Digoxin
Elixir: 0.05 mg/mL
Injection: 0.1, 0.25 mg/mL
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Heart failure with reduced ejection fraction (HFrEF) | Adults with mild-to-moderate HFrEF, typically symptomatic despite guideline-directed medical therapy | Adjunctive (added to ACEi/ARB/ARNI, β-blocker, MRA, SGLT2 inhibitor) | FDA Approved |
| Atrial fibrillation — ventricular rate control | Adults with chronic AF, especially those with concomitant HFrEF or sedentary patients | Adjunctive (commonly combined with β-blocker) | FDA Approved |
| Pediatric heart failure | Infants and children with congenital heart disease–related ventricular dysfunction | Adjunctive | FDA Approved |
Digoxin sits squarely in the second-line space across both of its core indications. In HFrEF, contemporary guidelines reserve it for patients who remain symptomatic despite four-pillar therapy, where it reduces hospitalization for heart failure but does not improve mortality. In atrial fibrillation, it has been displaced from first-line rate control by β-blockers and non-dihydropyridine calcium channel blockers but retains a role when those agents are contraindicated, poorly tolerated, or insufficient — particularly in coexisting HFrEF, where calcium channel blockers are unsafe.
Fetal supraventricular tachycardia / fetal hydrops — transplacental therapy via maternal oral or IV digoxin. Evidence: moderate quality (observational cohorts, FAST trial supportive).
Pediatric supraventricular tachycardia maintenance — chronic suppression in infants and young children when β-blockers are not tolerated. Evidence: moderate quality (small RCTs and registries).
Cor pulmonale and right heart failure — selective use in patients with overlapping left ventricular dysfunction. Evidence: low quality (legacy practice; modest physiologic rationale).
Atrial flutter rate control — adjunct when other AV nodal blockers are insufficient. Evidence: moderate quality (extrapolated from AF data).
Dosing
Digoxin is dosed by clinical scenario and tailored to lean body weight, renal function, and target serum concentration. For heart failure, contemporary practice targets the lower end of the historical therapeutic range (0.5–0.9 ng/mL), informed by post-hoc analysis of the DIG trial showing higher mortality at levels ≥1.2 ng/mL. Loading doses are reserved for acute rate control of atrial fibrillation; chronic oral therapy reaches steady state in approximately 5–7 days without loading.
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| HFrEF — adult, normal renal function, no loading | 0.125 mg PO once daily | 0.125–0.25 mg PO once daily | 0.25 mg/day | Steady state reached by day 5–7. Target trough 0.5–0.9 ng/mL. Levels >1.2 ng/mL associated with increased mortality. |
| HFrEF — elderly, low body weight, or CrCl 30–50 | 0.0625–0.125 mg PO once daily | 0.0625–0.125 mg PO once daily | 0.125 mg/day | Dose by lean body weight, not actual body weight. Recheck level after dose change at steady state. |
| Atrial fibrillation — acute IV rate control | 0.25 mg IV, then 0.125–0.25 mg IV q6h | Total load 0.75–1.5 mg over 24 h | 1.5 mg total IV load | Onset of AV nodal effect 30–60 min; peak effect 2–6 h. Less effective in high adrenergic states (sepsis, post-op). |
| Atrial fibrillation — chronic oral rate control | 0.125 mg PO once daily | 0.125–0.25 mg PO once daily | 0.25 mg/day | Most effective at rest; β-blocker preferred for exertional rate control. |
| Renal impairment — CrCl 10–30 mL/min | 0.0625 mg PO once daily | 0.0625 mg daily or 0.125 mg every other day | 0.125 mg every other day | Steady state delayed to 2–3 weeks. Frequent level monitoring (every 1–2 weeks) until stable. |
| End-stage renal disease / dialysis | 0.0625 mg PO every 48–72 h | 0.0625 mg PO every 48–72 h | 0.125 mg twice weekly | Not significantly removed by hemodialysis (large Vd). Empiric dose reduction; titrate to serum level. |
| Conversion IV to oral (tablet) | Multiply IV dose by 1.25 (tablet bioavailability ~80%) | Continue same daily total | — | Capsule form: dose 1:1 with IV (bioavailability ~100%). |
Pediatric Dosing
| Age Group | Total Digitalizing Dose (PO) | Daily Maintenance (PO) | Maximum Dose | Notes |
|---|---|---|---|---|
| Premature neonate | 20–30 mcg/kg over 24 h | 5–7.5 mcg/kg/day divided q12h | 7.5 mcg/kg/day | Reduced renal clearance; tighter monitoring required. |
| Term neonate (<1 month) | 25–35 mcg/kg over 24 h | 6–10 mcg/kg/day divided q12h | 10 mcg/kg/day | Give 50% load initially, then 25% q6–8h × 2. |
| Infant (1 month–2 y) | 35–60 mcg/kg over 24 h | 10–15 mcg/kg/day divided q12h | 15 mcg/kg/day | Highest weight-based dose due to large Vd and rapid clearance. |
| Child (2–10 y) | 30–40 mcg/kg over 24 h | 8–10 mcg/kg/day divided q12h | 10 mcg/kg/day | Transition to once-daily dosing as child grows. |
| Child >10 y / adolescent | 10–15 mcg/kg over 24 h | 3–5 mcg/kg/day once daily | 0.25 mg/day | Adult-pattern dosing; check level 6–8 h post-dose. |
Digoxin distributes minimally into adipose tissue. In obese patients, dosing by actual body weight risks toxicity. Calculate the dose using ideal or lean body weight, then adjust to serum trough concentration once steady state is reached. The same applies to elderly patients and those with sarcopenia, where reduced muscle mass (the major distribution compartment) shrinks Vd and prolongs half-life.
Pharmacology
Mechanism of Action
Digoxin binds and inhibits the α-subunit of cardiac membrane Na⁺/K⁺-ATPase, raising intracellular sodium. This blunts the sodium gradient that drives the sodium–calcium exchanger (NCX), so less calcium is pumped out of the myocyte during diastole. The resulting rise in intracellular calcium increases the force of myocardial contraction — the classic positive inotropic effect that defined digoxin’s role in heart failure for two centuries.
The rate-control effect in atrial fibrillation comes from a separate mechanism: digoxin enhances central vagal tone, slowing AV nodal conduction and prolonging the AV refractory period. This vagally mediated action is most pronounced at rest, which is why digoxin controls resting ventricular rate well but is overpowered during exercise or sympathetic surge. Crucially, digoxin does not improve mortality in HFrEF; it reduces hospitalizations and improves symptoms, with the most favorable risk–benefit profile at low therapeutic concentrations.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tablet F = 60–80%; capsule and elixir F = 90–100%; IV F = 100%; Tmax 1–3 h orally | High-fiber meals and antacids reduce absorption; switching formulations requires dose adjustment. |
| Distribution | Vd 6–10 L/kg (lean body weight); ~25% protein bound; concentrates in skeletal muscle and myocardium | Large Vd means dialysis cannot remove digoxin meaningfully; Fab fragments bind tissue stores. |
| Metabolism | ~16% hepatic (minor CYP3A4); P-glycoprotein substrate (intestine and kidney); some patients harbor gut Eubacterium lentum that degrades digoxin | P-gp inhibitors (amiodarone, verapamil, clarithromycin) drive most clinically relevant interactions. |
| Elimination | 50–70% renal as unchanged drug; t½ 36–48 h with normal function, prolonged to 3.5–5 days in severe renal impairment | Renal dose adjustment is the single most important PK consideration; dose changes take 5+ half-lives to reach new steady state. |
Side Effects
At therapeutic serum concentrations (0.5–0.9 ng/mL), digoxin is generally well tolerated, with no individual adverse effect reaching ≥10% incidence at standard doses. The toxicity profile becomes problematic at supratherapeutic levels, where gastrointestinal, neurologic, visual, and life-threatening cardiac effects emerge. The DIG trial reported suspected digoxin toxicity in 11.9% of treated patients versus 7.9% on placebo.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Suspected digoxin toxicity (composite — DIG trial) | 11.9% | vs 7.9% on placebo; absolute increase ~4%. Strongly correlates with serum levels >1.2 ng/mL. |
| Anorexia, nausea, vomiting (at supratherapeutic levels) | 15–25% | Often the earliest symptom of toxicity; may precede cardiac manifestations by hours to days. |
| Visual disturbances at toxic levels (yellow halos, blurred or hazy vision, scotomata) | 10–25% | Distinctive xanthopsia is highly suggestive of toxicity in the right clinical context. |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | 4.9% | Often improves with dose reduction; consider checking serum level before attributing to other causes. |
| Mental disturbances (confusion, apathy, mild cognitive blunting) | 4.1–5.0% | Higher incidence in elderly; can be mistaken for dementia or depression. |
| Headache | 4.1% | Usually mild; reassess if persistent or worsening. |
| Diarrhea | 3.2% | May reflect rising serum level; check trough if new-onset. |
| Nausea (at therapeutic levels) | 1.6–3.2% | Distinguish from toxicity-related nausea, which is often more severe and accompanied by anorexia. |
| Rash (urticarial, scarlatiniform, or maculopapular) | 1.6–2.1% | Typically mild; rare progression to severe cutaneous reactions. |
| Cardiac arrhythmias (PVCs, first-degree AV block, junctional rhythms) at therapeutic levels | 0.9–1.5% | Frequency rises sharply once serum level exceeds 2 ng/mL. |
| Gynecomastia (with long-term use) | ~1% | Estrogen-like effect; usually reversible with discontinuation. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Life-threatening ventricular arrhythmia (sustained VT, VF, bidirectional VT) | Rare at therapeutic levels; up to 30% of severe toxicity cases | Hours after acute overdose; days into chronic toxicity | Hold drug; check level and potassium; administer digoxin-specific Fab (DigiFab) if hemodynamically significant. |
| High-grade AV block / complete heart block | ~1–3% of toxic cases | Hours to days | Discontinue; transcutaneous or transvenous pacing if symptomatic; Fab for severe cases. |
| Symptomatic bradycardia or sinus arrest | Uncommon | Hours after dose change or interaction | Hold drug; atropine for symptomatic bradycardia; Fab for hemodynamic instability. |
| Hyperkalemia (acute toxicity) | Common in acute overdose | Within hours of acute ingestion | K⁺ >5.5 mEq/L is a Fab indication; avoid calcium (theoretical risk of “stone heart”). |
| Atrial tachycardia with AV block (“PAT with block”) | Rare but classic for toxicity | Days into chronic toxicity | Hold drug; check level; Fab if hemodynamically significant. |
| Mesenteric ischemia (rare; from splanchnic vasoconstriction) | Very rare | Within hours of IV administration | Avoid in suspected mesenteric ischemia; supportive care if recognized. |
| Severe cutaneous reaction (toxic epidermal necrolysis, erythema multiforme) | Very rare | Days to weeks | Discontinue immediately; supportive dermatologic care; do not rechallenge. |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Suspected digoxin toxicity | ~2% | Most common cause for permanent discontinuation in DIG trial. |
| GI intolerance (nausea, anorexia, diarrhea) | ~1–2% | Often resolves with dose reduction before requiring full discontinuation. |
| Arrhythmia (new or worsening) | ~0.5–1% | Usually reflects elevated serum levels; check level before discontinuation. |
| Renal function decline (resulting in unsafe levels) | ~0.5% | Common driver of dose reduction or discontinuation in elderly heart failure cohorts. |
The earliest symptoms of digoxin toxicity are usually non-cardiac: anorexia, nausea, fatigue, or visual disturbance. Any new GI symptom in a patient on chronic digoxin should prompt a serum level (drawn ≥6–8 hours post-dose), creatinine, and potassium. Digoxin-specific Fab fragments (DigiFab) reverse cardiac toxicity within 30–60 minutes and are indicated for life-threatening arrhythmia, K⁺ >5.5 mEq/L in acute toxicity, ingestion >10 mg in adults (or >4 mg in children), or serum level >10 ng/mL at any time.
Drug Interactions
Digoxin is not significantly metabolized by CYP enzymes, so most clinically meaningful interactions are pharmacokinetic (P-glycoprotein inhibition, altered renal clearance) or pharmacodynamic (electrolyte effects, additive AV nodal blockade). The narrow therapeutic index amplifies the consequences of even modest level changes.
Monitoring
Monitoring digoxin centers on three axes: serum drug concentration, renal function, and electrolytes. The narrow therapeutic window means that small shifts in any of these can move a stable patient into the toxic range.
-
Serum digoxin level
Baseline at 5–7 days, then 6 months, then annually
Routine Draw ≥6–8 hours after the last dose to allow distribution. Target 0.5–0.9 ng/mL in HFrEF; up to 2.0 ng/mL acceptable for AF rate control if tolerated. Recheck after any dose change, renal function shift, or interacting drug initiation. -
Serum digoxin level
Whenever toxicity suspected
Trigger-based Any new GI symptoms, visual disturbance, confusion, bradyarrhythmia, or unexplained worsening of cardiac status warrants an immediate level along with electrolytes and creatinine. -
Renal function (creatinine, eGFR)
Baseline, every 6 months
Routine Check more frequently in elderly, dehydration, heart failure decompensation, or any acute illness. Even small declines in eGFR can produce clinically significant level rises given the long half-life. -
Serum potassium
Baseline, every 3–6 months
Routine Maintain K⁺ ≥4.0 mEq/L. Hypokalemia sensitizes the myocardium to digoxin and can precipitate toxicity at otherwise safe levels — particularly relevant in patients on loop diuretics. -
Serum magnesium
Baseline, when K⁺ is low or replacing
Trigger-based Hypomagnesemia is a frequent and underrecognized contributor to toxicity. Replete to >2.0 mg/dL; correcting magnesium often restores potassium when both are low. -
Electrocardiogram
Baseline, when toxicity suspected
Trigger-based Look for the digitalis effect (downsloping ST depression, T-wave inversion, shortened QT) at baseline — a normal finding. Toxicity manifests as bradyarrhythmias, AV block, atrial tachycardia with block, junctional rhythms, or bidirectional VT. -
Heart rate and blood pressure
Each clinic visit
Routine Resting heart rate <60 bpm with symptoms warrants level check and reassessment of dosing. In AF, target a resting rate <110 bpm (lenient) or <80 bpm (strict) per indication. -
Thyroid function (TSH)
Baseline, then annually if clinically indicated
Trigger-based Hypothyroidism prolongs digoxin half-life and increases sensitivity; hyperthyroidism reduces sensitivity. New AF should always prompt thyroid screening regardless. -
Symptoms of toxicity (patient interview)
Each clinic visit
Routine Specifically ask about appetite, nausea, vision (yellow halos, blurring), and confusion. Patients often dismiss these as “getting older” — direct questioning catches early toxicity.
Contraindications & Cautions
Absolute Contraindications
- Ventricular fibrillation — digoxin worsens ventricular ectopy and is never indicated.
- Known hypersensitivity to digoxin or any cardiac glycoside.
- Active digoxin toxicity — discontinue and treat; do not continue dosing.
- Wolff-Parkinson-White syndrome with atrial fibrillation — digoxin shortens accessory pathway refractoriness and can precipitate VF.
Relative Contraindications (Specialist Input Recommended)
- Hypertrophic obstructive cardiomyopathy — positive inotropy worsens outflow tract obstruction; cardiology input required if rate control or HF therapy is being considered.
- Restrictive cardiomyopathy and cardiac amyloidosis — increased sensitivity and arrhythmia risk; specialist guidance essential.
- Second- or third-degree AV block without pacemaker — digoxin worsens AV conduction; consider only with electrophysiology consultation.
- Sick sinus syndrome without pacemaker — risk of profound bradycardia or sinus arrest.
- Acute myocardial infarction — increased oxygen demand and arrhythmogenicity; defer unless rate control or HF management is otherwise unmanageable.
- End-stage renal disease without close monitoring access — drug accumulation is unpredictable; document risk-benefit discussion.
- Severe pulmonary hypertension with right heart failure — limited efficacy and arrhythmia risk; specialist evaluation before initiation.
Use with Caution
- Hypokalemia, hypomagnesemia, or hypercalcemia — correct before and during therapy.
- Hypothyroidism — start at lower dose; reduced clearance.
- Hyperthyroidism — increased dose may be needed; reassess at euthyroidism.
- Elderly (age ≥75) — start at 0.0625–0.125 mg daily; reduced renal clearance and lean body mass.
- Concomitant cardioversion — withhold digoxin 24–48 hours pre-procedure if possible; toxicity-related arrhythmias may be precipitated by electrical cardioversion.
- Active myocarditis or pericarditis — increased arrhythmia susceptibility.
- Recent thiamine deficiency or alcohol use disorder — beriberi heart can mimic the digitalis-responsive failure pattern; assess thiamine status.
Digoxin is classified by FDA as a narrow therapeutic index drug. The toxic-to-therapeutic ratio is approximately 2:1, meaning routine doses can become toxic with modest changes in renal function, electrolyte status, or interacting medications. Toxicity can present with minimal warning and may be fatal.
Switching between brand and generic formulations, or between manufacturers of generics, may result in clinically significant changes in serum concentration. Maintain consistent product where possible and recheck a level if formulation changes are unavoidable.
Digoxin-specific antibody fragments (DigiFab) should be readily available wherever digoxin is administered IV or used in critically ill patients. Indications for Fab include serum level >10 ng/mL at any time, K⁺ >5.5 mEq/L in acute poisoning, life-threatening arrhythmia, or ingestion exceeding 10 mg in adults (or 4 mg in children).
Patient Counselling
Purpose of Therapy
Digoxin is being prescribed either to help your heart pump more strongly (heart failure) or to slow your heart rate when it beats too fast from atrial fibrillation. It is added to your other heart medicines, not used alone. Digoxin works well at controlling symptoms but does not extend life on its own — it is one piece of a larger treatment plan.
How to Take
Take digoxin once a day, ideally at the same time each day. It can be taken with or without food, but try to be consistent — taking it with meals every day is fine, as long as the routine stays the same. High-fiber foods, antacids, and certain other medicines can reduce absorption, so separate digoxin from these by at least two hours. Never double up if you miss a dose more than 12 hours late: skip it and take your next regular dose. Bring your medicine bottle to every appointment so the team can confirm strength and refill timing.
Sources
- U.S. Food and Drug Administration. Lanoxin (digoxin) tablets — Prescribing Information. accessdata.fda.gov Primary source for FDA-approved indications, dosing, contraindications, and adverse reaction frequencies.
- U.S. Food and Drug Administration. DigiFab (digoxin immune Fab) — Prescribing Information. accessdata.fda.gov Reference for indications, dosing, and clinical use of digoxin-specific antibody fragments in toxicity.
- European Medicines Agency / national SmPC for digoxin. medicines.org.uk European prescribing information aligning UK/EU practice with US labelling.
- The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525–533. doi.org/10.1056/NEJM199702203360801 Landmark trial establishing that digoxin reduces hospitalization but not mortality in HFrEF — defines the modern role of the drug.
- Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA. 2003;289(7):871–878. doi.org/10.1001/jama.289.7.871 Post-hoc DIG analysis showing higher mortality at serum levels ≥1.2 ng/mL — basis for the modern lower target range.
- Kotecha D, Bunting KV, Gill SK, et al. Effect of digoxin vs bisoprolol for heart rate control in atrial fibrillation on patient-reported quality of life: the RATE-AF randomized clinical trial. JAMA. 2020;324(24):2497–2508. doi.org/10.1001/jama.2020.23138 Contemporary RCT demonstrating non-inferiority of digoxin to bisoprolol for symptomatic rate control in older AF patients.
- Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation (ATHENA). N Engl J Med. 2009;360(7):668–678. doi.org/10.1056/NEJMoa0803778 Provides context for dronedarone–digoxin interaction and the broader rate-control literature.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. J Am Coll Cardiol. 2022;79(17):e263–e421. doi.org/10.1016/j.jacc.2021.12.012 Defines the contemporary place of digoxin in HFrEF — second-line, symptom-driven, after guideline-directed quadruple therapy.
- Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation. Circulation. 2024;149(1):e1–e156. doi.org/10.1161/CIR.0000000000001193 Current US guideline framing of digoxin’s role in AF rate control, including class of recommendation and level of evidence.
- McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599–3726. doi.org/10.1093/eurheartj/ehab368 European HF guideline, complementary to AHA/ACC, with consistent positioning of digoxin in symptomatic HFrEF despite GDMT.
- Van Gelder IC, Rienstra M, Bunting KV, et al. 2024 ESC guidelines for the management of atrial fibrillation. Eur Heart J. 2024;45(36):3314–3414. doi.org/10.1093/eurheartj/ehae176 Most recent European AF guideline, covering rate-control targets and the place of digoxin in modern practice.
- Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis. 2002;44(4):251–266. doi.org/10.1053/pcad.2002.31591 Detailed review of Na/K-ATPase inhibition and the dual inotropic and neurohormonal mechanisms of digoxin action.
- Smith TW. Digitalis: mechanisms of action and clinical use. N Engl J Med. 1988;318(6):358–365. doi.org/10.1056/NEJM198802113180606 Foundational pharmacology review — still the clearest exposition of the calcium-mediated inotropic mechanism.
- Aronson JK. Clinical pharmacokinetics of digoxin 1980. Clin Pharmacokinet. 1980;5(2):137–149. doi.org/10.2165/00003088-198005020-00002 Classical PK reference for half-life, distribution, and renal clearance values still used in clinical dosing.
- Antman EM, Wenger TL, Butler VP Jr, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Circulation. 1990;81(6):1744–1752. doi.org/10.1161/01.CIR.81.6.1744 Pivotal multicenter case series defining Fab indications, dosing, and outcomes in severe toxicity.
- Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: a systematic review and meta-analysis of the literature. Eur Heart J. 2015;36(28):1831–1838. doi.org/10.1093/eurheartj/ehv143 Meta-analysis of digoxin and mortality in AF and HF; informs current cautious use and target serum levels.