Digoxin is a cardiac glycoside with positive inotropic and antiarrhythmic effects.398, 400, 402
Digoxin is used for the treatment of mild to moderate heart failure in adults.398, 400, 402 Digoxin is also used to increase myocardial contractility in pediatric patients with heart failure.398, 400, 402
The Digitalis Investigation Group was a randomized, double-blind study enrolling 6800 adults with heart failure and a left ventricular ejection fraction ≤0.45.384, 398, 400, 402 Patients (N=6800) were randomized to treatment with either digoxin or placebo for 37 weeks.398, 400, 402 At randomization, 67% of patients were in New York Heart Association (NYHA) class I or II.398 The primary outcome was overall mortality, with secondary outcomes of mortality from cardiovascular causes, death from worsening heart failure, hospitalization for worsening heart failure, and other cause hospitalization.384 After a mean follow-up of 37 months, digoxin was associated with a reduction in the risk of hospitalization from worsening heart failure or any cause hospitalization.384, 398 However, there was no significant difference in mortality (overall, cardiovascular, or noncardiovascular) between digoxin and placebo.384, 398
Two additional, smaller trials (RADIANCE and PROVED) enrolled a total of 266 adult patients with NYHA class II or III heart failure previously treated with digoxin, a diuretic (PROVED and RADIANCE), and an angiotensin-converting enzyme (ACE) inhibitor (RADIANCE only).398, 1002, 1003 In both trials, patients underwent an 8-week stabilization period, followed by a 12-week double-blind phase with randomization to either placebo or digoxin.1002, 1003 In both trials, patients were continued on a diuretic, and in the RADIANCE trial, continued on an ACE inhibitor.1002, 1003 Withdrawal of digoxin was associated with decreased exercise tolerance and a worsening of heart failure.398, 1002, 1003
Clinical data on the use of digoxin in pediatric patients with heart failure are limited.398, 400, 402 In a retrospective analysis of the National Pediatric Cardiology Quality Improvement Collaborative registry, the effect of digoxin on mortality following initial surgery was assessed in a cohort of pediatric patients with single ventricle heart disease and no history of arrhythmia.1006 The estimated difference in interstage mortality between patients given digoxin and those not treated with digoxin was 9%.1006 In a second retrospective cohort study using data from the Pediatric Heart Network Single Ventricle Reconstruction trial, similar results were reported, with a reduction in interstage mortality associated with digoxin use (absolute risk reduction, 9.4%).1007
Current guidelines for the management of heart failure recommend guideline-directed medical therapy with a combination of drug therapies to reduce morbidity and mortality, including ACE inhibitors, sodium-glucose cotransporter 2 inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors (ARNIs), β-blockers, and mineralocorticoid receptor antagonists.800 Diuretics are recommended on an as-needed basis to improve symptoms of congestion and prevent worsening of disease in patients with fluid retention.800 Once guideline-directed medical therapy is optimized, additional therapies including ivabradine, vericiguat, polyunsaturated fatty acids, potassium binders, and digoxin may be considered based on patient-specific factors.800
In patients with structural heart disease who do not have any prior or current signs or symptoms of heart failure (i.e., Stage B disease) who have a left ventricular ejection fraction (LVEF) ≤40%, ACE inhibitors should be used to reduce mortality and prevent symptomatic heart failure; angiotensin II receptor antagonists may be used in such patients with a recent MI who are intolerant to ACE inhibitors.800 In patients with heart failure with reduced ejection fraction (HFrEF) and New York Heart Association (NYHA) class II to III symptoms, use of an ARNI is recommended first-line to reduce morbidity and mortality.800, 1005 Angiotensin II receptor antagonists are recommended for such patients only when an ARNI is contraindicated, inaccessible, or poorly tolerated.1005 In patients with symptomatic heart failure with a mildly reduced ejection fraction (i.e., LVEF 41-49%), angiotensin II receptor antagonists may be considered (particularly in patients with a LVEF on the lower end of the range) to reduce the risk of hospitalizations for heart failure and cardiovascular mortality.800
Specific for digoxin, current guidelines note the lack of contemporary data for the use of digoxin in HFrEF, with most use in heart failure treatment focused on rate control in patients with atrial fibrillation and low blood pressure.1005 Additionally, the benefits of digoxin in patients currently treated with guideline-directed medical therapy is unclear.800 Its use is generally reserved for patients remaining symptomatic despite optimal guideline recommended therapies.800
A statement from the American Heart Association (AHA) on management of chronic heart failure in pediatric patients discusses the use of several agents for medical management.1008 The authors note that digoxin has been used empirically for pediatric patients with a single ventricle and at risk for heart failure.1008
Digoxin is used for control of ventricular response rate in adults with chronic atrial fibrillation.398, 400, 402
In 3 separate randomized, double-blind trials, digoxin was compared to placebo for conversion to sinus rhythm in 315 adult patients with recent-onset atrial fibrillation.398, 400, 402 Digoxin and placebo resulted in similar rates and rapidity of conversion to normal sinus rhythm.398, 400, 402 In a comparative trial between digoxin, sotalol, and amiodarone, digoxin was associated with the lowest rate of conversion to sinus rhythm and the least acceptable rate control following conversion.398, 400, 402
Effects of digoxin on delaying reversion to atrial fibrillation in 43 adult patients with frequent recurrence were evaluated in a randomized, double-blind crossover trial.398, 400, 402, 1009 No difference was seen in the total number of atrial fibrillation episodes based on ambulatory recordings, duration of episodes, or ventricular rate during an episode.1009 Digoxin was associated with an increased (54%) mean time between symptomatic occurrences compared with placebo.398, 400, 402
In the AFFIRM (AF Follow-up Investigation of Rhythm Management) study, use of digoxin was associated with a 41% increase in mortality in patients with atrial fibrillation;395 however, additional post-hoc analyses have reported conflicting results.396, 397
Current guidelines on the management of atrial fibrillation recommend use of beta-blockers and nondihydropyridine calcium-channel blocking agents (e.g., diltiazem, verapamil) as standard of care for rate control in patients with atrial fibrillation.701 In patients with atrial fibrillation and heart failure, digoxin can be considered for long-term rate control in combination with other rate-controlling agents, or as monotherapy if other agents are contraindicated or cannot be tolerated.701
Supraventricular Tachyarrhythmia
Digoxin is used in the management of sustained fetal tachyarrhythmias†.1011, 1012 Supraventricular tachycardia (SVT) and atrial flutter (AF) are the most common types of fetal tachyarrhythmias and are treated via transplacental administration of digoxin, flecainide, sotalol, and/or amiodarone.1011, 1012 A meta-analysis evaluated 10 clinical trials on the use of antiarrhythmic transplacental treatment of fetal tachyarrhythmias, including digoxin, flecainide, sotalol, and amiodarone.1011 Average gestational age was 30.3 weeks.1011 Among patients with SVT, the rate of tachyarrhythmia termination was lower with digoxin compared to flecainide, with no difference seen between digoxin and sotalol.1011 For patients with AF, no difference was seen between digoxin and sotalol for termination of tachyarrhythmia.1011
A statement from the AHA on management of cardiac arrhythmias in the fetal and neonatal periods discusses treatment approaches to both SVT and AF.1012 Initial therapy for both SVT and AF includes monotherapy with either flecainide, sotalol, or digoxin, with addition of a second agent (i.e., either flecainide, sotalol, or digoxin) if cessation of arrhythmia is not achieved.1012 Monotherapy with amiodarone is a third-line option if arrhythmia persists despite dual therapy.1012
Supraventricular Tachyarrhythmia in Adults
Digoxin has been used in the management of SVT of unknown mechanism† in patients without pre-excitation and who are not candidates for catheter ablation.700 Beta-blockers, diltiazem, and verapamil, in absence of pre-excitation, have a stronger level of recommendation from the AHA compared to digoxin.700
Digoxin also is used in the management of SVTs due to AV nodal reentry tachycardia (AVNRT) or AV reentry tachycardia (AVRT)† in patients without pre-excitation and who are not candidates for catheter ablation.700 Similar to SVTs of unknown mechanism, beta-blockers, diltiazem, and verapamil have a stronger level of recommendation from the AHA compared to digoxin.700 Other available options, depending on characteristics of the SVT, include flecainide, propafenone, amiodarone, dofetilide, and/or sotalol.700
Dispensing and Administration Precautions
Digoxin usually is administered orally.398, 402 When oral therapy is not feasible or when rapid therapeutic effect is necessary, the drug may be administered parenterally.400 Although digoxin may be given IM or IV, the IV route of administration is preferred because IM injection can cause severe pain at the site of injection.400 If the drug must be administered by the IM route, injections should be made deep into the muscle followed by massage of the injection site, and no more than 2 mL of the drug should be injected at a single site in adult and pediatric patients.400
Digoxin is administered orally as tablets or oral solution.398, 402 The manufacturers recommend once-daily dosing in adults and children ≥10 years of a divided daily dosing is recommended in infants and children <10 years of age.398, 402
The manufacturer recommends that the oral solution be used to obtain the appropriate dose in infants, young children, or patients with very low body weights.398, 402 The calibrated dosing syringe supplied by the manufacturer should be used to measure doses of the oral digoxin solution; a separate measuring device should be used to accurately measure doses less than 0.1 mL.402
Store tablets in a dry place, protected from light at 25°C (excursions permitted to 15-30°C).398 Store solution protected from light at 20-25°C.402
For IV administration, digoxin injection may be given undiluted or may be diluted with a 4-fold or greater volume of sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection; use of less than a 4-fold volume of diluent may cause precipitation of the drug.400 Diluted IV solutions of digoxin should be used immediately.400
Digoxin should be administered by slow IV infusion (over at least 5 minutes); rapid IV (i.e., bolus) administration may cause systemic and coronary vasoconstriction and should be avoided.400
Mixing of digoxin injection with other drugs in the same container or simultaneous administration in the same IV line is not recommended.400
Digoxin injection should be protected from light and stored at 25°C (excursions permitted to 15-30°C).400
Digoxin has a narrow therapeutic index; therefore, cautious dosage determination is essential and dosage must be carefully individualized based on clinical assessment and therapeutic drug monitoring.398, 400, 402 Dosage guidelines provided are based upon average patient response and substantial patient variation can be expected.398, 400, 402 When selecting an appropriate dosage, the patient's renal function, body weight, age, concomitant disease states, concurrent drugs, and other factors likely to alter serum concentrations of digoxin should be considered.398, 400, 402 Because the distribution of digoxin is proportional to lean body weight, lean body weight should be used for dosage calculations.402 Serum digoxin concentrations can be used to guide dosing, but should always be interpreted in the overall clinical context.400
Digoxin dosage may be initiated with or without a loading dose depending on whether rapid titration or a more gradual titration is desired; the different approaches vary in dosage and frequency of administration but achieve the same total amount of digoxin accumulated in the body.398, 400, 402
Loading doses of digoxin are administered in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose and additional fractions (usually 25%) usually administered every 6-8 hours with careful assessment of the patient's clinical response (including possible toxicity) before each additional dose.398, 400, 402 If a change from the calculated loading dose is required, then the maintenance dosage should be calculated based upon the amount (i.e., total loading dose) actually administered.402
More gradual attainment of digoxin concentrations can be achieved by initiating therapy with a maintenance dosage without a loading dose.402 Steady-state serum digoxin concentrations will be achieved in about 5 half-lives of the drug for the individual patient; depending on the patient's renal function, this may take approximately 1-3 weeks.402
Differences in the bioavailability of parenteral and oral preparations of digoxin should be considered when patients are switched from one dosage form to another .398, 400, 402 Because the absolute bioavailability of digoxin tablets and solution are similar, equivalent dosages may be used.402 When switching from oral to IV therapy, dosage of digoxin should be reduced by about 20-25%.402
Since daily maintenance digoxin dosage is a replacement of daily digoxin loss from the body, an alternative dosing method has been used where the maintenance dosage for a particular patient is estimated by multiplying the daily percentage loss by the peak body stores (i.e., loading dose) that produced a satisfactory response.398, 400 The percentage of digoxin eliminated from the body daily can be estimated by the following equation:398, 400
daily % loss = 14 + [creatinine clearance (in mL/minute) / 5]
Loading doses are generally not required in patients with heart failure.800 If a loading dose is to be given, the manufacturers recommend an oral loading dose of 10-15 mcg/kg or an IV loading dose of 8-12 mcg/kg in adults, administered in divided doses.398, 400, 402
Experts state that digoxin is commonly initiated and maintained at a dosage of 125-250 mcg (0.125-0.25 mg) daily for the management of heart failure in adults.800 The manufacturers recommend an initial oral digoxin maintenance dosage of 3.4-5.1 mcg/kg once daily as tablets or 3-4.5 mcg/kg once daily as the oral solution in adults with normal renal function; dosage may be increased every 2 weeks according to clinical response, serum digoxin concentrations, and toxicity.398, 402 If IV administration is necessary, the manufacturer recommends an initial IV maintenance dosage of 2.4-3.6 mcg/kg once daily in adults with normal renal function; dosage may be increased every 2 weeks according to clinical response, serum digoxin concentrations, and toxicity.400 The manufacturer's prescribing information should be consulted for recommended maintenance oral and IV dosages based on renal function.398, 400, 402
If a loading dose is to be given for rate control in patients with atrial fibrillation, the manufacturers recommend an oral loading dose of 10-15 mcg/kg or an IV loading dose of 8-12 mcg/kg in adults, administered in divided doses.398, 400, 402 Some experts recommend an initial IV dose of 250-500 mcg (0.25-0.5 mg) with repeat dosing to a maximum of 1500 mcg (1.5 mg) over 24 hours.701 These experts state that the usual oral maintenance dosage of digoxin for ventricular rate control in adults with atrial fibrillation is 125-250 mcg daily.701
Dosage should be carefully titrated in neonates, especially in premature infants, because renal clearance of digoxin is reduced in such patients.398, 402 Infants and young children (up to 10 years of age) generally require proportionally larger doses than children ≥10 years of age and adults when calculated on the basis of lean body weight or body surface area.402 Children ≥10 years of age require adult dosages in proportion to the child's body weight.402
Loading doses and maintenance dosages recommended by the manufacturers for the treatment of heart failure in pediatric patients are given in the tables that follow based on the dosage form administered.398, 400, 402
Age | Oral Loading Dosea | Initial Oral Maintenance Dosage |
|---|---|---|
5-10 years | 20-45 mcg/kg | 3.2-6.4 mcg/kg twice daily |
>10 years | 10-15 mcg/kg | 3.4-5.1 mcg/kg once daily |
aLoading doses are administered in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose; additional 25% fractions are administered every 6-8 hours
Age | Oral Loading Dosea | Initial Oral Maintenance Dosage |
|---|---|---|
Premature neonates | 20-30 mcg/kg | 2.3-3.9 mcg/kg twice daily |
Full-term neonates | 25-35 mcg/kg | 3.8-5.6 mcg/kg twice daily |
1-24 months | 35-60 mcg/kg | 5.6-9.4 mcg/kg twice daily |
2-5 years | 30-45 mcg/kg | 4.7-6.6 mcg/kg twice daily |
5-10 years | 20-35 mcg/kg | 2.8-5.6 mcg/kg twice daily |
>10 years | 10-15 mcg/kg | 3-4.5 mcg/kg once daily |
aLoading doses are administered in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose; additional fractions may be administered every 4-8 hours
Age | IV Loading Dosea | Initial IV Maintenance Dosage |
|---|---|---|
Premature neonates | 15-25 mcg/kg | 1.9-3.1 mcg/kg twice daily |
Full-term neonates | 20-30 mcg/kg | 3-4.5 mcg/kg twice daily |
1-24 months | 30-50 mcg/kg | 4.5-7.5 mcg/kg twice daily |
2-5 years | 25-35 mcg/kg | 3.8-5.3 mcg/kg twice daily |
5-10 years | 15-30 mcg/kg | 2.3-4.5 mcg/kg twice daily |
>10 years | 8-12 mcg/kg | 2.4-3.6 mcg/kg once daily |
aLoading doses are administered in divided doses, with 50% of the total dose given as the first (i.e., initial) dose; additional 25% fractions are administered every 6-8 hours
No dosage adjustment is necessary in patients with hepatic impairment; however, serum digoxin concentrations may be used to guide dosing in such patients.398, 400, 402
Renal function should be considered during dosage selection.398, 400, 402 Digoxin is principally excreted by the kidneys and impaired renal function may predispose patients to digoxin toxicity.398, 400, 402 Dosage should be reduced and titrated carefully in patients with renal impairment based on clinical response and serum digoxin concentrations as appropriate.398, 400, 402
The manufacturer's prescribing information should be consulted for recommended maintenance oral and IV dosages based on renal function.398, 400, 402
Lower dosages (125 mcg [0.125 mg] daily or every other day) are recommended for the management of heart failure in adults with renal impairment.800
Dosage of digoxin should be selected carefully in geriatric patients since they are more likely to have impaired renal function.398, 400, 402 Lower dosages (125 mcg [0.125 mg] daily or every other day) are recommended for the management of heart failure in geriatric patients >70 years of age.800
The presence of hypothyroidism may reduce the dosage requirements for digoxin, warranting smaller dosages in patients with the condition.402
Patients with Malabsorptive Conditions
Although specific dosage adjustments are not provided, the absorption of digoxin may be reduced in patients with certain malabsorptive conditions such as chronic diarrhea.400
Ventricular Fibrillation in Patients with Accessory AV Pathway (Wolff-Parkinson-White Syndrome)
Digoxin should be used with caution in patients with Wolff-Parkinson-White (WPW) syndrome and atrial fibrillation since the drug may enhance conduction via the accessory pathway and result in extremely rapid ventricular rates and ventricular fibrillation.398
Sinus Bradycardia and Sino-atrial Block
Digoxin may cause severe sinus bradycardia or sinoatrial block, particularly in patients with a prior sinus node disease.398, 400, 402 Digoxin may also cause advanced or complete heart block in patients with pre-existing incomplete AV block.398, 400, 402 Consider pacemaker insertion in such patients prior to initiating digoxin therapy.398, 400, 402
If plasma concentrations of digoxin are to be determined, blood samples should be obtained at least 6-8 hours after the daily dose and preferably just prior to the next scheduled daily dose.398, 400, 402 Therapeutic plasma concentrations of digoxin in adults generally are 0.5-2 ng/mL.398, 400, 402 Some experts suggest that plasma concentrations of 0.5-0.9 ng/mL are sufficient for the treatment of heart failure in adults; however, limited data are available.800 In adults, toxicity is usually, but not always, associated with steady-state plasma digoxin concentrations exceeding 2 ng/mL.398, 400, 402 Toxicity may also occur with lower digoxin levels, especially in the presence of advanced age, impaired renal function, hypokalemia, hypomagnesemia, or hypothyroidism.398 Serum concentrations of digoxin should be interpreted in the overall clinical context; thus, an isolated serum concentration measurement should not be used alone as the basis for adjusting dosage.398, 400, 402
Digoxin concentrations can be falsely elevated because of endogenous digoxin-like immunoreactive substances (DLIS), which usually cause false-positive or falsely elevated concentrations, and less often, falsely reduced concentrations.398 Some assays are more susceptible to DLIS interference than others.398 DLIS are present in up to half of all neonates, varying percentages of pregnant individuals, and those with hypertrophic cardiomyopathy, volume expansion, and/or renal or hepatic dysfunction.398 Measured levels of DLIS (in digoxin equivalents) are typically low, ranging from 0.2-0.4 ng/mL, but sometimes can reach therapeutic or toxic levels.398
Some assays can falsely detect spironolactone, carenone, potassium canrenoate, and some traditional Chinese and Ayurvedic substances (e.g., Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha, Dashen) at digoxin levels up to 0.5 ng/mL.398
Digoxin toxicity is associated with digoxin serum levels >2 ng/mL, although the potential for adverse reactions increases at levels >1.2 ng/mL.398, 400 The presence of hypokalemia further increases the risk of adverse effects.398, 400 Additionally, patients with lower body weight, advanced age, impaired renal function, hypercalcemia, or hypomagnesemia may be predisposed to developing digoxin toxicity; therefore, serum electrolytes and renal function should be assessed periodically.398, 400
Signs and symptoms of digoxin toxicity can include anorexia, nausea, vomiting, visual changes, and cardiac arrhythmias such as first-degree AV block, Mobitz type I (Wenckebach) second-degree AV block, complete (third-degree) AV block (including asystole), atrial tachycardia with block, AV dissociation, accelerated junctional (nodal) rhythm, multiform or unifocal ventricular contractions, including bigeminy and trigeminy, ventricular fibrillation, and ventricular tachycardia.398, 400
Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants and children.398, 400 The use of digoxin, however, can produce any type of arrhythmia in children; the most common are conduction disturbances or supraventricular tachyarrhythmias such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia, and less commonly, ventricular arrhythmias.398, 400 Any cardiac conduction abnormalities or arrhythmias in children receiving digoxin should be considered a result of digoxin toxicity.398, 400
If signs of toxicity appear, digoxin should be discontinued immediately and serum digoxin concentrations obtained; the patient should be placed on a cardiac monitor while possible contributing factors (e.g., electrolyte and thyroid abnormalities, concomitant drugs) are addressed.398 Because heart failure may have symptoms in common with digoxin toxicity, when the etiology is unclear, assessment of serum digoxin levels is recommended.398, 400
Potassium supplementation should be administered in patients with hypokalemia to maintain serum concentrations between 4-5.5 mEq/L.398
Calcium should not be administered rapidly in patients receiving digoxin therapy, as rapid infusion may produce serious arrhythmias.398
Activated charcoal may be administered if acute ingestion (intentionally or accidentally) of a potentially toxic amount of digoxin occurs.398 Digoxin Immune Fab (DigiFab®) may be administered if life-threatening arrhythmias (ventricular tachycardia, ventricular fibrillation, high-degree AV block, bradyarrhythmia, sinus arrest) or hyperkalemia occur.398
In the event of chronic overdosage with digoxin, DigiFab® may be used in patients with symptomatic arrhythmia.398
Risk of Ventricular Arrhythmias During Elective Cardioversion
Since digoxin can induce ventricular arrhythmias, it is recommended that the dosage of the drug be reduced or therapy discontinued for 1-2 days before elective cardioversion in patients with atrial fibrillation; however, clinicians should consider the consequences of increasing the ventricular response if digoxin is decreased or withdrawn.398 Elective cardioversion should be postponed in patients with signs and symptoms of cardiac glycoside toxicity.398 If it is not possible to delay cardioversion, the lowest possible energy level should be used to avoid provoking ventricular arrhythmias.398
Risk of Ischemia in Acute Myocardial Infarction
The possibility that use of digoxin in patients with acute myocardial infarction (MI) may increase oxygen demand and associated ischemia should be considered.398 Digoxin is not recommended in patients with acute MI.398
Vasoconstriction in Myocarditis
Digoxin should be avoided in patients with myocarditis, as the drug can precipitate vasoconstriction and possibly promote the production of pro-inflammatory cytokines.398
Decreased Cardiac Output in Preserved Left Ventricular Systolic Function
Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction (e.g., restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, acute cor pulmonale) may experience decreased cardiac output with digoxin.398 Patients with idiopathic hypertrophic subaortic stenosis may experience worsening of their condition because of the inotropic effects of digoxin.398 Patients with amyloid heart disease may be more susceptible to digoxin toxicity because of increased binding to extracellular amyloid fibrils.398
Digoxin should be avoided in these patients, although the drug has been used for ventricular rate control in the subpopulation of patients with atrial fibrillation.398
Use in Patients with Electrolyte Abnormalities
Electrolyte imbalances, especially hypokalemia or hypomagnesemia, may predispose patients to the cardiotoxic effects of digoxin at serum digoxin concentrations within the therapeutic range.402 Potassium depletion sensitizes the myocardium to digoxin; therefore, it is recommended to maintain potassium and magnesium concentrations within normal ranges.402 Conversely, hypocalcemia may cause resistance to the effects of digoxin on the AV node, and digoxin may be ineffective until serum calcium is restored to normal.398 This is due to the fact that digoxin affects the contractility and excitability of the heart in a manner similar to calcium.398 Hypercalcemia can also increase the risk of digoxin toxicity.402
Serum potassium concentrations should be closely monitored in patients at high risk for hypokalemia (e.g., receiving diuretics, corticosteroids, or other drugs that cause potassium loss, those with GI losses from diarrhea, vomiting, or nasogastric suction, or those with endocrinopathies or nephropathies).402 The presence of hypomagnesemia also increases the risk of digoxin toxicity, and is common during situations where there is potassium loss.402 Hypomagnesemia is common in alcoholism and in patients with diabetes mellitus or hypercalcemia.402
Altered Response in Thyroid Disorders and Hypermetabolic States
Hypothyroidism may warrant lower dosages of digoxin.398
Heart failure and/or atrial arrhythmias caused by hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, arteriovenous shunt) are best treated by managing the underlying condition. Atrial arrhythmias caused by hypermetabolic states are resistant to digoxin therapy.398 Additionally, patients with beri beri heart disease may respond inadequately to digoxin therapy if underlying thiamine deficiency is not corrected.398
Digoxin may cause false-positive ST-T changes during exercise testing.398
Available data from retrospective clinical studies, case reports, and clinical experience over several decades have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal and fetal effects with digoxin.400 However, the untreated underlying maternal condition (e.g., heart failure, atrial fibrillation) may increase the risk of adverse pregnancy outcomes.400 Animal reproduction studies have not been conducted with the drug.400
Heart failure during pregnancy increases the risk of preterm birth.400 Additionally, atrial fibrillation increases the risk of delivering a low-birth-weight infant.400 Heart disease or atrial fibrillation may worsen with pregnancy and can lead to maternal or fetal death.400
Dosage requirements for digoxin may increase during pregnancy and decrease during the postpartum period; serum digoxin concentrations should be monitored during pregnancy and the postpartum period.400
Because digoxin crosses the placenta and is found in amniotic fluid, neonates should be monitored for signs and symptoms of digoxin toxicity (e.g., vomiting, cardiac arrhythmias).400
Because the risk of arrhythmias can increase during labor and delivery, patients should receive continuous monitoring.400
Although digoxin is distributed into human milk, the quantities present (up to 4% of the neonatal maintenance dosage) are unlikely to be clinically important.400 The effects of digoxin on the breast-fed infant or on milk production are not known.400
Safety and efficacy of digoxin in controlling ventricular rate have not been established in pediatric patients with atrial fibrillation.398, 400
The manufacturer states that safety and efficacy of digoxin in pediatric patients with heart failure have not been established in adequate and well-controlled studies; however, improvements in hemodynamics and clinical manifestations have been reported in pediatric patients with heart failure of various etiologies in the published literature.398, 400
Neonates exhibit considerable variability in their tolerance to digoxin.398, 400 Premature and immature infants are particularly sensitive to the drug, and dosage must be reduced and individualized according to maturity.398, 400 The adverse effect profile of digoxin differs in infants and children, particularly in regard to initial signs of toxicity.398, 400 Cardiac arrhythmias, including sinus bradycardia, usually occur earliest and most frequently.398, 400 In children, any arrhythmia can occur.398, 400 Therefore, any arrhythmia or alteration in cardiac conduction in a child should be considered a sign of toxicity.398, 400
Most clinical experience with digoxin has been in the geriatric patient population, and has not identified any differences in clinical efficacy or adverse effects between geriatric patients and younger adults.398 However, digoxin is primarily excreted by the kidneys; therefore, the risk of toxic reactions may be increased in patients with compromised renal function.398 Geriatric patients may also exhibit a smaller volume of distribution due to age-related decreases in lean muscle mass.398 Because of the greater likelihood of compromised renal function in geriatric patients, care should be taken with dosage selection based on renal function.398 Additionally, it may be useful to monitor renal function during therapy in geriatric patients.398
Only a small percentage (about 13%) of a dose of digoxin undergoes hepatic metabolism; therefore, hepatic impairment is not expected to significantly alter the pharmacokinetics of digoxin.400 In a small study, serum levels of digoxin in patients with acute hepatitis generally fell within the range of levels observed in healthy patients.400
Digoxin is primarily excreted by the kidneys.398 Patients with renal impairment are at a higher risk for digoxin toxicity; therefore, a dosage reduction is recommended.398
Overall, adverse effects have been reported in 5<20% of patients; 15<20% of these reported adverse effects were considered serious.398, 400, 402 Cardiac toxicity accounted for about 50% of these reactions, followed by GI disturbances for about 25%, and CNS and other toxicities for 25%.398, 400, 402
Because digoxin has a narrow therapeutic window, increased monitoring of serum digoxin concentrations and for possible clinical manifestations of digoxin toxicity is necessary when initiating, adjusting, or discontinuing therapy with any drugs that may interact with digoxin.398, 400 Clinicians should also consult the prescribing information for any drugs that are concurrently administered with digoxin for potential drug interaction information.398, 400
Concomitant use of certain drugs may increase serum concentrations of digoxin by interfering with absorption of the cardiac glycoside via P-glycoprotein (P-gp) interaction or other mechanisms.398 Drugs that have been shown to increase serum digoxin concentrations by more than 50% include amiodarone, captopril, clarithromycin, dronedarone, gentamicin, erythromycin, itraconazole, lapatinib, propafenone, quinidine, ranolazine, ritonavir, tetracycline, and verapamil.398 Serum digoxin concentrations should be measured prior to initiating these drugs and the dosage of digoxin should be adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency and continuing monitoring.398
Drugs that have been shown to increase digoxin concentrations by less than 50% include atorvastatin, carvedilol, conivaptan, diltiazem, indomethacin, mirabegron, nefazodone, nifedipine, propantheline, quinine, rabeprazole, spironolactone, telmisartan, ticagrelor, tolvaptan, and trimethoprim.398 Serum digoxin concentrations should be measured prior to initiating these drugs and dosage of digoxin should be adjusted by either decreasing the dose by approximately 15-30% or modifying the dosing frequency and continuing monitoring.398
Drugs that have been shown to increase serum digoxin concentrations with an unclear magnitude include alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, and omeprazole.398 Serum digoxin concentrations should be measured prior to initiating these drugs; monitoring should be continued and the dosage of digoxin should be reduced as necessary.398
Drugs or therapies that have been shown to decrease serum digoxin concentrations include acarbose, albuterol, antacids, certain chemotherapy or radiation therapy, cholestyramine, colestipol, exenatide, kaolin-pectin, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John's wort ( Hypericum perforatum ), sucralfate, and sulfasalazine.398 Serum digoxin concentrations should be measured prior to initiating these drugs or therapies; monitoring should be continued and dosage of digoxin should be increased by approximately 20-40% as necessary.398
Drugs Affecting P-glycoprotein Transport
Digoxin is a substrate of the P-gp transport protein at the level of intestinal absorption, renal tubular secretion, and biliary-intestinal secretion.398 Clinically important interactions may occur when digoxin is used concomitantly with drugs that induce (e.g., rifampin, neomycin, penicillamine) or inhibit (e.g., amiodarone, dronedarone, verapamil, propafenone, quinidine, cyclosporine, atorvastatin, simvastatin, darunavir, ritonavir) P-gp.398
Drugs Affecting Renal Function
Drugs that affect renal function (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory agents [NSAIAs], cyclooxygenase-2 [COX-2] inhibitors) may impair elimination of digoxin, and thus predispose patients to digoxin toxicity.398
The inotropic and toxic effects of digoxin and calcium are synergistic and arrhythmias may occur if these drugs are given together (particularly when calcium is administered rapidly IV).398
Concomitant administration of digoxin and amiodarone may result in increased serum digoxin concentrations by 70% and subsequent digoxin toxicity.398
When initiating amiodarone therapy in patients receiving digoxin, serum digoxin concentrations should be measured prior to therapy initiation and the dosage of digoxin adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398 Serum digoxin concentrations should be monitored and patients should be observed closely for signs of cardiac glycoside toxicity.398
Concomitant use of dofetilide and digoxin was associated with an increased risk of torsades de pointes.398 Dosage of digoxin should be individualized when used concomitantly with dofetilide.398
Concomitant use of digoxin and dronedarone (a P-gp inhibitor) may result in a substantial increase (150%) in systemic exposure to digoxin; possible digoxin toxicity may occur.398 In clinical studies, baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in patients receiving dronedarone.398 It is not known if this represents an adverse drug interaction or is related to the presence of advanced heart disease, which is a known risk factor for sudden death in patients receiving digoxin.398 If concomitant use of dronedarone is necessary in a patient receiving digoxin, serum digoxin concentrations should be determined prior to initiating therapy and the dosage of digoxin should be reduced by decreasing the dose by approximately 30-50% or modifying the dosing frequency.398
Concomitant administration of quinidine and digoxin increases serum concentrations of digoxin by 100%.398
When quinidine therapy is initiated in a patient receiving digoxin, serum digoxin concentrations should be determined prior to therapy initiation, and the digoxin dosage reduced (by decreasing dose by approximately 30-50% or modifying dosing frequency) as needed; the patient should be observed closely for signs of toxicity.398
In clinical studies, proarrhythmic events were more common in patients receiving sotalol and digoxin concomitantly than when either drug was used alone.398 It is not known if this represents an adverse drug interaction or is related to the presence of heart failure, which is a known risk factor for proarrhythmia, in patients receiving digoxin.398 Dosage of digoxin should be individualized when used concomitantly with sotalol.398
Beta-Adrenergic Blocking Agents
Concomitant use of digoxin and β-adrenergic blocking agents (β-blockers) can have additive negative effects on AV conduction, which can result in complete heart block.398 Digoxin dosage in patients receiving such therapy should be carefully individualized given the considerable variability of these interactions.398
Calcium-channel Blocking Agents
Although combination therapy with digoxin and calcium-channel blocking agents may be useful in controlling atrial fibrillation, such concomitant use can have negative effects on AV conduction, which can result in complete heart block.398 Digoxin dosage should be carefully individualized when used in conjunction with calcium-channel blocking agents because of the considerable variability of these interactions.398
When diltiazem is used concomitantly with digoxin, serum concentrations of digoxin are increased by 20%.398 Serum digoxin concentrations should be determined prior to initiating diltiazem and the dosage of digoxin should be reduced by either decreasing the dose by approximately 15-30% or modifying the dosing frequency.398
Some data suggest that serum digoxin concentrations may increase by about 45% during concomitant therapy with nifedipine.398 Patients receiving the drugs concomitantly should be monitored for signs and symptoms of digoxin toxicity.398 Serum digoxin concentrations should be determined prior to initiating nifedipine and the dosage of digoxin should be reduced by either decreasing the dose by approximately 15-30% or modifying the dosing frequency.398
Verapamil may increase serum digoxin concentrations by 50-75%.398 When verapamil is administered to a patient receiving digoxin, serum digoxin concentrations should be measured and the dosage of digoxin adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398 The patient should be monitored closely for clinical response and digoxin toxicity.398
Sympathomimetics (e.g., dopamine, epinephrine, norepinephrine) should be used with caution in patients receiving digoxin, since the risk of arrhythmias may be increased in patients receiving these drugs concomitantly.398
Concomitant use of captopril and digoxin has been reported to increase serum concentrations and systemic exposure to digoxin by about 58%.398 If captopril is initiated in a patient receiving digoxin, serum digoxin concentrations should be measured prior to initiating therapy and the dosage of digoxin should be adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398
Data suggest that, in about 10% of patients receiving digoxin, substantial amounts of the drug are metabolized by bacteria within the gut to compounds (reduced metabolites) following oral administration.398 Alteration of enteric bacterial flora by some anti-infective agents (e.g., oral erythromycin, clarithromycin, tetracycline hydrochloride) may result in an increase in the bioavailability of active drug and as much as a 2-fold increase in serum digoxin concentrations.398 When concomitant therapy with a systemic anti-infective agent is administered in patients receiving digoxin, serum digoxin concentrations should be measured before initiating the anti-infective agent, and the dosage of digoxin should be adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398
Concomitant administration of digoxin and itraconazole has been reported to increase serum concentrations of digoxin by 80%.398 If itraconazole is initiated in a patient receiving digoxin, serum digoxin concentrations should be measured prior to initiating therapy and the dosage of digoxin should be adjusted by either decreasing the dose by approximately 30-50% or modifying the dosing frequency.398 Such patients should be observed for clinical manifestations of digoxin toxicity.398
Succinylcholine can cause a sudden release of potassium from muscle cells, resulting in cardiac arrhythmias in patients receiving digoxin.398 Dosage of digoxin should be individualized when used concomitantly with neuromuscular blocking agents such as succinylcholine.398
Teriparatide can transiently increase serum calcium concentrations, which may predispose patients to digoxin toxicity.398
Thyroid supplements may increase dosage requirements of digoxin.398
Concomitant administration of digoxin and indomethacin has been reported to increase serum concentrations of digoxin by 40%.398 If indomethacin is initiated in a patient receiving digoxin, serum digoxin concentrations should be measured prior to initiating therapy, and the dosage of digoxin should be reduced by either decreasing the dose by approximately 15-30% or modifying the dosing frequency.398
Digoxin is a cardiac glycoside used for treating heart failure and controlling ventricular rate in atrial fibrillation.398 The pharmacologic properties of cardiac glycosides include their ability to increase the force and velocity of myocardial systolic contraction (positive inotropic action), slow heart rate (negative chronotropic action), decrease conduction velocity through the atrioventricular (AV) node, and reduce activation of the sympathetic nervous system and renin-angiotensin system.398 The pharmacologic activity of digoxin is mediated via the sodium-potassium-activated adenosine triphosphatase (Na+-K+-ATPase) pump in myocardial cells, which moves sodium ions extracellularly and potassium ions intracellularly.398 Inhibition of the Na+-K+-ATPase pump also increases intracellular calcium in the myocardium and conduction system.398 The resulting increase in calcium enhances myocardial contractility (positive inotropy), increases automaticity, and reduces conduction velocity.398 Digoxin also enhances parasympathetic tone, leading to decreased heart rate (negative chronotropy) and slowed conduction through the atrioventricular (AV) node.398 Reduced nervous system and renin-angiotensin system activity also further improves cardiovascular function.398
Peak concentrations of digoxin occur 1-3 hours following oral administration of the tablets, and 30-90 minutes following administration of the oral solution.398, 402 The presence of food in the GI tract may slow the rate, but not extent, of absorption of orally administered digoxin from the tablet formulation.398 Decreased absorption may occur if the drug is administered with a high fiber meal.398, 402 Digoxin absorption may be affected by concomitant medications affecting GI pH.402 Intestinal absorption of the drug may be impaired in patients with certain malabsorption states (e.g., short bowel syndrome, celiac sprue, jejunoileal bypass).398 Digoxin is a substrate of P-glycoprotein (P-gp), a transport protein involved in absorption of the drug.398 Following oral administration of a single dose of digoxin, onset of action occurs in 0.5-2 hours and maximal effects occur in 2-6 hours.398 After IV administration of a single dose of digoxin, the onset of action occurs in 5-30 minutes depending on the rate of infusion and maximal effects occur in 1-4 hours.398 The absolute bioavailability of digoxin tablets is 60-80% and the absolute bioavailability of the oral solution is 70-85%; when switching from IV to oral dosage forms, the differences in bioavailability should be considered.398, 400, 402
Following administration, digoxin is distributed into tissues over 6-8 hours.398, 400, 402 Digoxin is concentrated in tissues and crosses the blood-brain barrier and placenta.398, 400, 402 Upon delivery, serum concentrations in the newborn are similar to those observed in the mother.398, 400, 402 Digoxin distributes into breastmilk.400 Approximately 25% of digoxin in the blood is protein-bound.398, 400, 402
In patients with normal renal function, the elimination half-life (t½) of digoxin is 1.2-2 days.398 The elimination t½ of digoxin is increased to 3.5-5 days in anuric patients.398 Digoxin is not metabolized appreciably (only about 13%) prior to excretion.398 Metabolism involves hydrolysis, oxidation, and conjugation.398 The cytochrome P-450 (CYP) system is not involved in the metabolism of digoxin.398 Digoxin is also apparently metabolized by bacteria within the lumen of the large intestine following oral administration and possibly after biliary elimination following parenteral administration.398
In healthy individuals, about 50-70% of an IV dose of digoxin is excreted unchanged in urine.398 Digoxin is eliminated from the body by first-order kinetics, with the quantity of eliminated drug proportional to the total body content.398 Renal excretion of digoxin is proportional to creatinine clearance and is largely independent of urine flow.398 Activated charcoal administered orally or via nasogastric tube at any time after ingestion has been shown to decrease digoxin concentrations.398 Digoxin is not effectively removed from the body with dialysis, exchange transfusion, or cardiopulmonary bypass because the majority is bound to extravascular tissues.398
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 50 mcg/mL* | Digoxin Oral Solution | |
Tablets | 62.5 mcg* | Digoxin Tablets | ||
125 mcg* | Digoxin Tablets | |||
250 mcg* | Digoxin Tablets | |||
Parenteral | Injection | 100 mcg/mL | Lanoxin® Injection Pediatric | |
250 mcg/mL* | Digoxin Injection | |||
Lanoxin® | Covis |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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