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Pronunciation

(di JOKS in)

Generic Available (U.S.)

Yes

Index Terms

• Digitalis

U.S. Brand Names

• Lanoxin®

Canadian Brand Names

• Apo-Digoxin®
• Digoxin CSD
• Lanoxin®
• Pediatric Digoxin CSD
• PMS-Digoxin
• Toloxin®

Pharmacologic Category

• Antiarrhythmic Agent, Miscellaneous
• Cardiac Glycoside

Pharmacologic Category Synonyms

• Digitalis Glycoside

Use: Labeled Indications

Treatment of mild-to-moderate (or stage C as recommended by the ACCF/AHA) heart failure (HF); atrial fibrillation (rate-control)

Note: In treatment of atrial fibrillation (AF), use is not considered first-line unless AF coexistent with heart failure or in sedentary patients (Fuster, 2006).

Use: Unlabeled/Investigational

Fetal tachycardia with or without hydrops; to slow ventricular rate in supraventricular tachyarrhythmias such as supraventricular tachycardia (SVT) excluding atrioventricular reciprocating tachycardia (AVRT)

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted. Digoxin crosses the placenta and can be detected in the fetus. Digoxin is recommended as first-line in the treatment of fetal tachycardia determined to be SVT. In pregnant women with atrial fibrillation or SVT, use of digoxin is recommended (Class I recommendation; Blomström-Lundqvist, 2003; Fuster, 2006).

Lactation

Enters breast milk/use caution (AAP rates “compatible”; AAP 2001 update pending)

Breast-Feeding Considerations

Digoxin is excreted into breast milk and similar concentrations are found within mother's serum and milk. The manufacturer recommends that caution be used in nursing women.

Contraindications

Hypersensitivity to digoxin (rare) or other forms of digitalis, or any component of the formulation; ventricular fibrillation

Warnings/Precautions

Concerns related to adverse effects:

• Proarrhythmic effects: Monitor for proarrhythmic effects (especially with digoxin toxicity)

Disease-related concerns:

• Accessory bypass tract (eg, Wolff-Parkinson-White [WPW] syndrome): During an episode of atrial fibrillation or flutter in patients with an accessory bypass tract, use has been associated with increased anterograde conduction down the accessory pathway leading to ventricular fibrillation; avoid use in such patients.

• Acute MI: Use with caution in patients with an acute MI (within 6 months); may increase myocardial oxygen demand. During the immediate post-MI period, digoxin administered I.V. may be used in the acute treatment of refractory atrial fibrillation/flutter (especially when HF or LV dysfunction coexists) or refractory re-entrant PSVT (Antman, 2004).

• Atrioventricular (AV) block: Avoid use in patients with second- or third-degree heart block (except in patients with a functioning artificial pacemaker); incomplete AV block (eg, Stokes-Adams attacks) may progress to complete block with digoxin administration.

• Beri beri heart disease: Patients with beri beri heart disease may fail to adequately respond to digoxin therapy; treat underlying thiamine deficiency concomitantly.

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy; toxicity may occur despite therapeutic digoxin concentrations (eg, <2 ng/mL). Hypercalcemia may increase the risk of digoxin toxicity; maintain normocalcemia.

• Heart failure (HF): HF patients with preserved left ventricular function including patients with restrictive cardiomyopathy, constrictive pericarditis, and amyloid heart disease may be susceptible to digoxin toxicity; avoid use unless used to control ventricular response with atrial fibrillation. Digoxin should not be used in patients with low EF, sinus rhythm, and no HF symptoms since the risk of harm may be greater than clinical benefit (Hunt, 2009). Withdrawal of digoxin in clinically stable patients with HF may lead to recurrence of HF symptoms (Packer, 1993).

• Hypermetabolic states: Atrial arrhythmias associated with hypermetabolic states are very difficult to treat; treat underlying condition first. If digoxin is used, ensure digoxin toxicity does not occur.

• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Outflow obstruction may worsen due to the positive inotropic effects of digoxin; avoid use unless used to control ventricular response with atrial fibrillation.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment needed.

• Sinus nodal disease: Use with caution in patients with sinus nodal disease (eg, sick sinus syndrome); may worsen.

• Thyroid disease: Use with caution in patients with hypothyroidism, higher digoxin concentrations may result. Use with caution in patients with hyperthyroidism, lower digoxin concentrations may result due to decreased absorption. Note: New-onset atrial fibrillation or exacerbation of ventricular arrhythmias should prompt evaluation of thyroid status.

Concurrent drug therapy issues:

• Calcium: Avoid rapid I.V. administration of calcium in digitalized patients; may produce serious arrhythmias.

• High potential for interactions: Use caution in patients taking strong inducers or inhibitors of P-glycoprotein (eg, cyclosporine). Upon initiation of amiodarone, propafenone, quinidine, or verapamil the need for digoxin should be evaluated and the digoxin dose should be reduced (eg, by 50%) to avoid toxicity.

Special populations:

• Elderly: Use with caution in the elderly; may develop exaggerated serum/tissue concentrations due to age-related alterations in clearance and pharmacodynamics differences; dosage reduction may be necessary; in general, avoid doses >0.125 mg/day (Beers Criteria).

Other warnings/precautions:

• Elective electrical cardioversion: It is not necessary to routinely reduce or hold digoxin therapy prior to elective electrical cardioversion for atrial fibrillation; however, exclusion of digoxin toxicity (eg, clinical and ECG signs) is necessary prior to cardioversion. If signs of digoxin excess exist, withhold digoxin and delay cardioversion until toxicity subsides; usually >24 hours (Fuster, 2006).

Adverse Reactions

Incidence not always reported.

Cardiovascular: Accelerated junctional rhythm, asystole, atrial tachycardia with or without block, AV dissociation, first-, second- (Wenckebach), or third-degree heart block, facial edema, PR prolongation, PVCs (especially bigeminy or trigeminy), ST segment depression, ventricular tachycardia or ventricular fibrillation

Central nervous system: Dizziness (6%), mental disturbances (5%), headache (4%), apathy, anxiety, confusion, delirium, depression, fever, hallucinations

Dermatologic: Rash (erythematous, maculopapular [most common], papular, scarlatiniform, vesicular or bullous), pruritus, urticaria, angioneurotic edema

Gastrointestinal: Nausea (4%), vomiting (2%), diarrhea (4%), abdominal pain, anorexia

Neuromuscular & skeletal: Weakness

Ocular: Visual disturbances (blurred or yellow vision)

Respiratory: Laryngeal edema

<1%, postmarketing, and/or case reports (limited to important or life-threatening): Asymmetric chorea, gynecomastia, thrombocytopenia, palpitation, intestinal ischemia, hemorrhagic necrosis of the intestines, vaginal cornification, eosinophilia, sexual dysfunction, diaphoresis

Children are more likely to experience cardiac arrhythmia as a sign of excessive dosing. The most common are conduction disturbances or tachyarrhythmia (atrial tachycardia with or without block) and junctional tachycardia. Ventricular tachyarrhythmias are less common. In infants, sinus bradycardia may be a sign of digoxin toxicity. Any arrhythmia seen in a child on digoxin should be considered as digoxin toxicity. The gastrointestinal and central nervous system symptoms are not frequently seen in children.

Metabolism/Transport Effects

Substrate of CYP3A4 (minor), P-glycoprotein

Drug Interactions

5-ASA Derivatives: May decrease the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Acarbose: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy

Adenosine: Digoxin may enhance the adverse/toxic effect of Adenosine. Risk C: Monitor therapy

Aminoglycosides: May decrease the absorption of Cardiac Glycosides. This effect has only been demonstrated with oral aminoglycoside administration. Exceptions: Amikacin; Gentamicin; Gentamicin (Systemic); Streptomycin; Tobramycin; Tobramycin (Systemic, Oral Inhalation). Risk C: Monitor therapy

Aminoquinolines (Antimalarial): May increase the serum concentration of Cardiac Glycosides. Risk D: Consider therapy modification

Amiodarone: May increase the serum concentration of Cardiac Glycosides. Risk D: Consider therapy modification

Antineoplastic Agents: May decrease the absorption of Cardiac Glycosides. This may only affect digoxin tablets. Exceptions: Alitretinoin; Altretamine; Aminoglutethimide; Anastrozole; Asparaginase; AzaCITIDine; Busulfan; Capecitabine; CARBOplatin; Chlorambucil; CISplatin; Cladribine; Cytarabine (Liposomal); Dacarbazine; DACTINomycin; DAUNOrubicin Citrate (Liposomal); DAUNOrubicin Hydrochloride; Denileukin Diftitox; DOCEtaxel; Epirubicin; Estramustine; Etoposide; Etoposide Phosphate; Exemestane; Fludarabine; Fluorouracil; Fluorouracil (Systemic); Fluorouracil (Topical); Gemcitabine; Goserelin; Hydroxyurea; IDArubicin; Ifosfamide; Irinotecan; Letrozole; Leuprolide; Lomustine; Mechlorethamine; Megestrol; Mercaptopurine; MitoMYcin; Mitotane; MitoXANtrone; Nilutamide; PACLitaxel; Pegaspargase; Pentostatin; Polyestradiol; Porfimer; RiTUXimab; Streptozocin; Tamoxifen; Temozolomide; Teniposide; Thioguanine; Thiotepa; Topotecan; Toremifene; Tretinoin (Systemic); Valrubicin; VinBLAStine; Vinorelbine. Risk C: Monitor therapy

Antineoplastic Agents (Anthracycline): Cardiac Glycosides may diminish the cardiotoxic effect of Antineoplastic Agents (Anthracycline). Antineoplastic Agents (Anthracycline) may decrease the serum concentration of Cardiac Glycosides. The effects of liposomal formulations may be unique from those of the free drug, as liposomal formulation have unique drug disposition and toxicity profiles, and liposomes themselves may alter digoxin absorption/distribution. Risk C: Monitor therapy

Atorvastatin: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Beta-Blockers: May enhance the bradycardic effect of Cardiac Glycosides. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Cardiac Glycosides. Exceptions: Colesevelam. Risk C: Monitor therapy

Boceprevir: May increase the serum concentration of Digoxin. Management: In patients initiating digoxin during boceprevir treatment, initiate at the lowest possible digoxin dose, monitor serum digoxin concentrations, and titrate carefully due to a possible risk of elevated digoxin concentrations. Risk D: Consider therapy modification

Calcium Channel Blockers (Nondihydropyridine): May enhance the AV-blocking effect of Cardiac Glycosides. Calcium Channel Blockers (Nondihydropyridine) may decrease the metabolism of Cardiac Glycosides. Risk D: Consider therapy modification

Calcium Polystyrene Sulfonate: May enhance the adverse/toxic effect of Cardiac Glycosides. Risk C: Monitor therapy

Carvedilol: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Colchicine: Digoxin may increase the serum concentration of Colchicine. Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

CycloSPORINE: May decrease the metabolism of Cardiac Glycosides. Risk D: Consider therapy modification

CycloSPORINE (Systemic): May decrease the metabolism of Cardiac Glycosides. Risk D: Consider therapy modification

Dronedarone: Digoxin may enhance the AV-blocking effect of Dronedarone. Digoxin may also enhance the other electrophysiologic effects of Dronedarone. Dronedarone may increase the serum concentration of Digoxin. Management: Avoid concurrent use of digoxin when possible. If concurrent use is necessary, reduce adult digoxin dose by 50% and increase monitoring for both clinical response to therapy and the occurrence of adverse effects. Risk D: Consider therapy modification

Etravirine: May increase the serum concentration of Digoxin. Management: Monitor serum digoxin concentrations and adjust dose as needed. In patients initiating a regimen of digoxin with etravirine, digoxin should be initiated at the lowest dose. Risk C: Monitor therapy

Glycopyrrolate: May increase the serum concentration of Digoxin. This effect is specific to digoxin administered as slow dissolution oral tablets. Risk C: Monitor therapy

Itraconazole: May increase the serum concentration of Cardiac Glycosides. Management: Consider preemptive cardiac glycoside dose adjustments with initiation / changes / discontinuation of itraconazole. Risk D: Consider therapy modification

Kaolin: May decrease the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Cardiac Glycosides. Risk D: Consider therapy modification

Midodrine: Cardiac Glycosides may enhance the bradycardic effect of Midodrine. Risk C: Monitor therapy

Milnacipran: May enhance the adverse/toxic effect of Digoxin. The risk of postural hypotension and tachycardia may be increased, particularly with IV digoxin. Management: Avoid concurrent use of intravenous (IV) digoxin in patients receiving milnacipran. Use caution when using oral digoxin and milnacipran together, monitoring closely for possible postural hypotension and tachycardia. Risk D: Consider therapy modification

Nefazodone: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Neuromuscular-Blocking Agents: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Paricalcitol: May enhance the adverse/toxic effect of Digoxin. Risk C: Monitor therapy

Penicillamine: May decrease the serum concentration of Digoxin. Risk C: Monitor therapy

P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

Posaconazole: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Potassium-Sparing Diuretics: May diminish the therapeutic effect of Cardiac Glycosides. In particular, the inotropic effects of digoxin appear to be diminished. Potassium-Sparing Diuretics may increase the serum concentration of Cardiac Glycosides. This particular effect may be unique to Spironolactone. Risk C: Monitor therapy

Propafenone: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Protease Inhibitors: May increase the serum concentration of Digoxin. Increased serum concentrations of digoxin may increase risk of AV nodal blockade. Risk C: Monitor therapy

QuiNIDine: May increase the serum concentration of Cardiac Glycosides. Management: Upon quinidine initiation, consider reducing cardiac glycoside dose by 25% to 50%, with continued monitoring of glycoside serum concentrations and clinical response until the quinidine reaches steady state (5-10 days). Risk D: Consider therapy modification

QuiNINE: May increase the serum concentration of Cardiac Glycosides. Risk D: Consider therapy modification

Ranolazine: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Reserpine: May enhance the adverse/toxic effect of Cardiac Glycosides. Risk C: Monitor therapy

SitaGLIPtin: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Sodium Polystyrene Sulfonate: May enhance the adverse/toxic effect of Digoxin. Risk C: Monitor therapy

Spironolactone: May increase the serum concentration of Digoxin. Spironolactone (and/or its metabolites) may also interfere with the assays used to determine Digoxin concentrations, falsely increasing or decreasing Digoxin concentrations. Risk C: Monitor therapy

St Johns Wort: May decrease the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Sucralfate: May decrease the serum concentration of Digoxin. Specifically, sucralfate may decrease the absorption of digoxin. Management: Administer digoxin at least 2 hours before or at least 6 hours after sucralfate. Risk D: Consider therapy modification

Telmisartan: May increase the serum concentration of Cardiac Glycosides. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Tolvaptan: May increase the serum concentration of Digoxin. Risk C: Monitor therapy

Vitamin D Analogs: May enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions

Food: Digoxin peak serum concentrations may be decreased if taken with food. Meals containing increased fiber (bran) or foods high in pectin may decrease oral absorption of digoxin.

Herb/Nutraceutical: Avoid ephedra (risk of cardiac stimulation). Avoid natural licorice (causes sodium and water retention and increases potassium loss).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect elixir, injection, and tablets from light.

Compatibility

Stable in D₅1/2NS with KCl 20 mEq, D₅W, LR, 1/2NS, and NS. May be diluted fourfold in D₅W, NS, or SWFI for direct injection (or may be administered undiluted).

Y-site administration: Compatible: Alfentanil, amikacin, aminophylline, anidulafungin, ascorbic acid, atracurium, atropine, aztreonam, benztropine, bivalirudin, bumetanide, buprenorphine, butorphanol, calcium chloride, calcium gluconate, cefazolin, cefotaxime, cefotetan, cefoxitin, ceftazidime, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, chlorpromazine, cimetidine, ciprofloxacin, cisatracurium, clindamycin, cyanocobalamin, cyclosporine, dexamethasone, dexmedetomidine, diltiazem, diphenhydramine, dobutamine, dopamine, doripenem, doxycycline, enalaprilat, ephedrine, epinephrine, epoetin alfa, erythromycin, esmolol, famotidine, fenoldopam, fentanyl, fentanyl and droperidol, folic acid, furosemide, ganciclovir, gatifloxacin, gentamicin, glycopyrrolate, haloperidol, heparin, heparin with hydrocortisone sodium succinate, hetastarch in lactated electrolyte injection, hydrocortisone, hydroxyzine, imipenem-cilastatin, indomethacin, isoproterenol, ketorolac, labetalol, lidocaine, linezolid, magnesium, mannitol, meperidine, meropenem, methylprednisolone sodium succinate, metoclopramide, metoprolol, metronidazole, midazolam, milrinone, morphine, multivitamins, nafcillin, nalbuphine, naloxone, nesiritide, nitroglycerin, nitroprusside, norepinephrine, ondansetron, oxacillin, oxytocin, papaverine, penicillin G potassium, penicillin G sodium, pentazocine, pentobarbital, phenobarbital, phentolamine, phenylephrine, phytonadione, piperacillin, polymyxin B sulfate, potassium chloride, procainamide, prochlorperazine, promethazine, propofol, propranolol, protamine, pyridoxine, quinidine gluconate, ranitidine, remifentanil, sodium bicarbonate, succinylcholine, sufentanil, tacrolimus, theophylline, thiamine, ticarcillin-clavulanate, tobramycin, vancomycin, vasopressin, verapamil, vitamin B complex with C. Incompatible: Amiodarone, amphotericin B (conventional), amphotericin B cholesteryl sulfate complex, dantrolene, diazepam, foscarnet, inamrinone, lansoprazole, minocycline, pantoprazole, pentamidine, phenytoin, trimethoprim/sulfamethoxazole. Variable (consult detailed reference): Ampicillin, ampicillin-sulbactam sodium, azathioprine, fluconazole, haloperidol, hydralazine, insulin (regular).

Compatibility in syringe: Compatible: Heparin, hydralazine, milrinone. Incompatible: Doxapram, pantoprazole.

Compatibility when admixed: Compatible: Aminophylline, cefotetan, chloramphenicol, cimetidine, diazepam, esmolol, furosemide, inamrinone, lidocaine, milrinone, potassium chloride, ranitidine, verapamil. Incompatible: Dobutamine. Variable (consult detailed reference): Insulin (regular).

Mechanism of Action

Heart failure: Inhibition of the sodium/potassium ATPase pump in myocardial cells results in a transient increase of intracellular sodium, which in turn promotes calcium influx via the sodium-calcium exchange pump leading to increased contractility.

Supraventricular arrhythmias: Direct suppression of the AV node conduction to increase effective refractory period and decrease conduction velocity - positive inotropic effect, enhanced vagal tone, and decreased ventricular rate to fast atrial arrhythmias. Atrial fibrillation may decrease sensitivity and increase tolerance to higher serum digoxin concentrations.

Pharmacodynamics/Kinetics

Onset of action: Heart rate control: Oral: 1-2 hours; I.V.: 5-60 minutes

Peak effect: Heart rate control: Oral: 2-8 hours; I.V.: 1-6 hours; Note: In patients with atrial fibrillation, median time to ventricular rate control in one study was 6 hours (range: 3-15 hours) (Siu, 2009)

Duration: Adults: 3-4 days

Absorption: By passive nonsaturable diffusion in the upper small intestine; food may delay, but does not affect extent of absorption

Distribution:

Normal renal function: 6-7 L/kg

V_d: Extensive to peripheral tissues, with a distinct distribution phase which lasts 6-8 hours; concentrates in heart, liver, kidney, skeletal muscle, and intestines. Heart/serum concentration is 70:1. Pharmacologic effects are delayed and do not correlate well with serum concentrations during distribution phase.

Hyperthyroidism: Increased V_d

Hyperkalemia, hyponatremia: Decreased digoxin distribution to heart and muscle

Hypokalemia: Increased digoxin distribution to heart and muscles

Concomitant quinidine therapy: Decreased V_d

Chronic renal failure: 4-6 L/kg

Decreased sodium/potassium ATPase activity - decreased tissue binding

Neonates, full-term: 7.5-10 L/kg

Children: 16 L/kg

Adults: 7 L/kg, decreased with renal disease

Protein binding: ~25%; in uremic patients, digoxin is displaced from plasma protein binding sites

Metabolism: Via sequential sugar hydrolysis in the stomach or by reduction of lactone ring by intestinal bacteria (in ~10% of population, gut bacteria may metabolize up to 40% of digoxin dose); once absorbed, only ~16% is metabolized to 3-beta-digoxigenin, 3-keto-digoxigenin, and glucuronide and sulfate conjugates; metabolites may contribute to therapeutic and toxic effects of digoxin; metabolism is reduced with decompensated HF

Bioavailability: Oral (formulation dependent): Elixir: 70% to 85%; Tablet: 60% to 80%

Half-life elimination (age, renal and cardiac function dependent):

Neonates: Premature: 61-170 hours; Full-term: 35-45 hours

Infants: 18-25 hours

Children: 18-36 hours

Adults: 36-48 hours

Adults, anephric: 3.5-5 days

Half-life elimination: Parent drug: 38 hours; Metabolites: Digoxigenin: 4 hours; Monodigitoxoside: 3-12 hours

Time to peak, serum: Oral: 1-3 hours

Excretion: Urine (50% to 70% as unchanged drug)

Dosage

Children: When changing from oral (tablets or liquid) or I.M. to I.V. therapy, dosage should be reduced by 20% to 25%. Refer to the following: See table.

Adults:

Atrial fibrillation (rate control) in patients with heart failure: Loading dose: I.V.: 0.25 mg every 2 hours, up to 1.5 mg within 24 hours; for nonacute situations, may administer 0.5 mg orally once daily for 2 days followed by oral maintenance dose. Maintenance dose: I.V., Oral: 0.125-0.375 mg once daily (Fuster, 2006)

Heart failure: Daily maintenance dose (Note: Loading dose not recommended): Oral: 0.125-0.25 mg once daily; higher daily doses (up to 0.5 mg/day) are rarely necessary. If patient is >70 years of age, has impaired renal function, or has a low lean body mass, low doses (eg, 0.125 mg daily or every other day) should be used (Hunt, 2009).

Supraventricular tachyarrhythmias (rate control):

Initial: Total digitalizing dose:

Oral: 0.75-1.5 mg

I.V., I.M.: 0.5-1 mg (Note: I.M. not preferred due to severe injection site pain.)

Give 1/2 (one-half) of the total digitalizing dose (TDD) as the initial dose, then give 1/4 (one-quarter) of the TDD in each of 2 subsequent doses at 6- to 8-hour intervals. Obtain ECG 6 hours after each dose to assess potential toxicity.

Daily maintenance dose:

Oral: 0.125-0.5 mg once daily

I.V., I.M.: 0.1-0.4 mg once daily (Note: I.M. not preferred due to severe injection site pain.)

Elderly: Dose is based on lean body weight and normal renal function for age. Decrease dose in patients with decreased renal function (see dosing adjustment in renal impairment).

Heart failure: If patient is >70 years, low doses (eg, 0.125 mg daily or every other day) should be used (Hunt, 2009).

Dosing adjustment/interval in renal impairment:

Loading dose: If loading dose necessary, reduce dose by 50% in ESRD

Maintenance dose:

Cl_cr 10-50 mL/minute: Administer 25% to 75% of dose or every 36 hours

Cl_cr <10 mL/minute: Administer 10% to 25% of dose or every 48 hours

Hemodialysis: Not dialyzable (0% to 5%)

Administration: I.M.

I.V. route preferred. If I.M. injection necessary, administer by deep injection followed by massage at the injection site. Inject no more than 2 mL per injection site. May cause intense pain.

Administration: I.V.

May be administered undiluted or diluted fourfold in D₅W, NS, or SWFI for direct injection. Less than fourfold dilution may lead to drug precipitation. Inject slowly over ≥5 minutes

Administration: I.V. Detail

pH: 6.8-7.2

Monitoring Parameters

Heart rate and rhythm should be monitored along with periodic ECGs to assess desired effects and signs of toxicity; baseline and periodic serum creatinine. Periodically monitor serum potassium, magnesium, and calcium especially if on medications where these electrolyte disturbances can occur (eg, diuretics), or if patient has a history of hypokalemia or hypomagnesemia. Observe patients for noncardiac signs of toxicity, confusion, and depression.

When to draw serum digoxin concentrations: Digoxin serum concentrations are monitored because digoxin possesses a narrow therapeutic serum range; the therapeutic endpoint is difficult to quantify and digoxin toxicity may be life-threatening. Digoxin serum concentrations should be drawn at least 6-8 hours after last dose, regardless of route of administration (optimally 12-24 hours after a dose). Note: Serum digoxin concentrations may decrease in response to exercise due to increased skeletal muscle uptake; a period of rest (eg, ~2 hours) after exercise may be necessary prior to drawing serum digoxin concentrations.

Initiation of therapy:

If a loading dose is given: Digoxin serum concentration may be drawn within 12-24 hours after the initial loading dose administration. Concentrations drawn this early may confirm the relationship of digoxin plasma concentrations and response but are of little value in determining maintenance doses.

If a loading dose is not given: Digoxin serum concentration should be obtained after 3-5 days of therapy.

Maintenance therapy:

Trough concentrations should be followed just prior to the next dose or at a minimum of 6-8 hours after last dose.

Digoxin serum concentrations should be obtained within 5-7 days (approximate time to steady-state) after any dosage changes. Continue to obtain digoxin serum concentrations 7-14 days after any change in maintenance dose. Note: In patients with end-stage renal disease, it may take 15-20 days to reach steady-state.

Patients who are receiving electrolyte-depleting medications such as diuretics, serum potassium, magnesium, and calcium should be monitored closely.

Digoxin serum concentrations should be obtained whenever any of the following conditions occur:

Questionable patient compliance or to evaluate clinical deterioration following an initial good response

Changing renal function

Suspected digoxin toxicity

Initiation or discontinuation of therapy with drugs (eg, amiodarone, quinidine, verapamil) which potentially interact with digoxin.

Any disease changes (eg, thyroid disease)

Reference Range

Digoxin therapeutic serum concentrations:

Heart failure: 0.5-0.8 ng/mL

Adults: <0.5 ng/mL; probably indicates underdigitalization unless there are special circumstances

Toxic: >2 ng/mL

Digoxin-like immunoreactive substance (DLIS) may cross-react with digoxin immunoassay. DLIS has been found in patients with renal and liver disease, heart failure, neonates, and pregnant women (3rd trimester).

Test Interactions

Spironolactone may interfere with digoxin radioimmunoassay.

Dietary Considerations

Maintain adequate amounts of potassium in diet to decrease risk of hypokalemia (hypokalemia may increase risk of digoxin toxicity).

Patient Education

Maintain adequate dietary intake of potassium (do not increase without consulting prescriber). Adequate dietary potassium will reduce risk of digoxin toxicity. Take pulse at the same time each day; hold medication as directed by prescriber. Notify prescriber of acute changes in pulse. Report loss of appetite, nausea, vomiting, persistent diarrhea, swelling of extremities, palpitations, "yellowing" or blurred vision, mental confusion or depression, or unusual fatigue.

Geriatric Considerations

Digitalis preparations (primarily digoxin) are frequently used to treat common cardiac diseases in the elderly (heart failure, atrial fibrillation). Elderly are at risk for toxicity due to age-related changes; volume of distribution is diminished significantly; half-life is increased as a result of decreased total body clearance. Additionally, elderly frequently have concomitant diseases which affect the pharmacokinetics in digitalis glycosides; hypo- and hyperthyroidism and renal function decline will affect clearance of digoxin. Exercise in elderly will reduce serum concentrations of digoxin due to increased skeletal muscle uptake. Therefore, a knowledge of the physical activity of elderly helps interpret serum assays. Must be observant for noncardiac signs of toxicity in elderly such as anorexia, vision changes (blurred), confusion, and depression. Changes in dose may be necessary with declining renal function with age; monitor closely.

This medication is considered to be potentially inappropriate in this patient population (Beers Criteria severity: Low).

Anesthesia and Critical Care Concerns/Other Considerations

Clinical Pearls/Comments: Elderly are at risk for toxicity due to age-related changes; volume of distribution is diminished significantly; half-life is increased as a result of decreased total body clearance. Digoxin toxicity may be potentiated in patients with hypokalemia, hypomagnesemia, and hypercalcemia. Digoxin may also rapidly approach toxic concentrations in patients with renal failure. Signs of digoxin toxicity include both brady- and tachyarrhythmias. Bidirectional VT induced by digoxin indicates imminent development of ventricular fibrillation.

Digoxin has been used for many years in treatment of heart failure. Digoxin therapy is associated with a decrease in frequency in hospitalizations for exacerbations of heart failure. Digoxin use for ventricular rate control in patients with atrial fibrillation is a particularly useful strategy in those patients with coexisting systolic dysfunction. While digoxin may control ventricular response rate for atrial fibrillation at rest, the medication is less effective for rate control during exercise.

Cardiovascular Considerations

Heart Failure (HF): Digoxin has been used for many years in treatment of HF. Even though digoxin has a very narrow therapeutic index, it remains an important therapeutic strategy when added to standard therapy. When used in HF, it should be used only for systolic dysfunction and not diastolic dysfunction. While the long-term trials show no convincing reduction in cardiovascular mortality, digoxin therapy is associated with a decrease in frequency in hospitalizations for exacerbations of heart failure (DIG trial, 1997). In a post-hoc analysis of the DIG trial, low digoxin concentrations (eg, 0.5-0.8 ng/mL) were found to be associated with better clinical outcomes and lower mortality (Rathore, 2003). A potential mechanism of benefit in heart failure is that digoxin may improve baroreflex sensitivity.

Atrial Fibrillation: Digoxin use for ventricular rate control in patients with atrial fibrillation is a particularly useful strategy in those patients with coexisting systolic dysfunction. It is important to consider, however, that while digoxin may control ventricular response rate for atrial fibrillation at rest, it is less effective for rate control during exercise. With the availability of newer and somewhat safer medications for the treatment of atrial fibrillation, the use of digoxin is no longer first-line therapy unless the patient has HF or is sedentary (Fuster, 2006).

Digoxin Toxicity: Digoxin toxicity may be potentiated in patients with hypokalemia, hypomagnesemia, and hypercalcemia. Digoxin may also rapidly approach toxic concentrations in patients with renal failure. For patients with renal failure, the loading dose is unchanged but maintenance doses may be adjusted and concentrations should be monitored very carefully. Signs of digoxin toxicity are either extracardiac or cardiac manifestations. Extracardiac manifestations include anorexia, nausea, and fatigue. Cardiac signs of digoxin toxicity include both brady- and tachyarrhythmias (eg, sinus bradycardia, new-onset Mobitz type I AV block, accelerated junctional rhythm with or without AV block, atrial tachycardia with AV block). Bidirectional VT induced by digitalis toxicity indicates imminent development of ventricular fibrillation and requires immediate treatment. Hyperkalemia may result with extremely high concentrations of digoxin and must be addressed promptly. Digoxin immune Fab (Digibind®, DigiFab™) allows rapid intervention for acute digoxin toxicity. However, it is important to note that since digoxin immune Fab pulls digoxin from tissue stores, measured digoxin concentrations will rise rapidly after administration reflecting the Fab-digoxin complexes that result and cannot be used to follow effectiveness of antibody therapy. In general, digoxin immune Fab should be reserved for patients with severe symptoms of digoxin toxicity (eg, life-threatening arrhythmias or hyperkalemia).

Dental Health: Effects on Dental Treatment

Sensitive gag reflex may cause difficulty in taking a dental impression.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Use vasoconstrictor with caution due to risk of cardiac arrhythmias with digoxin

Mental Health: Effects on Mental Status

May cause sedation

Mental Health: Effects on Psychiatric Treatment

Phenytoin may decrease concentrations of digoxin; monitor concentrations

Nursing: Physical Assessment/Monitoring

Assess results of laboratory tests when beginning or changing dosage, especially with I.V. administration. Monitor for signs of digoxin toxicity. I.V.: Monitor ECG continuously. Oral: Monitor apical pulse before administering any dose.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Injection, solution: 250 mcg/mL (2 mL)

Lanoxin®: 250 mcg/mL (2 mL) [contains ethanol 10%, propylene glycol 40%]

Injection, solution [pediatric]:

Lanoxin®: 100 mcg/mL (1 mL) [contains ethanol 10%, propylene glycol 40%]

Solution, oral: 50 mcg/mL (2.5 mL [DSC], 60 mL)

Tablet, oral: 125 mcg, 250 mcg

Lanoxin®: 125 mcg, 250 mcg [scored]

Pricing: U.S. (www.drugstore.com)

Solution (Digoxin)

50 mcg/mL (60): $36.99

Tablets (Digoxin)

125 mcg (30): $19.26

250 mcg (30): $18.69

Tablets (Lanoxin)

125 mcg (30): $21.88

250 mcg (30): $19.69

References

American Academy of Pediatrics Committee on Drugs, “Transfer of Drugs and Other Chemicals Into Human Milk,” Pediatrics, 2001, 108(3):776-89.

Antman EM, Anbe DT, Armstrong PW, et al, “ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction),” Circulation, 2004, 110(9):e82-292.

Blomström-Lundqvist C, Scheinman MM, Aliot EM, et al, “ACC/AHA/ESC Guidelines for the Management of Patients With Supraventricular Arrhythmias--Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias) Developed in Collaboration With NASPE-Heart Rhythm Society,” J Am Coll Cardiol, 2003, 42(8):1493-531.

Eagle KA, Guyton RA, Davidoff R, et al, “ACC/AHA 2004 Guideline Update for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery),” Circulation, 2004, 110(14):e340-437.

Falk RH, Knowlton AA, Bernard SA, et al, “Digoxin for Converting Recent-Onset Atrial Fibrillation to Sinus Rhythm, A Randomized, Double-Blinded Trial,” Ann Int Med, 1987, 106(4):503-6

Fuster V, Ryden LE, Cannom DS, et al, “ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation-Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society,” J Am Coll Cardiol, 2006, 48(4):854-906.

Hunt SA, Abraham WT, Chin MH, et al, “2009 Focused Update Incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation,” J Am Coll Cardiol, 2009, 53(15):e1-90.

“Intravenous Digoxin in Acute Atrial Fibrillation. Results of a Randomized, Placebo-Controlled Multicentre Trial in 239 Patients. The Digitalis in Acute Atrial Fibrillation (DAAF) Trial Group,” Eur Heart J, 1997, 18(4):649-54

Jordaens L, Trouerbach J, Calle P, et al, “Conversion of Atrial Fibrillation to Sinus Rhythm and Rate Control by Digoxin in Comparison to Placebo,” Eur Heart J, 1997, 18(4):643-8.

Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.

Murgatroyd FD, Gibson SM, Baiyan X, et al, “Double-Blind Placebo-Controlled Trial of Digoxin in Symptomatic Paroxysmal Atrial Fibrillation,” Circulation, 1999, 99(21):2765-70.

Packer M, Gheorghiade M, Young JB, et al, “Withdrawal of Digoxin From Patients With Chronic Heart Failure Treated With Angiotensin-converting Enzyme Inhibitors, RADIANCE Study,” N Engl J Med, 1993, 329(1):1-77.

Rathore SS, Curtis JP, Wang Y, et al, “Association of Serum Digoxin Concentration and Outcomes in Patients With Heart Failure,” JAMA, 2003, 289(7):871-8.

Roberts SA, Diaz C, Nolan PE, et al, “Effectiveness and Costs of Digoxin Treatment for Atrial Fibrillation and Flutter,” Am J Cardiol, 1993, 72(7):567-73.

Rosenthal D, Chrisant MR, Edens E, et al, “International Society for Heart and Lung Transplantation: Practice Guidelines for Management of Heart Failure in Children,” J Heart Lung Transplant, 2004, 23(12):1313-33.

Siu CW, Lau CP, Lee WL, et al, “Intravenous Diltiazem is Superior to Intravenous Amiodarone or Digoxin for Achieving Ventricular Rate Control in Patients With Acute Uncomplicated Atrial Fibrillation,” Crit Care Med, 2009, 37(7):2174-9.

“The Effect of Digoxin on Mortality and Morbidity in Patients With Heart Failure. The Digitalis Investigation Group,” N Engl J Med, 1997, 336(8):525-33.

Ujhelyi MR and Robert S, “Pharmacokinetic Aspects of Digoxin-Specific Fab Therapy in the Management of Digitalis Toxicity,” Clin Pharmacokinet, 1995, 28(6):483-93.

Wann SL, Curtis AB, January CT, et al, “2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Updating the 2006 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Circulation, 2011, 123 (1):104-23.

International Brand Names

• Cardiacin (TW)
• Cardiogoxin (AR)
• Cardioxin (PH)
• Cardoxin (IL)
• Digosin (JP, KP)
• Digoxin (PL)
• Digoxin ”Dak” (DK)
• Digoxin-Sandoz (BF, BJ, CH, CI, ET, GH, GM, GN, ID, JP, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SL, SN, TN, TZ, UG, ZM, ZW)
• Digoxin-Zori (IL)
• Digoxina (CO, ES, GT, HN, NI, PE)
• Digoxina Boehringer (ES)
• Digoxine Nativelle (LU)
• Digoxine Navtivelle (FR)
• Dilacor (BG)
• Dilanacin (CY, EG, IQ, JO, SD)
• Eudigox (IT)
• Fargoxin (ID)
• Grexin (TH)
• Lanacordin (ES)
• Lanicor (AE, AR, AT, BB, BF, BH, BJ, BM, BS, BZ, CI, CZ, DE, EC, ET, GH, GM, GN, GR, GY, HR, IR, JM, KE, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, NE, NG, OM, QA, SA, SC, SL, SN, SR, SY, TN, TT, TZ, UG, VE, YE, ZM, ZW)
• Lanikor (RU)
• Lanox (PH)
• Lanoxin (AE, AR, BB, BE, BF, BH, BJ, BM, BR, BS, BZ, CI, ET, GB, GH, GM, GN, GR, GY, HK, IE, IN, IR, IT, JM, JP, KE, KP, KW, LB, LR, LU, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, NO, OM, PH, PK, PT, PY, QA, RU, SA, SC, SE, SG, SL, SN, SR, SY, TH, TN, TT, TW, TZ, UG, UY, YE, ZM, ZW)
• Lanoxin PG (NZ)
• Lenoxin (DE)
• Mapluxin (MX)
• Purgoxin (ZA)
• Sigmaxin (AU)
• Toloxin (TH)
• Vidaxil (MX)

Lexi-Comp.com

Last full review/revision May 2011

Content last modified May 2011