Digoxin

Pronunciation

(di JOKS in)

U.S. Brand Names

Digitek®; Lanoxicaps®; Lanoxin®

Generic Available

Yes; Excludes capsule

Canadian Brand Names

Digoxin CSD; Lanoxicaps®; Lanoxin®; Novo-Digoxin

Use

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

Pregnancy Risk Factor

Lactation

Enters breast milk (small amounts)/compatible

Contraindications

Hypersensitivity to digoxin or any component of the formulation; 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

Warnings/Precautions

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.

Adverse Reactions

Incidence of reactions are not always reported.

Cardiovascular: Heart block; first-, second- (Wenckebach), or third-degree heart block; asystole; atrial tachycardia with block; AV dissociation; accelerated junctional rhythm; ventricular tachycardia or ventricular fibrillation; PR prolongation; ST segment depression

Central nervous system: Visual disturbances (blurred or yellow vision), headache (3%), dizziness (5%), apathy, confusion, mental disturbances (4%), anxiety, depression, delirium, hallucinations, fever

Dermatologic: Maculopapular rash (2%), erythematous, scarlatiniform, papular, vesicular or bullous rash, urticaria, pruritus, facial, angioneurotic or laryngeal edema, shedding of fingernails or toenails, alopecia

Gastrointestinal: Nausea (3%), vomiting (2%), diarrhea (3%), abdominal pain

Neuromuscular & skeletal: Weakness

<1% (Limited to important or life-threatening): Gynecomastia, thrombocytopenia, palpitation, 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, 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 tachyarrhythmia 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.

Overdosage/Toxicology

Manifested by a wide variety of signs and symptoms difficult to distinguish from effects associated with cardiac disease. Nausea and vomiting are common early signs of toxicity and may precede or follow evidence of cardiotoxicity. Other symptoms include anorexia, diarrhea, abdominal discomfort, headache, weakness, drowsiness, visual disturbances, mental depression, confusion, restlessness, disorientation, seizures, and hallucinations. Cardiac abnormalities include ventricular tachycardia, unifocal or multifocal PVCs (bigeminal, trigeminal), paroxysmal nodal rhythms, AV dissociation, excessive slowing of the pulse, AV block of varying degree, P-R prolongation, S-T depression, and occasional atrial fibrillation. Ventricular fibrillation is a common cause of death (alterations in cardiac rate and rhythm can result in any type of known arrhythmia).

Antidote: Life-threatening digoxin toxicity is treated with Digibind®. Administer potassium except in cases of complete heart block or renal failure. Digitalis-induced arrhythmias not responsive to potassium may be treated with phenytoin or lidocaine. Cholestyramine and colestipol may decrease absorption. Other agents to consider, based on ECG and clinical assessment, include atropine, quinidine, procainamide, and propranolol. Note: Other antiarrhythmics appear more dangerous to use in toxicity.

Drug Interactions

Substrate of CYP3A4 (minor)

Amiloride may reduce the inotropic response to digoxin.

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.

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

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.

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

Metoclopramide may reduce the absorption of digoxin tablets.

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

Penicillamine has been associated with reductions in digoxin blood levels

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.

Ethanol/Nutrition/Herb Interactions

Food: Digoxin peak serum levels 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).

Stability

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

Compatibility

Stable in D5¹/2NS with KCl 20 mEq, D5W, LR, ¹/2NS, NS

Y-site administration: Compatible: Ciprofloxacin, cisatracurium, diltiazem, famotidine, gatifloxacin, heparin with hydrocortisone sodium succinate, inamrinone, linezolid, meperidine, meropenem, midazolam, milrinone, morphine, potassium chloride, remifentanil, tacrolimus, vitamin B complex with C. Incompatible: Amphotericin B cholesteryl sulfate complex, fluconazole, foscarnet, propofol. Variable (consult detailed reference): Insulin (regular)

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

Compatibility when admixed: Compatible: Bretylium, cimetidine, floxacillin, furosemide, lidocaine, ranitidine, verapamil. Incompatible: Dobutamine

Mechanism of Action

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 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: 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 absorption

Distribution:

Normal renal function: 6-7 L/kg

Vd: 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 Vd

Hyperkalemia, hyponatremia: Decreased digoxin distribution to heart and muscle

Hypokalemia: Increased digoxin distribution to heart and muscles

Concomitant quinidine therapy: Decreased Vd

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

Bioavailability: Oral (formulation dependent): Elixir: 75% to 85%; Tablet: 70% 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: 35 hours

Adults: 38-48 hours

Adults, anephric: 4-6 days

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

Time to peak, serum: Oral: ~1 hour

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

Dosage

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.

Dosing adjustment/interval in renal impairment:

Dosage Recommendations for Digoxin

Age	Total Digitalizing Dose² (mcg/kg¹)		Daily Maintenance Dose³ (mcg/kg¹)
Age	P.O.	I.V. or I.M.	P.O.	I.V. or I.M.
Preterm infant¹	20-30	15-25	5-7.5	4-6
Full-term infant¹	25-35	20-30	6-10	5-8
1 mo - 2 y¹	35-60	30-50	10-15	7.5-12
2-5 y¹	30-40	25-35	7.5-10	6-9
5-10 y¹	20-35	15-30	5-10	4-8
>10 y¹	10-15	8-12	2.5-5	2-3
Adults	0.75-1.5 mg	0.5-1 mg	0.125-0.5 mg	0.1-0.4 mg
¹Based on lean body weight and normal renal function for age. Decrease dose in patients with renal function; digitalizing dose often not recommended in infants and children.
²Give 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 ECG 6 hours after each dose to assess potential toxicity.
³Divided 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:

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

Clcr<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%)

Monitoring Parameters

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 ECGs 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

Observe patients for noncardiac signs of toxicity, confusion, and depression

Reference Range

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).

Dietary Considerations

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

Patient Education

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 precaution: Inform prescriber if you are or intend to become pregnant.

Anesthesia and Critical Care Concerns/Other Considerations

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 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.

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

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 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, the medication is less effective for rate control during exercise.

Digoxin toxicity may be potentiated in patients with hypokalemia, hypomagnesemia, and hypercalcemia. 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.

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 levels of digoxin; monitor levels

Dosage Forms

Capsule (Lanoxicaps®): 50 mcg, 100 mcg, 200 mcg [contains ethyl alcohol]

Elixir: 50 mcg/mL (2.5 mL, 5 mL, 60 mL) [contains alcohol 10%; lime flavor]

Lanoxin® (pediatric): 50 mcg/mL (60 mL) [contains alcohol 10%; lime flavor]

Injection: 250 mcg/mL (1 mL, 2 mL) [contains alcohol 10% and propylene glycol 40%]

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

Injection, pediatric: 100 mcg/mL (1 mL) [contains alcohol 10% and propylene glycol 40%]

Tablet: 125 mcg, 250 mcg, 500 mcg

Digitek®, Lanoxin®: 125 mcg, 250 mcg

References

"Consensus Recommendations for the Management of Chronic Heart Failure. On Behalf of the Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure,"Am J Cardiol, 1999, 83(2A):1A-38A.

"Guidelines for the Evaluation and Management of Heart Failure. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Committee on Evaluation and Management of Heart Failure,"Circulation, 1995, 92:2764-84.

Konstam MA, "Heart Failure Evaluation and Care of Patients With Left-Ventricular Systolic Dysfunction," U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy Research, 1994. Clinical Practice Guideline: Number 940612.

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.

"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.

International Brand Names

Cardiogoxin® (AR); Cardioxin® (IN); Corlan® (RO); Darrowcor® (BR); Digacin® (DE); Digoregen® (DE); Digosin® (JP); Digossina Fisiopharma® (IT); Digossina® (IT); Digoxina Biol® (AR); Digoxina Boehringer® (ES); Digoxina® (BR); Digoxina Darrow® (BR); Digoxina Larjan® (AR); Digoxina L.CH.® (CL); Digoxin CSD (CA); Digoxin® (CZ, FI, GB, HU, PL, RO, RU, YU); Digoxin Dak® (DK); Digoxine Nativelle® (FR, LU, TR); Digoxin NM Pharma® (SE); Digoxin Nycomed® (RU); Digoxin Paediatric® (GB); Digoxin Recip® (SE); Digoxin SAD® (DK); Digoxin-Sandoz® (CH, CL, ID, MT, TR); Digoxin Streuli® (CH); Digoxin-Zori® (IL); Dilacor® (RU, YU); Dilanacin® (DE); Dimecip® (AR); Eudigox® (IT); Fargoxin® (ID); Grexin® (TH); Hemigoxine Nativelle® (FR); Lanacordin® (ES); Lanacrist® (SE); Lanicor® (AR, AT, CZ, DE, HR, LU, RU, SI); Lanoxicaps® (CA); Lanoxin® (AU, BD, BE, BR, CA, CY, GB, HK, ID, IE, IL, IN, IT, JO, KW, LB, LU, MX, NL, NO, NZ, PT, RO, SE, SG, SY, TH, ZA); Lenoxin® (DE); Mapluxin® (MX); Novodigal® [inj.] (AT, RO); Novo-Digoxin (CA); Purgoxin® (ZA); Toloxin® (TH)