Digoxin and Clarithromycin: Interaction Details

a) In pharmacokinetic studies, coadministration of clarithromycin and digoxin resulted in a 70% increase in digoxin AUC ¹.

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 ⁵.

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 ⁶.

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 ⁷.

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 ⁸.

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 ⁹.

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 ¹⁰.

h) During a 7-year population-based, nested case-control study, among 231,257 elderly patients receiving digoxin during the study period, 1051 cases (median age, 80.6 years) were admitted with a diagnosis of digoxin toxicity. Digoxin treatment was received for a median (IQR) of 1.1 (0.2 to 3) years. The median (IQR) length of hospital stay for digoxin toxicity was 5 (3 to 8) days. Thirty-three patients (3%) died during hospitalization. For each case, 50 controls (n=51,896) were selected matching on age, sex, continuous use of the same long-term medication, and presence or absence of renal disease. Following multivariate analysis, patients admitted for digoxin toxicity were about 12 times more likely to have been treated with clarithromycin in the week prior to admission (adjusted OR, 11.7; 95% CI, 7.5 to 18.2). Authors estimated at least 2.3% of hospital admission for digoxin toxicity in elderly patients could have been prevented with the avoidance of clarithromycin. Risk of drug toxicity was not increased with the use of cefuroxime ⁴.