Digoxin (Monograph)

Brand names: Digitek, Lanoxin
Drug class: Cardiotonic Agents
- Inotropic Agents, Positive Cardiac

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Digoxin is a cardiac glycoside with positive inotropic and antiarrhythmic effects.³⁹⁸ ⁷⁰⁰ ⁷⁰¹

Uses for Digoxin

Heart Failure

Used in conjunction with other agents in the management of mild to moderate (NYHA class II-III) heart failure associated with left ventricular systolic dysfunction.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³ ⁵²⁴

Increases left ventricular ejection fraction and improves symptoms of heart failure (as evidenced by exercise capacity, heart failure-related hospitalizations and emergency care), while having no apparent effect on overall mortality.³⁸⁴ ³⁸⁶ ³⁸⁷ ³⁹⁰ ³⁹¹ ³⁹² ³⁹⁸ ⁵²⁴

Although digoxin has been used extensively in the management of heart failure, current use is generally limited because of lack of demonstrated survival benefit, potential for serious adverse effects, and availability of other drugs that have been shown to substantially reduce morbidity and mortality.³⁹⁵ ³⁹⁸ ³⁹⁹ ⁴⁰¹ ⁵²⁴

Current guidelines for the management of heart failure in adults generally recommend inhibition of the renin-angiotensin-aldosterone system with a combination of drug therapies (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-adrenergic blocking agents [β-blockers], aldosterone receptor antagonists) to reduce morbidity and mortality.⁵²⁴ ⁷⁰³ ⁸⁰⁰ ⁸⁰¹

Additional agents (e.g., digoxin, diuretics, sinoatrial modulators [i.e., ivabradine]) added to the treatment regimen in selected patients associated with symptomatic improvement of heart failure and/or reduction in heart failure-related hospitalizations.⁵²⁴ ⁸⁰⁰

Therapy with digoxin may be initiated in severely symptomatic patients with heart failure and reduced left ventricular ejection fraction who have started but not yet responded to an ACE inhibitor or a β-blocker; alternatively, digoxin may be withheld until the patient’s symptomatic response to the ACE inhibitor or β-blocker has been defined and then used only in those patients who remain symptomatic while receiving an ACE inhibitor or β-blocker.⁵²⁴

In heart failure patients receiving digoxin without an ACE inhibitor or β-blocker, digoxin should not be withdrawn, but appropriate therapy with an ACE inhibitor and/or a β-blocker should be added.⁵²⁴

Digoxin is less effective for high-output heart failure; heart failure resulting from hypermetabolic or hyperdynamic states is best treated by addressing underlying condition.^a

Patients with 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

Atrial Fibrillation

Used for ventricular rate control in patients with chronic atrial fibrillation; however, not considered first-line therapy, in part because of its slow onset of action.¹² ²⁵ ²⁸ ⁷¹ ³⁸⁶ ³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³ ⁷⁰¹ β-Blockers and nondihydropyridine calcium-channel blocking agents (e.g., diltiazem, verapamil) are preferred for this use.⁷⁰¹

Digoxin may be used in combination with a β-blocker or nondihydropyridine calcium-channel blocking agent to improve heart rate control during exercise; also may be useful in patients with concomitant heart failure.⁷⁰¹

Do not use in patients with preexcited atrial fibrillation because increased ventricular response and ventricular fibrillation may occur.⁷⁰⁰ ⁷⁰¹

Paroxysmal Supraventricular Tachycardia

Also has been used for management of paroxysmal supraventricular tachycardia (PSVT) due to AV nodal reentry tachycardia (AVNRT) or AV reentry tachycardia (AVRT)^{† [off-label]}.⁷⁰⁰

Some experts state that oral digoxin may be a reasonable choice for ongoing management of PSVT in patients who are not candidates for, or prefer not to undergo, catheter ablation.⁷⁰⁰ Because of potential for adverse effects, use of digoxin is generally reserved for patients who fail or cannot take preferred therapies (e.g., β-blockers, nondihydropyridine calcium-channel blocking agents, flecainide, propafenone).⁷⁰⁰

Has been used in the management of regular supraventricular (reciprocating) tachycardia associated with Wolff-Parkinson-White (WPW) syndrome^{† [off-label]}, but potentially harmful in patients with WPW syndrome and preexcited atrial fibrillation since acceleration in ventricular rate may occur.⁷⁰¹ Avoid use in such patients.⁷⁰¹

MI

Use in acute MI is controversial.¹² ³⁸⁶ ³⁸⁷ ³⁸⁸ ³⁸⁹ ³⁹⁰

Generally not recommended during acute MI because digoxin can increase myocardial oxygen demand and exacerbate ongoing ischemia.³⁹⁸ However, may be used in selected patients with left ventricular dysfunction after acute MI.³⁹⁸ ⁵²⁴ (See Heart Failure under Uses.)

Digoxin Dosage and Administration

General

General Dosage Considerations

Narrow therapeutic index; therefore, cautious dosage determination is essential.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³
When selecting an appropriate dosage, consider patient's renal function, body weight, age, concomitant disease states, concurrent drugs, and other factors likely to alter serum concentrations of digoxin.³⁹⁸ ³⁹⁹ ⁴⁰⁰ ⁴⁰² ⁴⁰³
Use lean body weight for dosage calculations since the drug is largely distributed into tissues.³⁹⁹

Therapeutic Drug Monitoring

Serum digoxin concentrations can be used to guide dosing.⁴⁰⁰
Determine serum concentrations by obtaining blood samples at least 6–8 hours after the daily dose and preferably just prior to the next scheduled daily dose.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³
Interpret serum concentrations in the overall clinical context; do not use an isolated measurement alone as the basis for adjusting dosage.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Switching Dosage Forms

Consider differences in the bioavailability of parenteral and oral preparations when patients are switched from one dosage form to another.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³ (See Bioavailability under Pharmacokinetics.)
When switching from oral (tablets or solution) to IV therapy, reduce digoxin dosage by about 20–25%.⁴⁰²

Administration

Administer orally or IV (when oral therapy not feasible or rapid therapeutic effect necessary).³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Although IM route also has been used, IM injections can cause severe local irritation and pain at the site of injection; IV route is therefore preferred.⁹⁸ ⁴⁰⁰ If IM administration is necessary, inject no more than 2 mL deep into the muscle and massage injection site after administration.⁴⁰⁰

Oral Administration

Administer once daily (as tablets or oral solution) in adults and children >10 years of age; divided daily dosing generally recommended in infants and young children <10 years of age.³⁹⁸ ⁴⁰² ⁴⁰³

The manufacturer recommends that the oral solution be used to obtain appropriate dose in infants, young children, or patients with very low body weights.³⁹⁸ ⁴⁰² Use calibrated oral dosing syringe supplied by the manufacturer to measure doses of the oral solution; use a separate measuring device to accurately measure doses <0.1 mL.⁴⁰²

IV Administration

May administer IV when oral therapy is not feasible or when rapid therapeutic effect is necessary.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Do not mix with other drugs in the same container or administer simultaneously in the same IV line.⁴⁰⁰

Dilution

May administer digoxin injection either undiluted or diluted with a fourfold or greater volume of sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection; use of a smaller volume of diluent may cause precipitation of digoxin.⁴⁰⁰

Use diluted IV solutions immediately.⁴⁰⁰

Rate of Administration

Administer by slow (over at least 5 minutes) IV infusion; avoid rapid (i.e., bolus) IV administration since systemic and coronary vasoconstriction may occur.⁴⁰⁰

Dosage

Dosage guidelines provided are based upon average patient response; substantial patient variation can be expected.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Dosage may be initiated with or without a loading dose depending on whether rapid titration or more gradual titration is desired.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³ Loading doses may be used to reach adequate and effective drug levels in patients with atrial fibrillation.³⁹⁹ However, loading doses generally not needed in patients with heart failure.³⁹⁹ ⁵²⁴

Administer loading dose in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose and additional fractions (usually 25%) usually every 6–8 hours; carefully assess patient's clinical response (including possible toxicity) before each additional dose.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³ If a change from the calculated loading dose is required, then calculate maintenance dosage based upon the amount (i.e., total loading dose) actually administered.⁴⁰²

Since daily maintenance dosage is a replacement of daily digoxin loss from the body, an alternative dosing method has been used where maintenance dosage is estimated by multiplying daily percentage loss by peak body stores (i.e., loading dose).³⁹⁸ ⁴⁰⁰ ⁴⁰³ The percentage of digoxin eliminated from the body daily can be estimated by the following equation:³⁹⁸ ⁴⁰⁰ ⁴⁰³

daily % loss = 14 + [creatinine clearance (in mL/minute) / 5]

Pediatric Patients

Titrate dosage carefully in neonates, especially premature infants, because renal clearance of digoxin is reduced.³⁹⁸ ⁴⁰² ⁴⁰³

Infants and young children (≤10 years of age) generally require proportionally larger doses than children >10 years of age and adults when calculated on the basis of lean or ideal body weight or body surface area.⁴⁰²

Children >10 years of age require adult dosages in proportion to the child’s body weight.⁴⁰²

Heart Failure

Loading Doses and Maintenance Dosages

Loading doses and maintenance dosages recommended by the manufacturers in pediatric patients are given in the tables that follow based on the dosage form administered.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Oral

Loading 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

Table 1. Usual Pediatric Loading Doses and Maintenance Dosages for Digoxin Tablets (normal renal function, based on lean body weight)398403
Age	Oral Loading Dose	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

Loading 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

Table 2. Usual Pediatric Loading Doses and Maintenance Dosages for Digoxin Solution (normal renal function, based on lean body weight)402
Age	Oral Loading Dose	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

Loading 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

Table 3. Usual Pediatric Loading Doses and Maintenance Dosages for IV Digoxin (normal renal function, based on lean body weight)400
Age	IV Loading Dose	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

Adults

Heart Failure

Loading Dose

Oral

Loading doses generally not required in patients with heart failure.³⁹⁹ ⁵²⁴ If a loading dose is given, manufacturers recommend an oral loading dose of 10–15 mcg/kg administered in divided doses.³⁹⁸ ⁴⁰² ⁴⁰³

Loading doses generally not required in patients with heart failure.³⁹⁹ ⁵²⁴ If a loading dose is given, manufacturers recommend an IV loading dose of 8–12 mcg/kg administered in divided doses.³⁹⁸ ⁴⁰² ⁴⁰³

Maintenance Dosage

Oral

Experts state that digoxin is commonly initiated and maintained at a dosage of 125–250 mcg (0.125–0.25 mg) daily for heart failure in adults.⁵²⁴

Manufacturers recommend an initial oral 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; may increase dosage every 2 weeks according to clinical response, serum digoxin concentrations, and toxicity.³⁹⁸ ⁴⁰² ⁴⁰³

If IV administration is necessary, manufacturer recommends an initial IV maintenance dosage of 2.4–3.6 mcg/kg once daily in adults with normal renal function; may increase dosage every 2 weeks according to clinical response, serum digoxin concentrations, and toxicity.⁴⁰⁰

Atrial Fibrillation

Loading Dose

Oral

If a loading dose is given for rate control in patients with atrial fibrillation, manufacturers recommend an oral loading dose of 10–15 mcg/kg.³⁹⁸ ⁴⁰² ⁴⁰³ Some experts state that usual oral maintenance dosage for ventricular rate control in adults with atrial fibrillation is 125–250 mcg (0.125–0.25 mg) daily.⁷⁰¹

If a loading dose is given for rate control in patients with atrial fibrillation, manufacturers recommend an IV loading dose of 8–12 mcg/kg.⁴⁰⁰ Some experts recommend an initial IV dose of 250 mcg (0.25 mg) with repeat dosing to a maximum of 1500 mcg (1.5 mg) over 24 hours.⁷⁰¹

Maintenance Dosage

Oral

Experts state that usual oral maintenance dosage for ventricular rate control in adults with atrial fibrillation is 125–250 mcg (0.125–0.25 mg) daily.⁷⁰¹

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment; however, serum digoxin concentrations may be used to guide dosing.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Renal Impairment

Must adjust dosage in patients with renal impairment.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³ (See Renal Impairment under Cautions.) Reduce and titrate dosage carefully based on clinical response and serum digoxin concentrations.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Consult manufacturer's prescribing information for recommended maintenance dosages based on renal function.⁴⁰⁰

Geriatric Patients

Select dosage carefully since geriatric patients may have impaired renal function.³⁹⁸ ³⁹⁹ ⁴⁰⁰ ⁴⁰² ⁴⁰³ ⁵²⁴ (See Renal Impairment under Dosage and Administration.)

Lower dosages (125 mcg [0.125 mg] daily or every other day) are recommended for management of heart failure in geriatric patients >70 years of age.³⁹⁹ ⁵²⁴

Cautions for Digoxin

Contraindications

Ventricular fibrillation.³⁹⁸ ⁴⁰⁰
Known hypersensitivity to digoxin or other digitalis preparations.³⁹⁸ ⁴⁰⁰

Warnings/Precautions

Warnings

Sinus Node Disease and AV Block

Do not administer to patients with substantial sinus or AV block unless a pacemaker is present.⁵²⁴ ⁷⁰⁰

Use cautiously with other drugs that can depress sinus or AV nodal function.⁵²⁴

Accessory AV Pathway (WPW Syndrome)

Use with caution in patients with 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.³⁹⁸ ⁷⁰⁰

Do not administer to patients with WPW syndrome and preexcited atrial fibrillation.⁷⁰¹

Acute MI

Use in acute MI may result in an undesirable increase in oxygen demand and associated ischemia.³⁹⁸

Patients with Preserved Left Ventricular Systolic Function

Idiopathic Hypertrophic Subaortic Stenosis

Worsening of outflow obstruction may occur in patients with idiopathic hypertrophic subaortic stenosis as a result of the inotropic effects of digoxin.³⁹⁸

Elective Cardioversion

Reduce dosage or withhold digoxin therapy for 1–2 days before elective cardioversion in patients with atrial fibrillation; consider consequences of increasing the ventricular response.³⁹⁸

Postpone elective cardioversion in patients with manifestations of digoxin toxicity.³⁹⁸

If it is not possible to delay cardioversion, use lowest possible energy level to avoid provoking ventricular arrhythmias.³⁹⁸

Comorbid Conditions

Certain conditions (e.g., hypo- or hyperthyroidism, hypocalcemia) can alter response to digoxin if the underlying condition is not treated appropriately.³⁹⁸

Major Toxicities

Pathogenesis

Widespread use and the very narrow margin between effective therapeutic and toxic dosages contribute to the high incidence of toxicity and the relatively high associated mortality rate.²⁵⁰ ²⁵¹ ²⁵⁷ ²⁵⁸ ²⁵⁹ ²⁶⁰ ²⁷⁰ ²⁹⁵

Toxic effects are mainly GI, CNS, biochemical, and cardiac in origin.⁴⁶ ¹⁰⁷ ²⁵⁷ ²⁶¹ ²⁶⁴ ²⁶⁵ ²⁶⁶ ³⁹⁸ ⁴⁰⁴

Minimum toxic and lethal doses are not well established.²⁵⁸ ²⁶⁷

Infants and children appear to be more tolerant to therapeutic and toxic actions;⁵¹ ²⁵⁸ ²⁶⁷ ²⁷⁰ ²⁷⁷ ²⁷⁸ ²⁸³ ²⁸⁵ children without underlying cardiac problems usually can tolerate an acute dose of several mg of digoxin without potentially life-threatening cardiac toxicity.²⁶⁷

Serum digoxin concentrations are useful in confirming the diagnosis of intoxication; however, clinical diagnosis and management should not be based on serum concentrations alone but should always be interpreted in the overall clinical context with all other relevant information.²³² ²⁵⁷ ²⁶⁵ ²⁷⁰ ²⁷⁴ ²⁷⁷

At least 6–10 hours usually are necessary for digoxin to equilibrate between plasma and tissue; plasma specimens drawn prior to this time may show glycoside concentrations greater than those present after equilibration.²⁴⁸ ²⁷⁵ ²⁹⁵ ³⁶⁰ ³⁶¹

Use in conjunction with diuretics is a frequent cause of chronic toxicity.²⁷⁰ ²⁷⁷

Failure to individualize dosage is another contributing factor.²⁵⁸ ²⁶⁶ ²⁷²

Manifestations

Overdosage is manifested by a wide variety of signs and symptoms that are difficult to distinguish from effects associated with cardiac disease (e.g., adverse GI effects, arrhythmias).¹² ²⁶⁶ ²⁷⁰ ²⁷³ ²⁷⁴ ²⁷⁵ ²⁷⁶ ²⁷⁸ ³⁹⁸

Before additional doses are administered, attempts should be made to determine whether the manifestations are digoxin induced.²⁶⁶ ²⁷⁶ ²⁷⁷ ³⁹⁸

Extracardiac Effects

Extracardiac manifestations of intoxication are similar in both acute and chronic intoxication.²⁶¹ ²⁷⁴

GI effects and, to a lesser extent, CNS and visual disturbances may be more pronounced following acute overdosage.²⁶¹ ²⁷⁴

In pediatric patients, drowsiness⁵² ²⁵⁸ ²⁶⁹ and vomiting⁵¹ ²⁶⁹ are most prominent extracardiac effects;²⁸¹ life-threatening cardiac arrhythmias have developed suddenly without evidence of any extracardiac signs of intoxication.²⁶⁹ ²⁸²

GI Effects

Anorexia,⁴⁶ ²⁶⁰ ²⁶⁵ ³⁹⁸ nausea,⁴⁶ ²⁶⁰ ²⁶⁵ ²⁶⁷ ³⁹⁸ and vomiting⁴⁶ ²⁶⁰ ²⁶⁵ ²⁶⁷ ³⁹⁸ are common early signs of toxicity and may precede or follow evidence of cardiotoxicity.⁵⁰ ²⁷⁷ ³⁸⁰

Large doses may produce emesis by direct GI irritation.²⁵⁸ ²⁷⁰ Episodes of nausea and vomiting may start and stop abruptly.²⁷⁰

Nervous System Effects

Headache,³⁸ ⁴⁶ ⁴⁸ ⁶⁶ ²⁶¹ ²⁶⁵ ²⁶⁶ ²⁶⁷ ²⁶⁸ ²⁷⁰ ³⁹⁸ fatigue,⁴⁶ ⁴⁸ ⁶⁶ ²⁶¹ ²⁶⁶ ²⁷⁰ ²⁷⁶ malaise,⁴⁶ ⁴⁸ ²⁶¹ ²⁶⁶ ²⁷⁰ ²⁷⁶ drowsiness,³⁸ ⁴⁶ ⁴⁸ ⁵² ¹²⁵ ²⁶¹ ²⁶⁵ ²⁶⁶ ²⁶⁹ ²⁷⁰ and generalized muscle weakness³⁸ ⁴⁶ ⁴⁸ ²⁶⁶ ²⁶⁷ ²⁶⁹ ²⁷⁰ are common.^a

Neuropsychiatric disturbances are especially likely to develop in geriatric patients with atherosclerotic disease²⁷⁰ and are easily overlooked in chronic digoxin therapy.⁴⁸ ²⁸⁹

Disorientation,³⁸ ⁴⁸ ¹⁰⁷ ²⁶⁴ ²⁶⁵ ²⁶⁷ ²⁷⁰ confusion,³⁸ ⁴⁷ ⁴⁸ ⁶⁶ ²⁶⁵ ²⁶⁶ ²⁷⁶ ²⁷⁷ depression,³⁸ ⁴⁸ ²⁶⁶ memory impairment,⁴⁰ ⁴⁸ ²⁶⁴ amnesia,³⁸ ⁴⁸ aphasia,³⁸ ⁴⁸ ²⁷⁰ bad dreams,⁴⁶ ²⁶⁶ ²⁸⁹ delirium,³⁸ ⁴⁰ ⁴⁶ ⁴⁸ ⁶⁶ ¹⁰⁷ ²⁶¹ ²⁶⁶ ²⁶⁸ ²⁷⁰ ²⁷⁶ ²⁸⁹ delusions,³⁸ ⁴⁸ ²⁶⁴ ²⁷⁶ illusions,⁴⁸ ²⁶⁴ and hallucinations.³⁸ ⁴⁰ ⁴⁶ ⁴⁷ ⁴⁸ ²⁶⁴ ²⁶⁵ ²⁷⁶ ³⁶²

Ocular Effects

Visual disturbances induced by toxic doses probably result from a direct effect on the retina³⁸ ⁷⁵ ²⁹⁰ ³⁶³ (cones are affected more than rods).⁷⁵ ³⁶³

Color vision is commonly affected⁷⁴ ³⁶³ and objects may appear yellow or green or, less commonly, brown, red, blue, or white.³⁸ ²⁷⁰

Visual disorders generally are reversible after digoxin withdrawal.³⁸ ⁴⁶ ⁷⁴ ¹⁰⁵

Effects on Potassium

Acute toxicity may cause hyperkalemia, whereas chronic toxicity may be associated with hypokalemia or normokalemia.²⁶¹ ²⁷⁴

Cardiovascular Effects

Most well defined and dangerous toxic actions.²⁷⁰ ²⁷⁴

Cardiac signs of toxicity may occur with or without other signs of toxicity⁴⁶ ⁵⁰ and often precede other toxic effects.⁵⁰

Arrhythmias associated with intoxication may result in worsening of heart failure.⁴⁷ ⁵⁰ ²⁷⁰ ²⁹⁵

It often is difficult to distinguish toxic cardiac effects caused by an underlying heart disease or digoxin.³⁸ ⁵⁴ ²⁶⁶ ²⁷⁰ ²⁷⁵ ²⁷⁶ ³⁹⁸

Chronic toxicity commonly presents with ventricular arrhythmias, such as PVCs or ventricular tachycardia.¹³⁹ ²⁶¹ ²⁷⁴ ²⁸⁴ ²⁹¹

AV conduction disturbances are frequent in chronic toxicity.²⁶¹ ²⁷⁴ ²⁸⁴ ²⁹¹

Pediatric patients with healthy hearts often present with sinus bradycardia and conduction disturbances; ventricular arrhythmias also occur but are less common than in adults.⁵¹ ⁵² ²²² ²⁶⁹ ²⁹⁷

In neonates, premonitory signs of toxicity may include sinus bradycardia, SA arrest, or prolongation of the PR interval.⁵¹ ⁵² ²²² ²⁶⁹ ²⁹⁷

First-degree AV block is common²⁵ ³⁸ ⁵⁰ ⁵³ ⁵⁴ and generally indicates a therapeutic rather than a toxic effect;²⁵ ⁵³ ¹⁰⁶ AV block may progressively increase in patients with toxicity.²⁵⁸

Electrolyte imbalances, especially hypokalemia,²³ ⁵² ⁵³ ⁵⁴ ⁶⁶ ²²⁵ ²⁵⁸ ²⁷⁰ ³⁸⁰ ³⁹⁸ and, to a lesser extent, hypomagnesemia²³ ⁶⁶ ²²⁴ ²⁷⁰ ³⁹⁸ or hypercalcemia,²³ ⁵³ ⁶⁶ ²⁷⁰ ³⁹⁸ may predispose to the cardiotoxic effects.²³ ²⁴ ²⁷⁰

Periodically assess serum electrolytes.³⁹⁸

Conditions causing hypokalemia increase the risk of cardiotoxicity.²³ ²⁴ ²⁷⁰

Treatment

Discontinue digoxin immediately if signs of toxicity appear;¹² ²⁵⁸ ²⁷⁷ ²⁸⁹ ³⁹⁸ obtain serum digoxin concentrations, place patient on a cardiac monitor, and address possible contributing factors (e.g., electrolyte and thyroid abnormalities, concomitant drugs).³⁹⁸

In patients with hypokalemia, administer potassium supplementation to maintain serum concentrations between 4 and 5.5 mEq/L.³⁹⁸

Avoid use of calcium infusions in the treatment of hyperkalemia because calcium may worsen cardiac irregularities.²⁶¹

In cases of potentially life-threatening cardiotoxicity or hyperkalemia, administer digoxin immune Fab.²⁴⁸ ²⁷⁶ ⁴⁰¹ (See Digoxin Immune Fab under Cautions.)

Activated charcoal may be administered if acute ingestion (intentionally or accidently) of a potentially toxic amount of digoxin occurs.³⁹⁸ ⁴⁰⁴ May be useful in preventing further absorption of the drug.²⁶¹ ²⁶⁵ ⁴⁰⁴

Other measures that can enhance digoxin elimination include multiple-dose oral activated charcoal²²⁷ ²²⁸ ²⁵⁰ ²⁵¹ ²⁶⁵ ²⁷⁶ ²⁷⁷ ²⁸⁹ ³⁷⁹ and oral anion-exchange resins.²⁴ ⁵⁹ ²³⁰ ²³¹ ²⁶¹ ²⁶⁵ ²⁷⁴ ²⁸⁹ ²⁹¹

Digoxin Immune Fab

Digoxin immune Fab is a specific antidote that binds to digoxin (preventing and reversing pharmacologic and toxic effects and enhancing elimination) and can be used in the treatment of potentially life-threatening acute or chronic digoxin toxicity.²³² ²³⁵ ²³⁶ ²⁴⁸ ²⁴⁹ ²⁸⁰

Massive digoxin overdosage may cause hyperkalemia,⁷⁷ ⁹⁷ ¹³⁹ ²⁶¹ ²⁷⁴ which can be refractory to conventional therapy.¹² ²⁴ ⁹⁷ ¹³⁹ ²³² ²³⁵ ²⁵⁷ ²⁶⁹

Prognosis appears to correlate with serum potassium concentration (i.e., the greater the serum potassium concentration, the worse the prognosis) in patients treated by conventional symptomatic and supportive measures that do not include digoxin immune Fab.⁹⁷ ²³² ²³⁶ ²⁴⁷ ²⁵⁸ ²⁶¹ ²⁶⁵ ²⁹⁴

Severe hyperkalemia refractory to standard measures is an indication for digoxin immune Fab.²⁴⁸ ²⁶⁷

Specific Populations

Pregnancy

Category C.³⁹⁸

Underlying maternal condition (e.g., heart failure, atrial fibrillation) may increase risk of adverse pregnancy outcomes.⁴⁰⁰

Dosage requirements may increase during pregnancy and decrease during postpartum period; monitor serum digoxin concentrations.⁴⁰⁰

Lactation

Distributed into milk; however, quantities present unlikely to be clinically important.⁴⁰⁰ Effects of digoxin on the breast-fed infant or on milk production not known.⁴⁰⁰

Pediatric Use

Safety and efficacy not established in pediatric patients with atrial fibrillation.³⁹⁸

Manufacturer states safety and efficacy in pediatric patients with heart failure not established in adequate and well-controlled studies; however, improvements in hemodynamics and clinical manifestations reported in published literature.³⁹⁸

Neonates exhibit considerable variability in their tolerance to digoxin.³⁹⁸

Premature and immature infants are particularly sensitive to digoxin, and dosage must be reduced and individualized according to maturity.³⁹⁸

Adverse effect profile differs in infants and children, particularly the initial signs of toxicity.³⁹⁸ Cardiac arrhythmias, including sinus bradycardia, usually occur earliest and most frequently.³⁹⁸ In children, any arrhythmia can occur.³⁹⁸

Any arrhythmia or alteration in cardiac conduction in a child should be considered a sign of toxicity.³⁹⁸

Geriatric Use

Most experience is in geriatric patients, and response and adverse effects do not appear to differ from those in younger patients; however, use with caution because of increased toxicity risk secondary to decreased renal function in the elderly.³⁹⁸

Monitor renal function.³⁹⁸

Hepatic Impairment

Hepatic impairment does not appear to alter serum digoxin concentrations.³⁹⁸

Renal Impairment

Eliminated renally; therefore, patients with renal impairment are at higher risk of toxicity.³⁹⁸ Must reduce dosage.³⁹⁸ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

In addition to toxic effects (see Major Toxicities under Cautions), other adverse effects, including GI effects (e.g., nausea, vomiting, abdominal pain, intestinal ischemia, intestinal hemorrhagic necrosis) and CNS effects (e.g., headache, weakness, dizziness, apathy, confusion, mental disturbances), have occurred.³⁹⁸ ^a

Estrogen-like effects may occur with chronic administration of digoxin, especially in geriatric men and women whose endogenous concentrations of sex hormones are low.^a

Gynecomastia and enlargement of the mammary glands in women reported after chronic therapy.^a

Drug Interactions

Digoxin has a narrow therapeutic window; increase monitoring of serum digoxin concentrations and for possible digoxin toxicity when initiating, adjusting, or discontinuing therapy with any drugs that may interact with digoxin.³⁹⁸ ⁴⁰⁰ Consult the prescribing information for any concurrently administered drugs for potential drug interaction information.³⁹⁸ ⁴⁰⁰

Drugs Affecting P-glycoprotein (P-gp) Transport

Digoxin is a substrate of P-gp at the level of intestinal absorption, renal tubular secretion, and biliary-intestinal secretion.³⁸¹ ³⁹⁸ ³⁹⁹ Clinically important interactions may occur when digoxin is used concomitantly with drugs that induce or inhibit P-gp.³⁸¹ ³⁹⁸ ³⁹⁹

Drugs Affecting Renal Function

Drugs that affect renal function may impair elimination of digoxin, and thus predispose patients to digoxin toxicity.³⁹⁸

Drugs and Radiation Therapy Affecting GI Absorption

A number of drugs are capable of binding digoxin and/or inhibiting its absorption from the GI tract, which may result in low serum concentrations of digoxin.³⁹⁸

GI absorption of oral digoxin tablets may be reduced substantially in patients receiving radiation therapy,³⁰⁰ ³⁹⁸ certain antineoplastic agents,³⁹⁸ or various combination chemotherapy regimens,³⁰¹ possibly as a result of temporary damage to intestinal mucosa caused by the radiation therapy or cytotoxic agents.³⁰⁰ ³⁰¹ ³⁰⁹

Drugs that alter GI transit time and/or motility of the GI tract (e.g., antimuscarinics, diphenoxylate) may alter the rate of digoxin absorption. Patients receiving an antimuscarinic and digoxin should be closely observed for signs of digitalis toxicity.

Specific Drugs

Drug	Interaction	Comments
Acarbose	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating acarbose; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
ACE inhibitors	May impair elimination of digoxin and predispose patients to digoxin toxicity³⁹⁸
β-Adrenergic blocking agents	Combined therapy may be useful in controlling ventricular rate in patient with atrial fibrillation; however, additive negative effects on AV conduction can occur³⁹⁸ ⁷⁰¹	Carefully individualize digoxin dosage³⁹⁸ ⁷⁰¹
Albuterol	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating albuterol; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Alprazolam	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Amiloride	Altered responses to digoxin therapy have occurred³³¹	Carefully observe patient³⁰³ ³³¹
Aminosalicylic acid	Reduced GI absorption of digoxin (resulting in low serum digoxin concentrations), especially when administered at the same time^a	Space administration as far apart as possible^a
Amiodarone	Increased serum digoxin concentrations by 70%; digoxin toxicity may occur³⁹⁸ ^a Magnitude of the increase may be much greater in children^a	Reassess need for continued digoxin therapy when initiating amiodarone, and discontinue digoxin if appropriate; if concomitant therapy is necessary, measure serum digoxin concentrations prior to initiating amiodarone and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸ ^a Closely observe patient for signs of digoxin toxicity^a Monitor thyroid function carefully, since amiodarone-induced changes in thyroid function may increase or decrease serum digoxin concentrations or alter sensitivity to the therapeutic and toxic effects of the cardiac glycoside^a
Angiotensin II receptor antagonists	May impair elimination of digoxin and predispose patients to digoxin toxicity³⁹⁸
Antacids (i.e., aluminum hydroxide, magnesium hydroxide, magnesium trisilicate)	Reduced GI absorption of digoxin (resulting in low serum digoxin concentrations), especially when administered at the same time^a	Space administration as far apart as possible^a Measure serum digoxin concentrations prior to initiating antacids; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Atorvastatin	Increased serum concentrations and systemic exposure of digoxin by <50%³⁹⁸	Measure serum digoxin concentrations prior to initiating atorvastatin and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Calcium salts	Inotropic and toxic effects of digoxin and calcium are synergistic and arrhythmias may occur if used concomitantly (particularly when calcium is given IV)³⁹⁸	Avoid IV administration of calcium in patients receiving digoxin^a
Captopril	Increased serum digoxin concentrations by >50%; digoxin toxicity may occur³⁶⁶ ³⁶⁷ ³⁶⁸ ³⁹⁸ Captopril has been administered concomitantly with digoxin in patients with heart failure without unusual adverse effects³⁶⁶ ³⁶⁷ or apparent increased risk of cardiac glycoside toxicity³⁶⁶ ³⁶⁷ ³⁶⁸	Measure serum digoxin concentrations prior to initiating captopril and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸
Carvedilol	Increased serum concentrations and systemic exposure of digoxin by <50%³⁹⁸	Measure serum digoxin concentrations prior to initiating carvedilol and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Cholestyramine and colestipol	May bind digoxin in the GI tract and impair its absorption (resulting in low serum digoxin concentrations), particularly if the glycoside and bile acid sequestrant are administered simultaneously or close together^a	Administer digoxin at least 1.5–2 hours before cholestyramine or colestipol^a
Conivaptan	Increased serum concentrations and systemic exposure of digoxin by <50%³⁹⁸	Measure serum digoxin concentrations prior to initiating conivaptan and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Cyclosporine	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Diclofenac	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Diltiazem	Conflicting reports on whether diltiazem substantially affects pharmacokinetics of digoxin when the drugs are administered concomitantly;³¹³ ³¹⁴ ³¹⁵ ³¹⁶ ³¹⁷ ³¹⁸ ³¹⁹ ³²⁰ ³²¹ in some studies, diltiazem reportedly increased average steady-state serum digoxin concentrations by about 20–50%³¹³ ³¹⁴ ³¹⁵ ³¹⁷ ³¹⁸ ³¹⁹ ³²⁰ ³²¹ Although concomitant use may be useful for control of ventricular rate in patients with atrial fibrillation, negative effects on AV conduction may be additive³⁹⁸ ⁷⁰¹	Observe patient closely for signs of digoxin toxicity during concomitant use³¹³ ³¹⁵ ³¹⁷ ³¹⁸ ³²² Measure serum digoxin concentrations prior to initiating diltiazem and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Diphenoxylate	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Dofetilide	Increased risk of torsades de pointes with concomitant use³⁹⁸	Individualize dosage of digoxin³⁹⁸
Dronedarone	Increased systemic exposure to digoxin by 150%; digoxin toxicity may occur³⁹⁸ Use of digoxin associated with increased risk of arrhythmic or sudden death in patients receiving dronedarone³⁹⁸ ⁴⁰⁵	Concomitant use not recommended; if concomitant use necessary, determine serum digoxin concentrations prior to initiating dronedarone and reduce dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸ ³⁹⁹ ⁴⁰⁵
Electrolyte balance, drugs affecting	Electrolyte disturbances produced by diuretics predispose to digoxin toxicity, including fatal cardiac arrhythmias^a Other drugs that deplete body potassium (e.g., amphotericin B, corticosteroids, corticotropin, edetate disodium, laxatives, sodium polystyrene sulfonate) or that reduce extracellular potassium (e.g., glucagon, large doses of dextrose, dextrose-insulin infusions) also may predispose patients to digoxin toxicity^a	Periodically monitor electrolytes during concomitant diuretic therapy and take corrective measures if warranted^a
Epoprostenol	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Exenatide	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating exenatide; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Flecainide	Serum digoxin concentrations may be increased; however, unlikely to be clinically important in most cases³⁰⁴ ³⁰⁵ ³⁰⁶ ³⁰⁷ ³⁰⁸ Patients with AV nodal dysfunction,³⁰⁶ serum digoxin concentrations in the upper end of the therapeutic range, and/or high plasma flecainide concentrations may be at increased risk of digoxin toxicity³⁰⁵ ³⁰⁶	Monitor for signs of digoxin toxicity³⁰⁵ ³⁰⁶
Gentamicin	Increased serum digoxin concentrations by 129–212%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating gentamicin and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸
HIV protease inhibitors (e.g., darunavir, saquinavir, ritonavir)	May increase serum digoxin concentrations by various magnitudes³⁹⁸	Measure serum digoxin concentrations prior to initiating the HIV protease inhibitor³⁹⁸ When initiating ritonavir, decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸ When initiating saquinavir, decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Ibuprofen	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Indomethacin	May prolong elimination half-life and increase serum concentrations of digoxin³⁷² ³⁷³ ³⁷⁴ ³⁹⁸	Measure serum digoxin concentrations prior to initiating indomethacin and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Itraconazole	Increased serum digoxin concentrations by 80%;³⁷⁷ ³⁷⁸ ³⁹⁸ digoxin toxicity may occur³⁷⁷ ³⁷⁸	Measure serum digoxin concentrations prior to initiating itraconazole and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸
Kaolin-pectin	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating kaolin-pectin; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Ketoconazole	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Lapatinib	Increased systemic exposure to digoxin by 180%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating lapatinib and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸
Macrolide antibiotics (i.e., azithromycin, clarithromycin, erythromycin)	Clarithromycin, erythromycin: Increased digoxin concentrations and/or systemic exposure by >50%; digoxin toxicity may occur³⁹⁸ Azithromycin: Increased digoxin concentrations, but magnitude unknown³⁹⁸	Clarithromycin, erythromycin: Measure serum digoxin concentrations prior to initiating the macrolide and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸ Azithromycin: Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Metformin	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Metoclopramide	Reduced GI absorption of digoxin (resulting in decreased serum digoxin concentrations), especially when administered at the same time^a	Space administration as far apart as possible^a
Miglitol	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating miglitol; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Mirabegron	Increased serum concentrations and systemic exposure of digoxin by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating mirabegron and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Nefazodone	Increased serum concentrations or systemic exposure of digoxin by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating nefazodone and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Neomycin	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating neomycin; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Nifedipine	Increased serum digoxin concentrations by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating nifedipine and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
NSAIAs	May impair elimination of digoxin and predispose patients to digoxin toxicity³⁹⁸
Penicillamine	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating penicillamine; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Phenytoin	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating phenytoin; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Propafenone	Increased systemic exposure of digoxin by 60–270%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating propafenone and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸
Propantheline	Increased serum concentrations and systemic exposure of digoxin by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating propantheline and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole)	Increased digoxin concentrations, but magnitude unknown³⁹⁸	Measure serum digoxin concentrations and reduce dosage of digoxin as necessary³⁹⁸
Quinidine	Increased serum digoxin concentrations by 100%; digoxin toxicity may occur³⁰³ ³⁰⁸ ³¹¹ ³¹² ³⁹⁸ ⁵²⁴	Measure serum digoxin concentrations prior to initiating quinidine and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸ If digoxin therapy is initiated in a patient receiving quinidine, lower than usual dosages of digoxin may be sufficient to produce desired serum concentrations³⁰² ³⁰³ ³⁰⁸ If quinidine is discontinued in a patient stabilized on therapy with both drugs, observe patient for signs of decreased response to digoxin and adjust dosage of digoxin as necessary³⁰² ³⁰³ ³⁰⁸
Quinine	Increased systemic exposure to digoxin by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating quinine and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Rabeprazole	Increased serum concentrations and systemic exposure to digoxin by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating rabeprazole and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Ranolazine	Increased digoxin concentrations by 50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating ranolazine and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸
Rifampin	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating rifampin; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Sotalol	Proarrhythmic events more common with concomitant use³⁹⁸	Individualize dosage of digoxin³⁹⁸
Spironolactone	Increased digoxin concentrations by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating spironolactone and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
St. John's wort (Hypericum perforatum)	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating St. John's wort; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Succinylcholine	Potentiates effects of digoxin on conduction and ventricular irritability³⁹⁸	Use concomitantly with caution and individualize digoxin dosage³⁹⁸
Sucralfate	Decreased serum digoxin concentrations³⁹⁸	Measure serum digoxin concentrations prior to initiating sucralfate; continue monitoring and increase digoxin dosage by approximately 20–40% as necessary³⁹⁸
Sulfasalazine	Reduced GI absorption of digoxin (resulting in decreased serum digoxin concentrations), especially when administered at the same time^a	Space administration as far apart as possible^a
Sympathomimetics (dopamine, epinephrine, norepinephrine)	Risk of arrhythmias may be increased³⁹⁸	Use concomitantly with caution³⁹⁸
Telmisartan	Increased serum digoxin concentrations by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating telmisartan and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Teriparatide	Can transiently increase serum calcium concentrations, which may predispose patients to digoxin toxicity³⁹⁸
Tetracycline	Increased serum digoxin concentrations by 100%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating tetracycline and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸
Thyroid supplements	May increase dosage requirements of digoxin³⁹⁸
Tolvaptan	Increased serum concentrations and systemic exposure to digoxin by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating tolvaptan and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Trimethoprim	Increased serum digoxin concentrations by <50%; digoxin toxicity may occur³⁹⁸	Measure serum digoxin concentrations prior to initiating trimethoprim and decrease dose of digoxin by approximately 15–30% or modify dosing frequency³⁹⁸
Verapamil	Increased serum digoxin concentrations by 50–75%; digoxin toxicity may occur³⁹⁸ ^a Concomitant use can have additive negative effects on AV conduction; however, combined therapy (e.g., for control of ventricular rate in patients with atrial fibrillation) usually well tolerated if digoxin dosage is properly adjusted ³⁷⁹ ³⁸⁰ ³⁸¹ ^a	Measure serum digoxin concentrations prior to initiating verapamil and decrease dose of digoxin by approximately 30–50% or modify dosing frequency³⁹⁸

Digoxin Pharmacokinetics

Absorption

Bioavailability

Mainly from the small intestine, presumably by a passive, nonsaturable process.^a

Absolute bioavailability is 60–80% for the tablets and 70–85% for the oral solution.³⁹⁸ ⁴⁰⁰ ⁴⁰²

Substrate of P-gp, a transport protein involved in absorption.³⁹⁸

Onset

Following oral administration, onset of action occurs in approximately 0.5–2 hours and maximal effect occurs in 2–6 hours.³⁹⁸

Following IV administration, onset of action occurs in 5–30 minutes depending on the rate of infusion and maximal effect occurs in 1–4 hours.³⁹⁸

Food

Presence of food in the GI tract may slow rate but not extent of absorption.³⁹⁸ ⁴⁰³

Plasma Concentrations

Determine plasma concentrations by obtaining blood samples at least 6–8 hours after the daily dose and preferably just prior to the next scheduled daily dose.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Therapeutic plasma concentrations in adults are generally 0.5–2 ng/mL.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

In adults, toxicity is usually, but not always, associated with steady-state plasma digoxin concentrations >2 ng/mL.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Neonates and infants appear to tolerate slightly higher plasma concentrations than adults,²³ ⁶⁵ ⁷⁶ ¹⁵¹ ¹⁶¹ ¹⁸² ²⁹⁷ ³⁹⁸ ⁴⁰² ⁴⁰³ but plasma concentrations >2 ng/mL are associated with little, if any, additional therapeutic benefit.²⁹⁷

Interpret plasma concentrations in the overall clinical context; thus, do not use an isolated plasma concentration measurement alone as the basis for adjusting dosage.³⁹⁸ ⁴⁰⁰ ⁴⁰² ⁴⁰³

Special Populations

Renal impairment: Systemic exposure is increased.³⁹⁸

Hepatic Impairment: Plasma digoxin concentrations in patients with acute hepatitis generally similar to those with normal hepatic function.³⁹⁸

Distribution

Extent

Widely distributed in body tissues; highest concentrations in the heart, kidneys, intestine, stomach, liver, and skeletal muscle.^a

In the myocardium, digoxin is found in the sarcolemma-T system bound to a receptor.^a

Crosses the placenta.^a

Distributes into breast milk.^a

Plasma Protein Binding

About 20–30%.^a

Elimination

Metabolism

Usually, only small amounts are metabolized.^a

Metabolism includes stepwise cleavage of the sugar molecules, hydroxylation, epimerization, and formation of glucuronide and sulfate conjugates.^a CYP enzymes not involved in metabolism.³⁹⁸

Apparently also metabolized by bacteria within the lumen of the large intestine following oral administration and possibly after biliary elimination following parenteral administration.³⁹⁸

Elimination Route

Mainly in urine, principally as unchanged drug.^a

Half-life

Approximately 36 hours in patients with normal renal function.^a

Special Populations

Renal impairment: Elimination half-life is prolonged.^a

Stability

Storage

Oral

Tablets

20–25°C; store in dry place and protect from light.³⁹⁸ ⁴⁰³

Oral Solution

20–25°C; protect from light.⁴⁰²

Parenteral

Injection

25°C (may be exposed to 15–30°C); protect from light.⁴⁰⁰

Diluted solutions of digoxin should be used immediately.⁴⁰⁰

Compatibility

Parenteral

Solution CompatibilityHID

Compatible
Dextrose 5% in sodium chloride 0.45% with potassium chloride 20 mEq/L
Dextrose 5% in water
Ringer’s injection, lactated
Sodium chloride 0.45 or 0.9%

Drug Compatibility

Admixture CompatibilityHID
Compatible
Floxacillin sodium
Furosemide
Lidocaine HCl
Ranitidine HCl
Verapamil HCl
Incompatible
Dobutamine HCl

Y-Site CompatibilityHID
Compatible
Anidulafungin
Bivalirudin
Cangrelor tetrasodium
Ceftaroline fosamil
Ceftolozane sulfate-tazobactam sodium
Ciprofloxacin
Cisatracurium besylate
Cloxacillin sodium
Dexmedetomidine HCl
Diltiazem HCl
Doripenem
Famotidine
Fenoldopam mesylate
Heparin sodium with hydrocortisone sodium succinate
Hetastarch in lactated electrolyte injection (Hextend)
Isavuconazonium sulfate
Linezolid
Meperidine HCl
Meropenem
Meropenem-vaborbactam
Midazolam HCl
Milrinone lactate
Morphine sulfate
Nesiritide
Potassium chloride
Remifentanil HCl
Tacrolimus
Tedizolid phosphate
Incompatible
Amiodarone HCl
Fluconazole
Foscarnet sodium
Quinupristin-dalfopristin
Telavancin HCl
Variable
Insulin, regular (Humulin R)

Actions

Digoxin is a cardiac glycoside.³⁹⁸ ⁷⁰⁰ ⁷⁰¹
The main pharmacologic property is its ability to increase the force and velocity of myocardial systolic contraction (positive inotropic action) by a direct action on the myocardium.³⁹⁹ ^a
Inhibits the activity of sodium-potassium-activated adenosine triphosphatase (Na⁺-K⁺-ATPase), an enzyme required for active transport of sodium across myocardial cell membranes.^a
Toxicity results in part from loss of intracellular potassium associated with inhibition of Na⁺-K⁺-ATPase.^a
With therapeutic doses, augmentation of calcium influx to the contractile proteins with resultant enhancement of excitation-contraction coupling is involved in the positive inotropic action of digoxin.^a
Causes reflex reduction in peripheral resistance by increasing myocardial contractility; this compensates for the direct vasoconstrictor action and, therefore, total peripheral resistance usually is reduced.^a
In patients with heart failure, myocardial contractility and cardiac output reflexly reduce sympathetic tone, thus slowing increased heart rate and causing diuresis in edematous patients.^a
In patients without heart failure, increased myocardial contractility produced by digoxin is accompanied by increased myocardial oxygen consumption.^a
Decreases conduction velocity through the atrioventricular (AV) node and prolongs the effective refractory period of the AV node by increasing vagal activity, by a direct effect on the AV node, and by a sympatholytic effect.^a
With therapeutic doses, may cause prolongation of the PR interval and ST segment depression, but these ECG effects are not indicative of toxicity.³⁹⁸
Toxic doses increase the automaticity (increased spontaneous diastolic depolarization) of all areas of the heart except the SA node.^a

Advice to Patients

Importance of explaining common signs and symptoms of digoxin toxicity and to contact a clinician if they occur.³⁹⁸ (See Major Toxicities under Cautions.)
Importance of warning patient to immediately contact a clinician if color vision is affected or objects appear yellow or green or, less commonly, brown, red, blue, or white;³⁸ ²⁷⁰ ³⁹⁸ halos or borders on objects (often are white and appear on dark objects) are also signs of toxicity and reason for consulting a clinician.⁷⁴ ²⁷⁰ ³⁹⁸
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses.³⁹⁸
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.³⁹⁸
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Digoxin
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Solution	50 mcg/mL*	Digoxin Oral Solution
	Tablets	62.5 mcg	Lanoxin	Concordia
		125 mcg*	Digitek	Mylan
			Digoxin Tablets
			Lanoxin (scored)	Concordia
		187.5 mcg	Lanoxin	Concordia
		250 mcg*	Digitek	Mylan
			Digoxin Tablets
			Lanoxin (scored)	Concordia
Parenteral	Injection	100 mcg/mL	Lanoxin Injection Pediatric	Covis
		250 mcg/mL*	Digoxin Injection
			Lanoxin	Covis

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

12. Smith TW. Digitalis glycosides (second of two parts). N Engl J Med. 1973; 288:942-6. http://www.ncbi.nlm.nih.gov/pubmed/4571350?dopt=AbstractPlus

23. Smith TW, Haber E. Digitalis (third of four parts). N Engl J Med. 1973; 289:1063-72. http://www.ncbi.nlm.nih.gov/pubmed/4590503?dopt=AbstractPlus

24. Smith TW, Haber E. Digitalis (fourth of four parts). N Engl J Med. 1973; 289:1125-9. http://www.ncbi.nlm.nih.gov/pubmed/4592149?dopt=AbstractPlus

25. Gill MA, Miscia VF, Gourley DR. The treatment of common cardiac arrhythmias. J Am Pharm Assoc. 1976; 16:20-9. http://www.ncbi.nlm.nih.gov/pubmed/1107399?dopt=AbstractPlus

27. Mason DT. Digitalis pharmacology and therapeutics: recent advances. Ann Intern Med. 1974; 80:520-30. http://www.ncbi.nlm.nih.gov/pubmed/4621264?dopt=AbstractPlus

28. Doherty JE, Kane JJ. Clinical pharmacology and therapeutic use of digitalis glycosides. Drugs. 1973; 6:182-221. http://www.ncbi.nlm.nih.gov/pubmed/4273255?dopt=AbstractPlus

29. Dreifus LS, Watanabe Y. Clinical correlates of the electrophysiologic action of digitalis on the heart. Semin Drug Treat. 1972; 2:179-201. http://www.ncbi.nlm.nih.gov/pubmed/4343767?dopt=AbstractPlus

38. Aronson JK. Cardiac glycosides and drugs used in dysrhythmias. In: Dukes MNG, ed. Meyler’s side effects of drugs. 10th ed. Amsterdam: Excerpta Medica; 1984:299-316.

39. Meyler L, ed. Side effects of drugs. 4th ed. Amsterdam: Excerpta Medica; 1963: 85-8.

40. Stafford A. Drugs acting on the heart. In: Meyler L, Herxheimer A, eds. Side effects of drugs. 6th ed. Amsterdam: Excerpta Medica; 1968:189-94.

46. Lely AH, van Enter CHJ. Non-cardiac symptoms of digitalis intoxication. Am Heart J. 1972; 83:149-52. http://www.ncbi.nlm.nih.gov/pubmed/4554547?dopt=AbstractPlus

47. Dall JLC. Digitalis intoxication in elderly patients. Lancet. 1965; 1:194-5. http://www.ncbi.nlm.nih.gov/pubmed/14238049?dopt=AbstractPlus

48. Batterman RC, Gutner LB. Hitherto undescribed neurological manifestations of digitalis toxicity. Am Heart J. 1948; 36:582-6. http://www.ncbi.nlm.nih.gov/pubmed/18886105?dopt=AbstractPlus

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