dose by approximately 30% to 50% or modify the dosing frequency. Monitor digoxin plasma concentration and for potential signs and symptoms of clinical toxicity when initiating, adjusting, or discontinuing clarithromycin .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of clarithromycin (a P-gp inhibitor) with digoxin (a P-gp substrate) may increase digoxin exposure and risk for toxicity, including potentially fatal arrhythmias. If concomitant use is required, reduce digoxin dose by approximately 30% to 50% or modify the dosing frequency. Monitor digoxin plasma concentration and for potential signs and symptoms of clinical toxicity when initiating, adjusting, or discontinuing clarithromycin .

Mechanism Of Interaction

Inhibition of P-gp-mediated digoxin efflux transport by clarithromycin

Literature Reports

A) In pharmacokinetic studies, coadministration of clarithromycin and digoxin resulted in a 70% increase in digoxin AUC .

B) An 80-year-old woman receiving digoxin 0.125 mg daily for heart rate control was prescribed clarithromycin 500 mg twice daily for 14 days as a component of Helicobacter pylori eradication therapy. On completion of eradication therapy, she presented to the emergency department with epigastric pain, nausea, diaphoresis, blurred vision, and light-headedness. Her heart rate was 124 beats per minute (bpm) and blood pressure was 153/78 mmHg. An electrocardiogram showed junctional tachycardia at a rate of 120 bpm with right bundle-branch block pattern and significant reverse tick ST segment depression. Initial laboratory abnormalities included acute kidney injury (serum creatinine, 163 micromoles/L from a baseline of 115 micromoles/L), hyperkalemia (6.04 mmol/L), and a serum digoxin concentration of 9.9 nanograms/mL (ng/mL; from a baseline of between 1.5 and 2 ng/mL before starting eradication therapy). She was admitted to the coronary care unit and 200 mg digoxin-specific antigen binding fragment was administered intravenously. She was monitored for bradyarrhythmias but did not require temporary pacing. She was subsequently discharged off digoxin but required carvedilol for heart rate control .

C) A 15-year 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) were matched with controls (n=6439). Analysis revealed a strong correlation between digoxin toxicity and recent treatment with clarithromycin (14.8-fold increase in risk of toxicity), as well as erythromycin (3.7-fold increase in risk of toxicity) and azithromycin (3.7-fold increase in risk of toxicity) compared with no antibiotic treatment. The risk of digoxin toxicity was 4 times greater following treatment with clarithromycin compared with erythromycin and azithromycin. No difference in risk of digoxin toxicity was observed between erythromycin and azithromycin .

D) Two elderly patients developed digoxin toxicity after clarithromycin was prescribed for a respiratory infection. The first patient, an 86-year-old woman, was taking digoxin 0.25 mg daily for congestive heart failure and had a digoxin level of 1.5 ng/mL two months prior to admission. Five days before presenting to the emergency department, she was prescribed clarithromycin 500 mg twice daily for bronchitis. She experienced radiating chest pain and nausea, and was found to have a digoxin level of 3.84 ng/mL. Creatinine values were within the normal range. Clarithromycin was discontinued, and digoxin was held for four days before being resumed at a dose of 0.125 mg daily. Eleven days after discharge, the digoxin level was 1.8 ng/mL. The second patient, an 89-year-old man, was seen in the emergency department for a 4-day history of nausea, vomiting, decreased appetite, and a productive cough. Drug therapy included digoxin 0.25 mg daily for the past five years, with a serum digoxin level of 1.3 ng/mL three weeks prior to admission. Nine days prior to admission, he had been prescribed clarithromycin 500 mg twice daily for an upper respiratory infection. After 6 days of therapy, he began to experience severe nausea, and discontinued the clarithromycin upon advice of his physician. Three days later, on admission to the emergency department, his digoxin level was 3.47 ng/mL. Digoxin was discontinued, and his digoxin level decreased to 1.36 ng/mL after five days .

E) A 70-year-old woman receiving digoxin 0.25 mg daily for idiopathic cardiomyopathy was prescribed clarithromycin 500 mg twice daily for bronchitis. Following four days of concomitant therapy, the patient was hospitalized due to nausea, vomiting, weakness, and altered vision. Upon admission, her digoxin serum level was measured at 4.8 ng/mL and increased to 5.4 ng/mL during the first day of hospitalization. Digoxin and clarithromycin were discontinued, and her digoxin level decreased to 1.7 ng/mL within two days, along with a resolution of her symptoms .

F) A 72-year-old woman stabilized on digoxin 0.25 mg daily and warfarin 22.5 mg weekly was prescribed clarithromycin 500 mg three times daily for two weeks for Helicobacter pylori eradication. Twelve days later, she presented to the emergency room with complaints of weakness, dizziness, diarrhea, and blurred vision. Her serum digoxin concentration was measured at 4.6 ng/mL, while her international normalized ratio (INR) was 7.3. Both digoxin and warfarin were held, and she was admitted to the hospital. Eleven days later she was discharged on digoxin 0.125 mg daily and warfarin 2.5 mg daily. On follow-up her digoxin levels and INR were within the therapeutic range .

G) The affects of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 mg) were studied in 9 healthy male volunteers. Subjects were randomly assigned to the following treatments: 1) digoxin only 2) digoxin plus erythromycin 3) digoxin plus clarithromycin. Subjects took erythromycin or clarithromycin on the day before digoxin dosing and during the following 4 days. Erythromycin 200 mg was given 4 times a day and clarithromycin 200 mg was given twice daily. Neither erythromycin or clarithromycin caused significant changes in AUC, clearance, volume of distribution and half-life of digoxin. There was a significant increase in urinary digoxin excretion when erythromycin and clarithromycin were coadministered (digoxin alone: 98.4 mL/min; digoxin with erythromycin: 137.3 mL/min; digoxin and clarithromycin: 133.6 mL/min). Digoxin is a substrate of P-gp while erythromycin and clarithromycin inhibit P-gp transport. Clarithromycin and erythromycin do not have a significant effect on serum digoxin disposition when digoxin is administered intravenously. This report does not support the hypothesis that the increase in digoxin concentrations by macrolides is due to reduced renal excretion of digoxin .

Clarithromycin Overview

• Clarithromycin is used to treat certain bacterial infections, such as pneumonia (a lung infection), bronchitis (infection of the tubes leading to the lungs), and infections of the ears, sinuses, skin, and throat. It also is used to treat and prevent disseminated Mycobacterium avium complex (MAC) infection [a type of lung infection that often affects people with human immunodeficiency virus (HIV)]. It is used in combination with other medications to eliminate H. pylori, a bacterium that causes ulcers. Clarithromycin is in a class of medications called macrolide antibiotics. It works by stopping the growth of bacteria.

• Antibiotics such as clarithromycin 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.

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.

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.