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Digoxin

Class: Cardiotonic Agents
- Inotropic Agents, Positive Cardiac
VA Class: CV050
Chemical Name: (3β,5β,12β)-3-[(O-2,6-dideoxy-b-d-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl) oxy]-12,14-dihydroxy-card-20(22)-enolide
Molecular Formula: C41H64O14
CAS Number: 20830-75-5
Brands: Digitek, Lanoxin

Medically reviewed by Drugs.com. Last updated on Sep 23, 2019.

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).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, 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

IV

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

IV

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

IV

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

IV

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

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.385 398

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

Interactions for Digoxin

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 timea

Space administration as far apart as possiblea

Amiodarone

Increased serum digoxin concentrations by 70%; digoxin toxicity may occur398 a

Magnitude of the increase may be much greater in childrena

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 toxicitya

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 glycosidea

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 timea

Space administration as far apart as possiblea

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 digoxina

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 togethera

Administer digoxin at least 1.5–2 hours before cholestyramine or colestipola

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 arrhythmiasa

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 toxicitya

Periodically monitor electrolytes during concomitant diuretic therapy and take corrective measures if warranteda

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 timea

Space administration as far apart as possiblea

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 timea

Space administration as far apart as possiblea

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

For information on systemic interactions resulting from concomitant use, see Interactions.

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

AHFS DI Essentials™. © Copyright 2021, Selected Revisions September 23, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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