What are the recommended dosing and serum levels for digoxin (digitalis glycoside) therapy?

Digoxin Dosing and Therapeutic Levels

Recommended Therapeutic Serum Concentrations

The optimal therapeutic range for digoxin is 0.5-0.9 ng/mL, with concentrations above 1.0 ng/mL associated with increased mortality risk without additional clinical benefit. 1

• The American Heart Association recommends maintaining serum concentrations between 0.5-1.0 ng/mL for optimal clinical benefit with minimal toxicity risk 1
• Retrospective analysis of the Digitalis Investigation Group trial demonstrated that risk-adjusted mortality increased as plasma concentrations exceeded 1.0 ng/mL 1
• Prevention of worsening heart failure at lower concentrations (0.5-0.9 ng/mL) was as effective as higher concentrations 1
• Overt toxicity is commonly associated with levels >2.0 ng/mL, but toxicity can occur at lower levels in the presence of hypokalemia, hypomagnesemia, hypothyroidism, or drug interactions 2, 3

Standard Maintenance Dosing

For most adults under 70 years with normal renal function, initiate digoxin at 0.25 mg once daily; for patients over 70 years or with impaired renal function, start at 0.125 mg daily; and for marked renal impairment, begin at 0.0625 mg daily. 4

Dosing Algorithm by Patient Characteristics:

Patients <70 years with normal renal function:

• Initial dose: 0.25 mg daily 4
• Target serum level: 0.5-0.9 ng/mL 1

Patients >70 years OR impaired renal function:

• Initial dose: 0.125 mg daily 4
• Consider every-other-day dosing for high-risk populations 5

Marked renal impairment (CrCl <30 mL/min):

• Initial dose: 0.0625 mg daily 4
• When combined with amiodarone and CrCl ≤30 mL/min with N-desethylamiodarone >600 ng/mL, reduce to 0.03125 mg daily 6

Maximum recommended dose:

• 0.375 mg daily is the maximum for atrial fibrillation, though doses this high are rarely needed 5
• Higher doses (0.375-0.50 mg daily) are rarely appropriate for heart failure 7

Loading Dose Regimens (When Rapid Digitalization Required)

For rapid digitalization in acute settings, administer 0.25-0.5 mg IV initially, followed by additional 0.25 mg doses at 6-8 hour intervals, up to a maximum of 1.0 mg over 24 hours. 2

• The loading dose should be administered in portions, with approximately half given as the first dose 4
• For oral loading: 0.5-0.75 mg produces detectable effect in 0.5-2 hours, maximal effect in 2-6 hours 4
• Additional oral doses of 0.125-0.375 mg may be given at 6-8 hour intervals until adequate clinical effect 4
• Loading doses are NOT recommended for chronic heart failure management—use gradual digitalization with maintenance dosing instead 7

Critical Dose Adjustments for Drug Interactions

When digoxin is combined with interacting medications, mandatory dose reductions are required:

• Amiodarone: Reduce digoxin dose by 30-50% 2, 3
• Dronedarone: Reduce digoxin dose by at least 50% 2, 3
• Verapamil, clarithromycin, erythromycin, itraconazole, cyclosporine, propafenone: Monitor digoxin levels closely and reduce dose as needed 2, 3

Monitoring Recommendations

Timing of serum level measurement:

• Draw levels just before the next scheduled dose, or at least 6-8 hours after the last dose 4
• On once-daily dosing, concentrations will be 10-25% lower at 24 hours versus 8 hours post-dose, depending on renal function 4
• Steady-state concentrations achieved in approximately 5 half-lives (1-3 weeks depending on renal function) 4

When to check levels:

• Initial monitoring early during chronic therapy, especially with renal impairment 1
• When adding medications that increase digoxin levels 1
• When signs/symptoms of toxicity appear (confusion, nausea, anorexia, visual disturbances, cardiac arrhythmias) 1
• Serial assessment is unnecessary in stable patients without concerning features 7

Renal Dosing Adjustments

Digoxin maintenance dose must be adjusted based on creatinine clearance (CrCl):

For a 70 kg patient with heart failure 4:

• CrCl 10 mL/min: 0.125 mg daily (steady state in 19 days)
• CrCl 30 mL/min: 0.125-0.1875 mg daily (steady state in 14 days)
• CrCl 50 mL/min: 0.1875-0.25 mg daily (steady state in 12 days)
• CrCl 70 mL/min: 0.1875-0.25 mg daily (steady state in 10 days)
• CrCl 100 mL/min: 0.25-0.375 mg daily (steady state in 7 days)

Common Pitfalls and Contraindications

Absolute contraindications:

• Second or third-degree AV block without permanent pacemaker 2, 5
• Pre-excitation syndromes (WPW with AF/atrial flutter) 2, 5
• Previous digoxin intolerance 5

High-risk conditions requiring extreme caution:

• Hypokalemia (K+ <4.0 mEq/L): Correct BEFORE administering digoxin 3
• Hypomagnesemia: Correct before or concurrent with digoxin 3
• Hypothyroidism: Increases toxicity risk even at therapeutic levels 3
• Advanced age (>70 years) and low lean body mass 3

Critical clinical caveat:

• Digoxin toxicity can occur even when serum concentration is within the previously considered "therapeutic range" of 0.5-1.2 ng/mL, particularly with electrolyte abnormalities 3
• Women may not benefit from digoxin therapy and may be at increased risk for death 1
• Use with caution or avoid in post-MI patients, particularly those with ongoing ischemia 1