Yes: Tablet

Antiarrhythmic Agent, Class IV; Cardiac Glycoside

Treatment of congestive heart failure and to slow the ventricular rate in tachyarrhythmias such as atrial fibrillation, atrial flutter, and supraventricular tachycardia (paroxysmal atrial tachycardia); cardiogenic shock

C

Hypersensitivity to digoxin or any component; hypersensitivity to cardiac glycosides (another may be tried); history of toxicity; ventricular tachycardia or fibrillation; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; amyloid disease; second- or third-degree heart block (except in patients with a functioning artificial pacemaker); Wolff-Parkinson-White syndrome and atrial fibrillation concurrently

Withdrawal in CHF patients may lead to recurrence of CHF symptoms. Some arrhythmias that digoxin is used to treat may be exacerbated in digoxin toxicity. Sinus nodal disease may be worsened. Adjust doses in renal impairment and when verapamil, quinidine or amiodarone are added to a patient on digoxin. Correct hypokalemia and hypomagnesemia before initiating therapy. Calcium, especially when administered rapidly I.V., can produce serious arrhythmias. Atrial arrhythmias associated with hypermetabolic states are very difficult to treat. Rate control in atrial fibrillation may be better in a sedentary patient than an active one. Use with caution in acute MI (within 6 months). Serum concentration monitoring should be done before the next dose (patient can hold AM dose for blood test) for an accurate assessment. Reduce or hold dose 1-2 days before elective electrical cardioversion.

Incidence of reactions are not always reported.

Central nervous system: Visual disturbances (blurred or yellow vision), headache (3.2%), weakness, dizziness (4.9%), apathy, confusion, mental disturbances (4.1%), anxiety, depression, delirium, hallucinations, fever

Dermatologic: Maculopapular rash (1.6%), erythematous, scarlatiniform, papular, vesicular or bullous rashes, urticaria, pruritus, facial, angioneurotic or laryngeal edema, shedding of fingernails or toenails, alopecia

Gastrointestinal: Nausea (3.2%), vomiting (1.6%), diarrhea (3.2%), abdominal pain

<1% (Limited to important or life-threatening symptoms): Gynecomastia, thrombocytopenia, palpitations, unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy), anorexia, abdominal pain, intestinal ischemia, hemorrhagic necrosis of the intestines, increase plasma estrogen and decreased serum luteinizing hormone in men and postmenopausal women and decreased plasma testosterone in men, vaginal cornification, eosinophilia, sexual dysfunction, sweating

Children are more likely to experience cardiac arrhythmias as a sign of excessive dosing. The most common are conduction disturbances or tachyarrhythmias (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.

Symptoms of acute overdose: Vomiting, hyperkalemia, sinus bradycardia, S-A arrest and A-V block are common, ventricular tachycardia, and fibrillation may occur

Chronic intoxication: Visual disturbances, weakness, sinus bradycardia, atrial fibrillation with slowed ventricular response, and ventricular arrhythmias

After GI decontamination, treat hyperkalemia if >5.5 mEq/L with sodium bicarbonate and glucose with insulin or Kayexalate®. Treat bradycardia or heart block with atropine or pacemaker and other arrhythmias with conventional antiarrhythmics. Use Digibind® for severe hyperkalemia, symptomatic arrhythmias unresponsive to other drugs, and for prophylactic treatment in massive overdose.

Amiloride may reduce the inotropic response to digoxin.

Cholestyramine, colestipol, kaolin-pectin may reduce digoxin absorption. Separate administration.

Levothyroxine (and other thyroid supplements) may decrease digoxin blood levels.

Metoclopramide may reduce the absorption of digoxin tablets.

Penicillamine has been associated with reductions in digoxin blood levels

Amiodarone reduces renal and nonrenal clearance of digoxin and may have additive effects on heart rate. Reduce digoxin dose by 50% with start of amiodarone.

Benzodiazepines (alprazolam, diazepam) have been associated with isolated reports of digoxin toxicity.

Beta-blocking agents (propranolol) may have additive effects on heart rate.

Calcium preparations: Rare cases of acute digoxin toxicity have been associated with parenteral calcium (bolus) administration.

Carvedilol may increase digoxin blood levels in addition to potentiating its effects on heart rate.

Cyclosporine may increase digoxin levels, possibly due to reduced renal clearance.

Erythromycin, clarithromycin, and tetracyclines may increase digoxin (not capsule form) blood levels in a subset of patients.

Indomethacin has been associated with isolated reports of increased digoxin blood levels/toxicity.

Itraconazole may increase digoxin blood levels in some patients; monitor.

Moricizine may increase the toxicity of digoxin (mechanism undefined).

Propafenone increases digoxin blood levels. Effects are highly variable; monitor closely.

Propylthiouracil (and methimazole) may increase digoxin blood levels by reducing thyroid hormone.

Quinidine increases digoxin blood levels substantially. Effect is variable (33% to 50%). Monitor digoxin blood levels/effect closely. Reduce digoxin dose by 50% with start of quinidine. Other related agents (hydroxychloroquine, quinine) should be used with caution.

Spironolactone may interfere with some digoxin assays, but may also increase blood levels directly. However, spironolactone may attenuate the inotropic effect of digoxin. Monitor effects of digoxin closely.

Succinylcholine administration to patients on digoxin has been associated with an increased risk of arrhythmias.

Verapamil diltiazem, bepridil, and nitrendipine increased serum digoxin concentrations. Other calcium channel blocking agents do not appear to share this effect. Reduce digoxin's dose with the start of verapamil.

Drugs which cause hypokalemia (thiazide and loop diuretics, amphotericin B): Hypokalemia may potentiate digoxin toxicity.

These medications have been associated with reduced digoxin blood levels which appear to be of limited clinical significance: Aminoglutethimide, aminosalicylic acid, aluminum-containing antacids, sucralfate, sulfasalazine, neomycin, ticlopidine.

These medications have been associated with increased digoxin blood levels which appear to be of limited clinical significance: Famciclovir, flecainide, ibuprofen, fluoxetine, nefazodone, cimetidine, famotidine, ranitidine, omeprazole, trimethoprim.

Protect elixir and injection from light; solution compatibility: D₅W, D₁₀W, NS, sterile water for injection (when diluted fourfold or greater)

Congestive heart failure: Inhibition of the sodium/potassium ATPase pump which acts to increase the intracellular sodium-calcium exchange to increase intracellular calcium leading to increased contractility

Supraventricular arrhythmias: Direct suppression of the A-V 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.

Onset of action: Oral: 1-2 hours; I.V.: 5-30 minutes

Peak effect: Oral: 2-8 hours; I.V.: 1-4 hours

Duration: Adults: 3-4 days both forms

Absorption: By passive nonsaturable diffusion in the upper small intestine; food may delay, but does not affect extent of digoxin 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: 30% (in uremic patients, digoxin is displaced from plasma protein binding sites)

Metabolism: By 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); metabolites may contribute to therapeutic and toxic effects of digoxin; metabolism is reduced in patients with CHF

Bioavailability: Oral (dependent upon formulation): Elixir: 75% to 85%; Tablets: 70% to 80%

Half-life: Dependent upon age, renal and cardiac function:

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

Infants: 18-25 hours

Children: 35 hours

Adults: 38-48 hours

Adults, anephric: 4-6 days

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

Time to peak serum concentration: Oral: Within 1 hour

Elimination: 50% to 70% excreted unchanged in urine

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: Refer to the following:

Preterm infant*

Total digitalizing dose **: Oral: 20-30 mcg/kg*; I.V. or I.M.: 15-25 mcg/kg*

Daily maintenance dose***: Oral: 5-7.5 mcg/kg*; I.V. or I.M.: 4-6 mcg/kg* I.V. or I.M.

Full-term infant*

Total digitalizing dose **: Oral: 25-35 mcg/kg*; I.V. or I.M.: 20-30 mcg/kg* I.V. or I.M.

Daily maintenance dose***: Oral: 6-10 mcg/kg*; I.V. or I.M.: 5-8 mcg/kg* I.V. or I.M.

1 month to 2 years*

Total digitalizing dose **: Oral: 35-60 mcg/kg*; I.V. or I.M.: 30-50 mcg/kg* I.V. or I.M.

Daily maintenance dose***: Oral: 10-15 mcg/kg*; I.V. or I.M.: 7.5- 12 mcg/kg*

2-5 years*

Total digitalizing dose **: Oral: 30-40 mcg/kg*; I.V. or I.M.: 25-35 mcg/kg*

Daily maintenance dose***: Oral: 7.5-10 mcg/kg*; I.V. or I.M.: 6-9 mcg/kg*

5-10 years*

Total digitalizing dose **: Oral: 20-35 mcg/kg*; I.V. or I.M.: 15-30 mcg/kg*

Daily maintenance dose***: Oral: 5-10 mcg/kg*; I.V. or I.M.: 4-8 mcg/kg*

>10 years*

Total digitalizing dose **: Oral: 10-15 mcg/kg*; I.V. or I.M.: 8-12 mcg/kg*

Daily maintenance dose***: Oral: 2.5-5 mcg/kg*; I.V. or I.M.: 2-3 mcg/kg*

Adults

Total digitalizing dose **: Oral: 0.75-1.5 mg; I.V. or I.M.: 0.5-1 mg

Daily maintenance dose***: Oral: 0.125 mg- 0.5 mg; I.V. or I.M.: 0.1 mg- 0.4 mg

*Based on lean body weight and normal renal function for age. Decrease dose in patients with decreased renal function; digitalizing dose often not recommended in infants and children.

**Give one-half of the total digitalizing dose (TDD) in the initial dose, then give one-quarter of the TDD in each of two subsequent doses at 8- to 12-hour intervals. Obtain EKG 6 hours after each dose to assess potential toxicity.

***Divided every 12 hours in infants and children <10 years of age; given once daily to children >10 years of age and adults

Dosing adjustment/interval in renal impairment:

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

Reduce loading dose by 50% in ESRD

Hemodialysis: Not dialyzable (0% to 5%)

Meals containing increased fiber (bran) or foods high in pectin, may decrease oral absorption of digoxin; avoid natural licorice (causes sodium and water retention and increases potassium loss); maintain adequate amounts of potassium in diet to decrease risk of hypokalemia (hypokalemia may increase risk of digoxin toxicity)

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 levels should be drawn at least 4 hours after an intravenous dose and at least 6 hours after an oral dose (optimally 12-24 hours after a dose).

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. Levels drawn this early may confirm the relationship of digoxin plasma levels 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 4 hours after an I.V. dose and at least 6 hours after an oral 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.

Additionally, patients who are receiving potassium-depleting medications such as diuretics, should be monitored for potassium, magnesium, and calcium levels

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 (amiodarone, quinidine, verapamil) which potentially interact with digoxin; if quinidine therapy is started; digoxin levels should be drawn within the first 24 hours after starting quinidine therapy, then 7-14 days later or empirically skip one day's digoxin dose and decrease the daily dose by 50%

Any disease changes (hypothyroidism)

Heart rate and rhythm should be monitored along with periodic EKGs to assess both desired effects and signs of toxicity

Follow closely (especially in patients receiving diuretics or amphotericin) for decreased serum potassium and magnesium or increased calcium, all of which predispose to digoxin toxicity

Assess renal function

Be aware of drug interactions

Digoxin therapeutic serum concentrations:

Congestive heart failure: 0.8-2 ng/mL

Arrhythmias: 1.5-2.5 ng/mL

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

Toxic: >2.5 ng/mL; tachyarrhythmias commonly require levels >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, congestive heart failure, neonates, and pregnant women (3rd trimester).

Digoxin has been used for many years in treatment of heart failure. Even though digoxin has a very narrow therapeutic index, it remains an important therapeutic strategy when added to standard therapy. When used in heart failure, 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. A potential mechanism of benefit in heart failure is that digoxin may improve baroreflex sensitivity.

Digoxin toxicity may be potentiated in patients with hypokalemia, hypomagnesemia, and hypocalcemia. Digoxin may also rapidly approach toxic levels in patients with renal failure. For patients with renal failure, the loading dose is unchanged but maintenance doses may be adjusted and levels should be monitored very carefully. Signs of digoxin toxicity include both brady- and tachyarrhythmias. Bidirectional VT induced by digitalis toxicity indicates imminent development of ventricular fibrillation. The recent development of digoxin antibodies (Digibind®) allows rapid intervention for acute digoxin toxicity. However, it is important to note that after administration of Digibind®, measured digoxin levels cannot be used to follow effectiveness of antibody therapy because they seem to rise rapidly.

May cause sedation

Phenytoin may decrease levels of digoxin; monitor levels

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

Sensitive gag reflex may cause difficulty in taking a dental impression

Take as directed; do not discontinue without consulting prescriber. 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; follow prescriber instructions for holding medication if pulse is below 50. 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. Pregnancy precautions: Inform prescriber if you are or intend to be pregnant.

Observe patients for noncardiac signs of toxicity, ie, anorexia, vision changes (blurred), confusion, and depression

Capsule: 50 mcg, 100 mcg, 200 mcg

Elixir, pediatric (lime flavor): 50 mcg/mL with alcohol 10% (60 mL)

Injection: 250 mcg/mL (1 mL, 2 mL)

Injection, pediatric: 100 mcg/mL (1 mL)

Tablet: 125 mcg, 250 mcg, 500 mcg

Agency for Health Care Policy and Research, Clinical Practice Guidelines, "Heart Failure: Evaluation and Care of Patients With Left-Ventricular Systolic Dysfunction," U.S. Department of Health and Human Services, Pub No 94-0612, June 1994.

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