What are the potential risks and interactions between digoxin and clarithromycin (Biaxin), particularly in older adults with impaired renal function?

Digoxin-Clarithromycin Interaction: High Risk of Toxicity Requiring Dose Reduction or Alternative Antibiotic

Clarithromycin significantly increases digoxin levels by 1.8-4.0-fold through P-glycoprotein inhibition, creating substantial risk of life-threatening digoxin toxicity—particularly in older adults with renal impairment—and should be avoided or require empiric digoxin dose reduction of 50% with intensive monitoring. 1, 2, 3

Mechanism and Magnitude of Interaction

• Clarithromycin inhibits P-glycoprotein-mediated tubular secretion of digoxin in the kidney, reducing renal digoxin clearance by 56-60% and prolonging elimination half-life by 82% 4, 5
• This interaction also occurs through P-glycoprotein inhibition in the intestine and bile capillary, increasing digoxin absorption and reducing biliary excretion 3
• The FDA drug label explicitly lists clarithromycin among macrolide antibiotics that raise serum digoxin concentration due to reduced clearance and/or volume of distribution, with the implication that digitalis intoxication may result 2
• In elderly patients, digoxin concentrations increased significantly after only 4-7 days of clarithromycin treatment, though some cases showed delayed increases occurring 53-190 days after co-administration 5, 3

Amplified Risk in Your Patient Population

Older adults with impaired renal function face compounded risk because:

• The American College of Cardiology identifies both advanced age and renal dysfunction as independent risk factors for digoxin toxicity 1
• Renal impairment already reduces digoxin clearance, and clarithromycin further decreases it by an additional 56-60% 5
• Even patients with end-stage renal disease on dialysis (including anuric patients) experienced 1.8-4.0-fold increases in digoxin levels when clarithromycin was added 3
• The interaction remains clinically significant even when renal function is dramatically impaired, as P-glycoprotein inhibition in the intestine and bile continues to elevate digoxin levels 3

Clinical Manifestations to Monitor

Watch for these signs of digoxin toxicity:

• Cardiac: Ventricular ectopy, bradyarrhythmias, AV block, or bidirectional ventricular tachycardia (highly specific for digoxin toxicity) 1
• Gastrointestinal: Anorexia, nausea, vomiting 1, 6
• Neurological: Confusion, weakness, asthenia, visual disturbances (blurred or yellow vision) 1, 6
• Toxicity can occur even when serum concentration remains within the therapeutic range (0.5-1.2 ng/mL), especially with concurrent risk factors 1

Management Algorithm

If clarithromycin must be used with digoxin:

1. Check baseline digoxin level immediately before starting clarithromycin 1
2. Reduce digoxin dose empirically by 50% during the entire clarithromycin course 1
3. Recheck digoxin level 24-48 hours after starting clarithromycin and again 24-48 hours after completing the course 1
4. Maintain continuous cardiac rhythm monitoring for at least 24-48 hours after starting clarithromycin 1
5. Verify and maintain serum potassium 4.0-5.5 mEq/L and correct any hypomagnesemia, as these electrolyte abnormalities compound toxicity risk 1

Preferred approach: Select an alternative non-interacting antibiotic 6

• Azithromycin also interacts with digoxin through P-glycoprotein inhibition and is not a safe alternative 1
• Consider fluoroquinolones or other non-macrolide antibiotics based on the infection being treated 6

Management of Established Toxicity

If digoxin toxicity develops:

• Immediately discontinue both digoxin and clarithromycin 1, 6
• For mild toxicity: Monitor cardiac rhythm continuously, maintain potassium >4.0 mEq/L (ideally 4.0-5.5 mEq/L), correct hypomagnesemia 1
• For severe toxicity (sustained ventricular arrhythmias, advanced AV block, digoxin level >4 ng/mL, or severe hyperkalemia): Administer digoxin-specific Fab antibody fragments immediately, with response typically occurring within 30 minutes to 4 hours 1
• Intravenous magnesium sulfate is reasonable for ventricular arrhythmias 1
• Temporary cardiac pacing may be needed for symptomatic bradyarrhythmias or heart block 1

Critical Pitfalls to Avoid

• Do not assume the interaction is clinically insignificant in patients with severe renal impairment or on dialysis—the interaction remains potent through non-renal mechanisms 3
• Do not wait for symptoms before checking digoxin levels—toxicity can develop within 4-7 days but may also occur much later 5, 3
• Do not rely solely on digoxin levels to exclude toxicity—toxicity can occur at therapeutic levels when risk factors are present 1
• Do not use hemodialysis to remove digoxin—it is ineffective except for life-threatening hyperkalemia in massive overdose 1