Diltiazem Moderately Increases Digoxin Levels by Approximately 20-50%
Cardizem (diltiazem) increases serum digoxin concentrations by approximately 20-50%, which is clinically significant and requires dose adjustment and monitoring, but is generally manageable and less severe than interactions with some other drugs like verapamil or quinidine.
Magnitude of the Interaction
The FDA-approved drug label for Cardizem states that administration with digoxin in 24 healthy subjects increased plasma digoxin concentrations by approximately 20% 1. However, this represents the lower end of observed increases, and clinical studies demonstrate a broader range:
- Clinical studies show increases of 22-50% in steady-state digoxin levels when diltiazem is added 2, 3
- One study in heart failure patients found diltiazem (180 mg/day) increased steady-state digoxin levels from 1.11 ng/mL to 1.54 ng/mL—a 39% increase—within 3-7 days 3
- Another controlled study showed diltiazem increased digoxin AUC by 51%, prolonged elimination half-life by 37%, and reduced total digoxin clearance by 50% 4
- Individual variability exists: one study reported 8 of 12 patients experienced increases ranging from 24-70% (mean 46%) 5
Mechanism and Clinical Implications
The interaction occurs through two mechanisms:
- Prolongation of digoxin elimination half-life (from ~36 hours to ~45 hours) 2
- Reduction in total body clearance and extrarenal clearance of digoxin 4, 5
- Renal clearance is generally not significantly affected 4, 5, 2
This is a moderate-severity interaction that requires action but is less concerning than interactions with verapamil or quinidine, which are specifically highlighted in major guidelines 6. The 2013 ACC/AHA Heart Failure Guidelines list verapamil and quinidine as drugs that increase digoxin concentrations and toxicity risk, but notably diltiazem is mentioned less prominently in the toxicity warnings compared to these agents 6.
Clinical Management Algorithm
When initiating diltiazem in a patient on digoxin:
- Check baseline digoxin level before starting diltiazem
- Reduce digoxin dose by 25-50% when adding diltiazem, particularly if baseline digoxin level is >0.7 ng/mL 1
- Recheck digoxin level in 3-7 days after starting diltiazem (new steady state is reached quickly) 3
- Target therapeutic range: 0.5-0.9 ng/mL (lower than historically recommended) 6
- Monitor for toxicity signs: arrhythmias, GI symptoms (nausea, anorexia), visual disturbances, confusion 6
Risk factors that amplify concern:
- Age >70 years
- Impaired renal function
- Low lean body mass
- Hypokalemia or hypomagnesemia
- Concurrent use of other drugs affecting digoxin levels (amiodarone, beta-blockers) 6
Important Caveats
The ESC 2008 Guidelines specifically note that "certain drugs may increase plasma digoxin levels (amiodarone, diltiazem, verapamil, certain antibiotics, quinidine)" 7, placing diltiazem in the same category as verapamil but without distinguishing severity.
One study reported ECG signs of digitalis toxicity in 4 of 10 patients when diltiazem increased digoxin levels by 39-50%, even though levels remained within what was then considered therapeutic 8. This underscores that toxicity can occur at "therapeutic" levels, especially with the now-recognized lower optimal target range of 0.5-0.9 ng/mL.
The FDA label emphasizes conflicting results exist in the literature—one investigator found no increase in digoxin levels in 12 patients with coronary artery disease 1—but the preponderance of evidence supports a clinically significant interaction requiring monitoring.
Combination therapy with digoxin and diltiazem is commonly used for rate control in atrial fibrillation and is more effective than either agent alone 9, 10, so the interaction should not prevent combined use—it simply requires appropriate dose adjustment and monitoring.