digoxin
Digitek, Lanoxicaps, Lanoxin, Novodigoxin ◆

Available forms
Available by prescription only
Capsules: 0.05 mg, 0.10 mg, 0.20 mg
Elixir: 0.05 mg/ml
Injection: 0.1 mg/ml (pediatric), 0.25 mg/ml, 0.5 mg/ 2 ml
Tablets: 0.125 mg, 0.25 mg

Indications and dosages
 Heart failure, atrial fibrillation and flutter, paroxysmal atrial tachycardia. Tablets, elixir Adults: For rapid digitalization, give 0.75 to 1.25 mg P.O. over 24 hours in two or more divided doses q 6 to 8 hours. For slow digitalization, give 0.125 to 0.5 mg daily for 5 to 7 days. Maintenance dosage is 0.125 to 0.5 mg daily.
Children age 10 and older: 10 to 15 mcg/kg P.O. over 24 hours in two or more divided doses q 6 to 8 hours. Maintenance dosage is 25% to 35% of total digitalizing dose.
Children ages 5 to 10: 20 to 35 mcg/kg P.O. over 24 hours in two or more divided doses q 6 to 8 hours. Maintenance dosage is 25% to 35% of total digitalizing dose.
Children ages 2 to 5: 30 to 40 mcg/kg P.O. over 24 hours in two or more divided doses q 6 to 8 hours. Maintenance dosage is 25% to 35% of total digitalizing dose.
Infants ages 1 month to 2 years: 35 to 60 mcg/kg P.O. over 24 hours in two or more divided doses q 6 to 8 hours. Maintenance dosage is 25% to 35% of total digitalizing dose.
Neonates: 25 to 35 mcg/kg P.O. over 24 hours in two or more divided doses q 6 to 8 hours. Maintenance dosage is 25% to 35% of total digitalizing dose.
Premature infants: 20 to 30 mcg/kg P.O. over 24 hours in two or more divided doses q 6 to 8 hours. Maintenance dosage is 20% to 30% of total digitalizing dose.
Capsules
Adults: For rapid digitalization, give 0.4 to 0.6 mg P.O. initially, followed by 0.1 to 0.3 mg q 6 to 8 hours, as needed and tolerated, for 24 hours. For slow digitalization, give 0.05 to 0.35 mg daily in two divided doses for 7 to 22 days, as needed, until therapeutic serum levels are reached. Maintenance dosage is 0.05 to 0.35 mg daily in one or two divided doses.
Children: Digitalizing dose is based on child’s age and is administered in three or more divided doses over the first 24 hours. Initial dose should be 50% of the total dose; subsequent doses are given q 4 to 8 hours as needed and tolerated.
Children age 10 and older: For rapid digitalization, give 8 to 12 mcg/kg P.O. over 24 hours, divided as above. Maintenance dosage is 25% to 35% of total digitalizing dose, given daily as a single dose.
Children ages 5 to 10: For rapid digitalization, give 15 to 30 mcg/kg P.O. over 24 hours, divided as above. Maintenance dosage is 25% to 35% of total digitalizing dose, divided and given in two or three equal portions daily.
Children ages 2 to 5: For rapid digitalization, give 25 to 35 mcg/kg P.O. over 24 hours, divided as above. Maintenance dosage is 25% to 35% of total digitalizing dose, divided and given in two or three equal portions daily.
Injection
Adults: For rapid digitalization, give 0.4 to 0.6 mg I.V. initially, followed by 0.1 to 0.3 mg I.V. q 4 to 8 hours, as needed and tolerated, for 24 hours. For slow digitalization, give appropriate daily maintenance dosage for 7 to 22 days as needed until therapeutic serum levels are reached. Maintenance dosage is 0.125 to 0.5 mg I.V. daily in one or two divided doses.
Children: Digitalizing dose is based on child’s age and is administered in three or more divided doses over the first 24 hours. Initial dose should be 50% of total dose; subsequent doses are given q 4 to 8 hours as needed and tolerated.
Children age 10 and older: For rapid digitalization, give 8 to 12 mcg/kg I.V. over 24 hours, divided as above. Maintenance dosage is 25% to 35% of total digitalizing dose, given daily as a single dose.
Children ages 5 to 10: For rapid digitalization, give 15 to 30 mcg/kg I.V. over 24 hours, divided as above. Maintenance dosage is 25% to 35% of total digitalizing dose, divided and given in two or three equal portions daily.
Children ages 2 to 5: For rapid digitalization, give 25 to 35 mcg/kg I.V. over 24 hours, divided as above. Maintenance dosage is 25% to 35% of total digitalizing dose, divided and given in two or three equal portions daily.
Infants ages 1 month to 2 years: For rapid digitalization, give 30 to 50 mcg/kg I.V. over 24 hours, divided as above. Maintenance dosage is 25% to 35% of total digitalizing dose, divided and given in two or three equal portions daily.
Neonates: For rapid digitalization, give 20 to 30 mcg/kg I.V. over 24 hours, divided as above. Maintenance dosage is 25% to 35% of the total digitalizing dose, divided and given in two or three equal portions daily.
Premature infants: For rapid digitalization, give 15 to 25 mcg/kg I.V. over 24 hours, divided as above. Maintenance dosage is 20% to 30% of the total digitalizing dose, divided and given in two or three equal portions daily.
≡ Dosage adjustment. Reduce dosage in patients with impaired renal function. Hypothyroid patients are highly sensitive to glycosides; hyperthyroid patients may need larger doses.

Pharmacodynamics
Antiarrhythmic action: Digoxin-induced heart-rate slowing in patients without heart failure is negligible and stems mainly from vagal (cholinergic) and sympatholytic effects on the SA node; however, with toxic doses, heart-rate slowing results from direct depression of SA node automaticity. Therapeutic doses produce little effect on the action potential, but toxic doses increase the automaticity (spontaneous diastolic depolarization) of all cardiac regions except the SA node.
Inotropic action: The effect of digoxin on the myocardium is dose related and involves both direct and indirect mechanisms. It directly increases the force and velocity of myocardial contraction, AV node refractory period, and total peripheral resistance; at higher doses, it also increases sympathetic outflow. It indirectly depresses the SA node and prolongs conduction to the AV node. In patients with heart failure, increased contractile force boosts cardiac output, improves systolic emptying, and decreases diastolic heart size. It also reduces ventricular end-diastolic pressure and, consequently, pulmonary and systemic venous pressures. Increased myocardial contractility and cardiac output reflexively reduce sympathetic tone in patients with heart failure. This compensates for the direct vasoconstrictive action of the drug, thereby reducing total peripheral resistance. It also slows increased heart rate and causes diuresis in edematous patients.

Pharmacokinetics
Absorption: With tablet or elixir, 60% to 85% of dose is absorbed. With capsule form, bioavailability increases. About 90% to 100% of a dose is absorbed. With I.M. administration, about 80% of dose is absorbed.
Distribution: Distributed widely in body tissues. Highest levels occur in the heart, kidneys, intestine, stomach, liver, and skeletal muscle; lowest levels are in the plasma and brain. Digoxin crosses both the blood-brain barrier and the placental barrier; fetal and maternal digoxin levels are equivalent at birth. About 20% to 30% of drug is bound to plasma proteins. Usual therapeutic range for steady state serum levels is 0.5 to 2 ng/ml. In treatment of atrial tachyarrhythmias, higher serum levels (such as 2 to 4 ng/ml) may be needed. Because of long half-life of drug, achievement of steady state levels may take 7 days or longer, depending on patient’s renal function. Toxic symptoms may appear within the usual therapeutic range; however, these are more frequent and serious with levels above 2.5 ng/ml.
Metabolism: In most patients, a small amount of digoxin apparently is metabolized in the liver and gut by bacteria. This metabolism varies and may be substantial in some patients. Drug undergoes some enterohepatic recirculation (also variable). Metabolites have minimal cardiac activity.
Excretion: Most of dose is excreted by the kidneys as unchanged drug. Some patients excrete a substantial amount of metabolized or reduced drug. In patients with renal failure, biliary excretion is a more important excretion route. In healthy patients, terminal half-life is 30 to 40 hours. In patients lacking functioning kidneys, half-life increases to at least 4 days.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug and in those with digitalis-induced toxicity, ventricular fibrillation, or ventricular tachycardia unless caused by heart failure.
  Use very cautiously in elderly patients and in patients with acute MI, incomplete AV block, sinus bradycardia, PVCs, chronic constrictive pericarditis, hypertrophic cardiomyopathy, renal insufficiency, severe pulmonary disease, hypothyroidism, and in patients with hypokalemia or hypomagnesemia.

Interactions
Drug-drug. Amiloride: Inhibits digoxin effect and increases digoxin excretion. Monitor patient for altered digoxin effect.
Aminosalicylic acid, antacids, kaolin-pectin, magnesium trisilicate, sulfasalazine: Decreases absorption of orally administered digoxin. Monitor patient for altered digoxin effect. Separate administration times as much as possible.
Amiodarone, diltiazem, nifedipine, quinidine, verapamil: Increases serum digoxin levels, predisposing patient to toxicity. Avoid use together.
Amphotericin B, carbenicillin, corticosteroids, corticotropin, edetate disodium, laxatives, sodium polystyrene sulfonate, ticarcillin: May cause digoxin toxicity. Monitor digoxin levels closely.
Antibiotics: Increases digoxin bioavailability and serum levels. Monitor digoxin levels closely. Separate administration times.
Anticholinergics: May increase digoxin absorption of oral digoxin tablets. Monitor blood levels and observe patient for toxicity.
Beta blockers, calcium channel blockers: May cause heart block. Monitor ECG and vital signs.
Cholestyramine, colestipol, metoclopramide: Impairs absorption. Monitor digoxin levels closely. Space doses by giving digoxin 1 1/4 hours before or 2 hours after other drugs.
Cytotoxic drugs, radiation therapy: Decreases digoxin absorption if intestinal mucosa is damaged. Digoxin elixir or capsules are recommended in this situation.
Dextrose-insulin infusions, glucagon, large dextrose doses: Causes digitalis toxicity. Avoid use together.
Diuretics, such as bumetanide, ethacrynic acid, furosemide: May cause hypokalemia and hypomagnesemia. Monitor blood levels closely.
I.V. calcium: Causes synergistic effects that precipitate arrhythmias. Avoid use together.
Parenteral calcium, thiazides: May cause hypercalcemia. Monitor serum calcium levels.
Procainamide, propranolol, verapamil: Causes additive cardiac effects. Avoid use together.
Rauwolfia alkaloids, sympathomimetics (such as ephedrine, epinephrine, isoproterenol): Increases risk of arrhythmias. Avoid use together.
Succinylcholine: May precipitate cardiac arrhythmias by potentiating digoxin effects. Avoid use together.
Drug-herb. Betel palm, fumitory, goldenseal, lily-of-the-valley, motherwort, rue, shepherd’s purse: Enhances cardiac effects. Monitor patient closely.
Gossypol, hawthorn, licorice, oleander, Siberian ginseng, squill: May enhance toxicity. Discourage use together.
Plantain, St. John’s wort: Decreases digoxin level and decreases efficacy. Discourage use together.
Drug-food. Meals high in fiber: May decrease digoxin absorption. Advise patient not to take digoxin with high-fiber foods.

Adverse reactions
The following signs of toxicity may occur with all cardiac glycosides.
CNS: fatigue, generalized muscle weakness, agitation, hallucinations, headache, malaise, dizziness, vertigo, stupor, paresthesia.
CV: arrhythmias (most commonly, conduction disturbances with or without AV block, PVCs, and supraventricular arrhythmias) that may lead to increased severity of heart failure and hypotension.
EENT: yellow-green halos around visual images, blurred vision, light flashes, photophobia, diplopia.
GI: anorexia, nausea, vomiting, diarrhea, abdominal pain.

Effects on lab test results
None reported.

Overdose and treatment
Overdose primarily causes GI, CNS, and cardiac reactions. Severe intoxication may cause hyperkalemia, which may develop rapidly into life-threatening cardiac changes. Cardiac signs and symptoms of digoxin toxicity may occur with or without other evidence of toxicity and commonly precede other toxic effects. Because toxic cardiac effects also can occur as effects of heart disease, determining whether these effects result from underlying heart disease or digoxin toxicity may be difficult. Digoxin has caused almost every kind of arrhythmia; various combinations of arrhythmias may occur in the same patient. Patients with chronic digoxin toxicity commonly have ventricular arrhythmias or AV conduction disturbances. Patients with digoxin-induced ventricular tachycardia have a high risk of mortality because ventricular fibrillation or asystole may result.
 If toxicity is suspected, discontinue drug and measure serum drug levels. Usually, drug takes at least 6 hours to distribute between plasma and tissue and reach equilibrium; plasma levels drawn earlier may show higher digoxin levels than those present after drug is distributed into the tissues.
 Other treatment measures include immediate emesis induction, gastric lavage, and administration of activated charcoal to reduce absorption of drug remaining in the gut. If patient has signs and symptoms of toxicity 2 hours or more postingestion, avoid inducing vomiting because it may worsen arrhythmias. Repeated doses of activated charcoal (such as 50 g q 6 hours) may help reduce further absorption, especially of any drug undergoing enterohepatic recirculation.
 Some clinicians advocate cholestyramine administration if digoxin was recently ingested; however, it may not be useful if the ingestion is life-threatening. Interacting drugs probably should be discontinued. Ventricular arrhythmias may be treated with I.V. potassium (replacement dose; but not in patients with significant AV block), I.V. phenytoin, I.V. lidocaine, or I.V. propranolol. Refractory ventricular tachyarrhythmias may be controlled with overdrive pacing. Procainamide may be used for ventricular arrhythmias that don’t respond to the above treatments. In severe AV block, asystole, and hemodynamically significant sinus bradycardia, atropine restores a normal rate.
 Administration of digoxin-specific antibody fragments (digoxin immune Fab or Digibind) is a treatment for life-threatening digoxin toxicity. Each 40 mg of digoxin immune Fab binds about 0.6 mg of digoxin in the bloodstream. The complex is then excreted in the urine, rapidly decreasing serum levels and, therefore, cardiac drug levels.

Special considerations
• Digoxin is the most widely used cardiac glycoside. Many oral forms and a parenteral form are available, facilitating use of the drug in both acute and long-term clinical settings.
 ALERT Don’t confuse digoxin with doxepin, desoxyn, or digitoxin.
 ALERT Excessive slowing of heart rate (60 beats/ minute or less) may be a sign of digitalis toxicity. Withhold drug and check serum levels.
• Drug may cause ECG changes, including increased PR interval and depression of ST segment.
• Drug may cause false-positive ST-T changes on an ECG during exercise testing.
• Ask patient about use of cardiac glycosides within the previous 2 to 3 weeks before administering a loading dose. Always divide loading dose over first 24 hours unless clinical situation indicates otherwise.
• GI absorption may be reduced in patients with heart failure, especially right-sided heart failure.
• Because digoxin may predispose patients to postcardioversion asystole, most clinicians withhold digoxin 1 or 2 days before elective cardioversion in patients with atrial fibrillation. (However, consider consequences of increased ventricular response to atrial fibrillation if drug is withheld.)
• Calcium must not be given rapidly I.V. to patient receiving digoxin. Calcium affects cardiac contractility and excitability in much the same way that digoxin does and may lead to serious arrhythmias.
• Digoxin solution is enclosed in a soft capsule (Lanoxicaps). Because these capsules are better absorbed than tablets, dose is usually slightly less. Lanoxicaps contain 8% alcohol.
• Monitor clinical status. Take apical pulse for a full minute. Watch for significant changes (sudden rate increase or decrease, pulse deficit, irregular beats, and especially regularization of a previously irregular rhythm). Check blood pressure and obtain 12-lead ECG if these changes occur.
• Adjust dose to patient’s condition and renal function; monitor ECG and serum levels of digoxin, calcium, potassium, magnesium, and creatinine. Therapeutic digoxin levels range from 0.5 to 2 ng/ml. Take corrective action before hypokalemia develops.
Pregnant patients
• Safety isn’t known. Only use if clearly needed.
Breast-feeding patients
• Serum levels and milk levels are similar; however, the amount a breast-fed infant would be exposed to is far below the usual infant maintenance dose. Caution is recommended when drug is used in a breast-feeding mother.
Pediatric patients
• Children have a poorly defined range of serum levels; however, toxicity apparently doesn’t occur at same levels considered toxic in adults. Divided daily dosing is recommended for infants and children younger than age 10; older children need adult doses proportional to body weight.
Geriatric patients
• Use digoxin cautiously (especially in renally compromised patients), and adjust dosage to prevent systemic accumulation.

Patient education
• Inform patient and responsible family member about drug action, drug regimen, ways to take pulse, reportable signs, and follow-up plans. Patient must understand importance of follow-up laboratory tests and have access to outpatient laboratory facilities.
• Instruct patient not to take an extra dose of digoxin if dose is missed.
• Tell patient to report severe nausea, vomiting, or diarrhea because these conditions may make patient more susceptible to toxicity.
• Advise patient to use the same brand consistently.
• Tell patient to call before using OTC or herbal preparations, especially those high in sodium.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use