LANOXIN (Brand for DIGOXIN)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-All dosage forms: May be administered without regard to meals.
Oral Solid Formulations
-Tablets: May be crushed and administered with food or fluids.

Oral Liquid Formulations
-Administer using a calibrated measuring device.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Administer intramuscularly (IM) or intravenously (IV). The IV route is preferred due to more rapid therapeutic effect and less pain.
-Double check the concentration of the product being used to avoid medication errors. The pediatric concentration (100 mcg/mL) is most appropriate for measuring and administering small doses.
-Oral therapy should replace parenteral therapy as soon as possible.
Intravenous Administration
Dilution
-The pediatric digoxin product (100 mcg/mL) may be given undiluted or each 1 mL may be diluted in 4 mL of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection to provide a final concentration of 20 mcg/mL. Diluent volumes less than 4 mL may cause precipitation.
-The 2-syringe technique is recommended when making a dilution to avoid overdosage due to injection of drug contained in the dead space of the syringe.-Draw the digoxin up in one syringe and the diluent up in a separate syringe. Inject the digoxin into the syringe containing the diluent.

-Use diluted solutions immediately.

Intermittent IV Infusion
-Inject over at least 5 minutes. Rapid injection may cause systemic and coronary arteriolar constriction.
-If tuberculin syringes are used to measure very small doses, do not flush the syringe with the parenteral solution after its contents are expelled into an indwelling vascular catheter to avoid over administration of digoxin.

Intramuscular Administration
-IM injection of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes are contraindicated.
-Do not administer more than 200 mcg at any one injection site.
-If IM administration must be used, inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [children and adolescents only]). Aspirate prior to injection to avoid injection into a blood vessel. Massage area after administration.

Unlike in adults who often experience gastrointestinal symptoms first, early manifestations of excessive dosing of digoxin in infants and children are usually arrhythmias including bradycardia, conduction disturbances, or supraventricular tachyarrhythmias (atrial tachycardia and junctional tachycardia). Ventricular arrhythmias are relatively rare in children. Assume arrhythmias or disturbances in cardiac conduction in pediatric patients receiving digoxin are caused by digoxin until proven otherwise. Cardiac effects may occur in the absence of non-cardiac toxicity (e.g. GI side effects). In 2 randomized, double-blind, placebo-controlled trials of 123 adult patients receiving digoxin, the following adverse reactions were reported: palpitations (1 patient or 0.8%), ventricular extrasystole/premature ventricular contractions (PVCs) (1 patients vs. 1 of 125 placebo patients or 0.8%), sinus tachycardia (2 patients or 1.6%), and cardiac arrest (1 patient or 0.8%). Other cardiac effects associated with digitalis toxicity include variable degrees of AV block including complete heart block, PR prolongation, supraventricular tachycardia (SVT), atrial tachycardia with or without block, sinus bradycardia with junctional escape, AV dissociation, and an accelerated junctional rhythm. Other rhythm disturbances have included bigeminal or trigeminal rhythms, premature atrial contractions (PACs), atrial fibrillation, ventricular fibrillation and ventricular tachycardia. ECG changes, such as ST-T wave changes, can occur during digitalis administration and may or may not indicate digitalis toxicity. Treat cardiac toxicity by discontinuing therapy, instituting appropriate antiarrhythmic therapy if indicated, and correcting any associated electrolyte imbalances (e.g., potassium, magnesium). Digoxin serum concentrations may be used to evaluate and to prevent digoxin toxicity. However, digoxin serum concentrations do not consistently correlate with drug toxicity as there is considerable overlap between the therapeutic range for efficacy and toxicity, especially when used for the treatment of atrial arrhythmias. Chronic digoxin toxicity can lead to hypokalemia, which can increase the risk of digoxin-induced cardiac toxicity. Treat patients receiving digoxin who are at risk for potassium deficiency preventively with potassium supplements. Acute intoxication with digoxin can cause hyperkalemia, presumably due to inhibition of the Na-K-ATPase pump. Hyperkalemia can lead to AV block and asystole; patients who develop hyperkalemia during the initial stages of intoxication generally have a poor prognosis.

Although possible, gastrointestinal adverse effects of digoxin do not appear to be as common in pediatric patients as in adults; however, exact incidences are not known. In 2 randomized, double-blind, placebo-controlled trials of 123 adult patients taking digoxin, the following gastrointestinal adverse events were reported: anorexia (1 patient or 0.8%), nausea (4 patients or 3.3%), vomiting (2 patients or 1.6%), and diarrhea (4 patients or 3.3%). Digoxin has also been associated with abdominal pain, bowel ischemia, and hemorrhagic bowel necrosis of the intestines. Anorexia, nausea, vomiting, and diarrhea may be early signs of intoxication in adults; however, these are not seen as frequently in pediatric patients, especially infants and young children. These effects can precede or follow cardiotoxicity. Such symptoms, however, can also be associated with uncontrolled heart failure.

Digoxin therapy can produce visual disturbances such as blurred vision or yellow vision (xanthopsia). Visual disturbances are also common in patients with digoxin toxicity and may persist after other signs of toxicity have resolved.

In 2 randomized, double-blind, placebo-controlled trials of 123 adult patients taking digoxin, rash (unspecified) was reported in 2 patients (1.6%). Also, maculopapular rash and thrombocytopenia (immunologically-mediated) have been reported in patients taking digoxin. Digoxin therapy can increase plasma estrogen and cause gynecomastia.

The incidence of neurological adverse effects in pediatric patients is not known. CNS effects reported in 2 randomized, double-blind, placebo-controlled trials that enrolled 123 adult patients taking digoxin include headache (4 patients or 3.3%), dizziness (6 patients or 4.9%), and mental disturbances (5 patients or 4.1%). Mental disturbances were reported as anxiety, depression, delirium, and hallucinations. Other CNS effects that have been reported include weakness, apathy, and confusion.

Use digoxin with caution in patients with sinus node disease and AV block because severe bradycardia or complete heart block can result. Consider the insertion of a pacemaker before treatment with digoxin. Use digoxin with caution in patients with severe pulmonary disease, acute cor pulmonale, hypoxemia, hypothyroidism or myxedema, acute myocardial infarction, severe heart failure, acute myocarditis, amyloid cardiomyopathy, restrictive cardiomyopathy, or an otherwise damaged myocardium because the myocardium is more sensitive to the effects of digoxin, increasing the risk of digitalis-induced arrhythmias. Digoxin should generally be avoided in patients with left ventricular failure associated with predominant diastolic dysfunction, since increased cytosolic calcium levels could worsen diastolic dysfunction and digoxin is less effective for this type of heart failure. Digoxin dose requirements may be reduced in patients with hypothyroidism. Use caution when administering digoxin to patients with heart failure or arrhythmias due to hypermetabolic and hyperdynamic states, such as hyperthyroidism; patients with these conditions are often resistant to digoxin therapy and may be more likely to experience toxicity. Treat these conditions by addressing the underlying cause. Consider dose reduction of digoxin 1-2 days prior to defibrillation (cardioversion) of atrial fibrillation to avoid the induction of ventricular arrhythmias. Delay cardioversion or use the lowest possible energy level if digoxin toxicity is suspected.

Digoxin is contraindicated in patients with ventricular fibrillation; carotid sinus massage has been reported to cause ventricular fibrillation in patients receiving digoxin. Avoid digoxin use in patients with ventricular arrhythmias including premature ventricular contractions or ventricular tachycardia because the drug can exacerbate these arrhythmias. Digoxin generally should not be used in patients with carotid sinus hypersensitivity because the drug increases vagal tone. The use of digoxin in patients with Wolff-Parkinson-White syndrome can cause fatal ventricular arrhythmias, especially when this condition is associated with atrial fibrillation.

Use digoxin with caution in patients with renal disease associated with heart failure, such as acute glomerulonephritis, renal impairment, and renal failure. Use of a lower daily dose is recommended with appropriate ECG monitoring based on clinical goals and patient conditions. Renal impairment reduces the excretion of the drug and can cause toxicity. The time required to reach steady-state concentrations can be prolonged in patients with renal failure.

Digoxin should be used with caution in patients with hepatic disease. No specific dosage adjustments are recommended for patients with hepatic impairment. However, patients with combined renal and hepatic impairment may have reduced digoxin clearance and potential for drug accumulation; monitor serum digoxin concentrations and therapeutic response closely in such patients.

Patients with chronic constrictive pericarditis can respond unfavorably to digoxin therapy because the drug slows the heart rate, which further reduces cardiac output. Digoxin is relatively contraindicated in patients with idiopathic hypertrophic subaortic stenosis because the drug can increase the obstruction to the left ventricular outflow.

Digoxin should be used with caution in patients with electrolyte imbalance. Conditions such as hypokalemia, hypomagnesemia, hypercalcemia, chronic pulmonary disease, and acute hypoxemia can increase cardiac sensitivity to digoxin, resulting in toxicity and potential for proarrhythmias. Patients with hypercalcemia or severe hyperkalemia can have an increased risk of digitalis-induced arrhythmias, particularly heart block. Digoxin may not be effective in patients with hypocalcemia; administration of calcium may be necessary.

Neonates and young infants display considerable variability in their tolerance and response to digoxin. Premature neonates are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity and renal function. There may be difficulty, particularly in neonates, in interpreting serum digoxin concentrations as a result of an increase in an endogenous digoxin-like substance that may interfere with the digoxin assays. Thus, digoxin concentrations may give the impression of supratherapeutic dosing; clinicians should interpret the results in accordance with the clinical status of the neonate before making dosage adjustments based on concentrations alone.

Intramuscular administration of digoxin causes considerable pain at the injection site and is generally not recommended unless other routes are contraindicated. If IM administration must be used, inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [children and adolescents only]). Aspirate prior to injection to avoid injection into a blood vessel. Massage area after administration.

Description: Digoxin is an oral and parenteral cardiac glycoside indicated for the treatment of congestive heart failure in pediatric and adult patients and to control ventricular rate in adult patients with atrial fibrillation. Digoxin has also been used off-label in pediatric patients for the treatment and/or prophylaxis of supraventricular arrhythmias, including atrioventricular reentrant tachycardias, atrial fibrillation, and atrial flutter; however, digoxin should not be used in patients with Wolff-Parkinson-White (WPW) syndrome as it increases the risk of rapid ventricular response. Due to the digoxin's ability to cross the placenta and obtain therapeutic concentrations in fetal circulation, it has been used for the treatment of fetal supraventricular arrhythmias via maternal administration. Initial signs and symptoms of digoxin toxicity in pediatric patients may consist of conduction disturbance or supraventricular tachyarrhythmias; sinus bradycardia is often a sign of potential digoxin toxicity, especially in infants. While digoxin increases left ventricular ejection fraction, improves symptoms, and reduces the need for hospitalization in adult patients with systolic heart failure, overall mortality is not affected. Although digoxin has been used for decades in patients with heart failure (HF), ACE inhibitors have replaced digoxin as first line therapy for HF due to systolic dysfunction in adults, but digoxin continues to be used as adjunctive therapy. When used to treat adults with diastolic heart failure (HF with normal ejection fraction) and normal sinus rhythm who were also receiving ACE inhibitors, digoxin is not associated with a benefit on overall mortality or cardiovascular morbidity. Digoxin is FDA approved in pediatric patients as young as premature neonates.

General dosing information
-Loading Dose Administration: In patients with undetectable serum digoxin concentrations, the total loading dose should be based on lean body weight and clinical response. The loading dose should be divided and given in several doses; the first dose should be roughly half of the total loading dose and the remainder should be divided and administered at 4-8 hour intervals.
-Higher doses may be required for treating arrhythmias than for treating cardiac failure.

For the treatment of heart failure:
Intravenous or Intramuscular dosage:
Premature Neonates: 1.9 to 3.1 mcg/kg/dose IV or IM twice daily. May consider a loading dose of 7.5 to 12.5 mcg/kg/dose IV or IM as a single dose, then 3.75 to 6.25 mcg/kg/dose IV or IM every 6 to 8 hours for 2 doses for a total loading dose of 15 to 25 mcg/kg IV or IM. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations. IV administration is preferred.
Term Neonates: 3 to 4.5 mcg/kg/dose IV or IM twice daily. May consider a loading dose of 10 to 15 mcg/kg/dose IV or IM as a single dose, then 5 to 7.5 mcg/kg/dose IV or IM every 6 to 8 hours for 2 doses for a total loading dose of 20 to 30 mcg/kg IV or IM. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations. IV administration is preferred.
Infants and Children 1 year: 4.5 to 7.5 mcg/kg/dose IV or IM twice daily. May consider a loading dose of 15 to 25 mcg/kg/dose IV or IM as a single dose, then 7.5 to 12.5 mcg/kg/dose IV or IM every 6 to 8 hours for 2 doses for a total loading dose of 30 to 50 mcg/kg IV or IM. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations. IV administration is preferred.
Children 2 to 4 years: 3.8 to 5.3 mcg/kg/dose IV or IM twice daily. May consider a loading dose of 12.5 to 17.5 mcg/kg/dose IV or IM as a single dose, then 6.25 to 8.75 mcg/kg/dose IV or IM every 6 to 8 hours for 2 doses for a total loading dose of 25 to 35 mcg/kg IV or IM. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations. IV administration is preferred.
Children 5 to 10 years: 2.3 to 4.5 mcg/kg/dose IV or IM twice daily. May consider a loading dose of 7.5 to 15 mcg/kg/dose IV or IM as a single dose, then 3.75 to 7.5 mcg/kg/dose IV or IM every 6 to 8 hours for 2 doses for a total loading dose of 15 to 30 mcg/kg IV or IM. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations. IV administration is preferred.
Children and Adolescents 11 to 17 years: 2.4 to 3.6 mcg/kg/dose IV or IM once daily. May consider a loading dose of 4 to 6 mcg/kg/dose IV or IM as a single dose, then 2 to 3 mcg/kg/dose IV or IM every 6 to 8 hours for 2 doses for a total loading dose of 8 to 12 mcg/kg IV or IM. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations. IV administration is preferred.
Oral dosage (tablets):
Children 5 to 10 years: 3.2 to 6.4 mcg/kg/dose PO twice daily. May consider a loading dose of 10 to 22.5 mcg/kg/dose PO as a single dose, then 5 to 11.25 mcg/kg/dose PO every 6 to 8 hours for 2 doses for a total loading dose of 20 to 45 mcg/kg PO. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations. Round dose to the nearest whole/half tablet.
Children and Adolescents 11 to 17 years: 3.4 to 5.1 mcg/kg/dose PO once daily. May consider a loading dose of 5 to 7.5 mcg/kg/dose PO as a single dose, then 2.5 to 3.75 mcg/kg/dose PO every 6 to 8 hours for 2 doses for a total loading dose of 10 to 15 mcg/kg PO. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations. Round dose to the nearest whole/half tablet.
Oral dosage (liquid):
Premature Neonates: 2.3 to 3.9 mcg/kg/dose PO twice daily. May consider a loading dose of 10 to 15 mcg/kg/dose PO as a single dose, then 5 to 7.5 mcg/kg/dose PO every 4 to 8 hours for 2 doses for a total loading dose of 20 to 30 mcg/kg PO. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations.
Term Neonates: 3.8 to 5.6 mcg/kg/dose PO twice daily. May consider a loading dose of 12.5 to 17.5 mcg/kg/dose PO as a single dose, then 6.25 to 8.75 mcg/kg/dose PO every 4 to 8 hours for 2 doses for a total loading dose of 25 to 35 mcg/kg PO. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations.
Infants and Children 1 year: 5.6 to 9.4 mcg/kg/dose PO twice daily. May consider a loading dose of 17.5 to 30 mcg/kg/dose PO as a single dose, then 8.75 to 15 mcg/kg/dose PO every 4 to 8 hours for 2 doses for a total loading dose of 35 to 60 mcg/kg PO. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations.
Children 2 to 4 years: 4.7 to 6.6 mcg/kg/dose PO twice daily. May consider a loading dose of 15 to 22.5 mcg/kg/dose PO as a single dose, then 7.5 to 11.25 mcg/kg/dose PO every 4 to 8 hours for 2 doses for a total loading dose of 30 to 45 mcg/kg PO. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations.
Children 5 to 10 years: 2.8 to 5.6 mcg/kg/dose PO twice daily. May consider a loading dose of 10 to 17.5 mcg/kg/dose PO as a single dose, then 5 to 8.75 mcg/kg/dose PO every 4 to 8 hours for 2 doses for a total loading dose of 20 to 35 mcg/kg PO. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations.
Children and Adolescents 11 to 17 years: 3 to 4.5 mcg/kg/dose PO once daily. May consider a loading dose of 5 to 7.5 mcg/kg/dose PO as a single dose, then 2.5 to 3.75 mcg/kg/dose PO every 4 to 8 hours for 2 doses for a total loading dose of 10 to 15 mcg/kg PO. Base dose on lean body weight. Adjust dose based on toxicity, efficacy, and serum digoxin concentrations.
Oral dosage (conversion from intravenous digoxin):
Children and Adolescents 11 to 17 years: 62.5 mcg/dose PO for 50 mcg/dose IV, 125 mcg/dose PO for 100 mcg/dose IV, 250 mcg/dose PO for 200 mcg/dose IV, and 500 mcg/dose PO for 400 mcg/dose IV.

Therapeutic Drug Monitoring:
Usual target serum concentration: 0.8-2 ng/ml
-Serum digoxin concentrations can be used to help to guide dosage adjustments; however, they should always be interpreted in the context of the patient's overall clinical status.
-Serum digoxin concentrations should be drawn at least 6-8 hours after a dose (a trough concentration is preferable) to avoid the distribution phase, which may produce falsely elevated concentrations.
-The digoxin concentration is likely to be 10-25% lower when sampled right before the next dose (24 hours after dosing) compared to sampling 8 hours after dosing (using once daily dosing). However, there will be only minor differences in digoxin concentrations using twice daily dosing whether sampling is done at 8 or 12 hours after a dose.
-About two-thirds of adults considered adequately digitalized (without evidence of toxicity) have serum digoxin concentrations ranging from 0.8-2.0 ng/ml and about two-thirds with clinical toxicity have concentrations > 2 ng/ml. However, since one-third of patients with clinical digoxin toxicity have a digoxin concentration below 2 ng/ml, values below 2 ng/ml do not rule out the possibility that a sign or symptom is related to digoxin toxicity, especially in the presence of electrolyte imbalances like hypokalemia or hypomagnesemia.
-Digoxin-like immunoreactive substance (DLIS) may cross-react with digoxin immunoassay and falsely increase serum concentrations. DLIS has been found in patients with renal and liver disease, heart failure, and neonates.

Maximum Dosage Limits:
Digoxin has a narrow therapeutic index. In all populations, the dosage is individualized based on patient weight, renal function, clinical goals, patient response, and when needed, serum digoxin concentrations.

Patients with Hepatic Impairment Dosing
No specific dosage adjustments are recommended for patients with hepatic impairment. However, patients with combined renal and hepatic impairment may have reduced digoxin clearance and potential for drug accumulation; monitor serum digoxin concentrations and therapeutic response closely in such patients.

Patients with Renal Impairment Dosing
Loading dose
Administer 50% of usual load in patients with end-stage renal disease (ESRD). Specific pediatric recommendations are not available.

Maintenance dose
GFR more than 50 mL/minute/1.73 m2: No dosage adjustment necessary.

GFR 30 to 50 mL/minute/1.73 m2: Administer 75% of usual dose at usual intervals.

GFR 10 to 29 mL/minute/1.73 m2: Administer 50% of usual dose at usual intervals, or usual dose every 36 hours.
GFR less than 10 mL/minute/1.73 m2: Administer 25% of usual dose at usual intervals, or usual dose every 48 hours.

FDA-approved labeling recommends the following daily maintenance dose requirements for heart failure based on corrected CrCl (mL/minute/1.73m2) and lean body weight (LBW). Higher doses may be required for treating arrhythmias than for treating heart failure.

Intravenous dosage: Infants and Children 10 years and younger
CrCl 100 mL/minute/1.73m2 or more:
LBW 5 to 9 kg: 17 mcg IV twice daily.
LBW 10 to 19 kg: 34 mcg IV twice daily.
LBW 20 to 29 kg: 68 mcg IV twice daily.
LBW 30 to 39 kg: 102 mcg IV twice daily.
LBW 40 to 49 kg: 136 mcg IV twice daily.
LBW 50 to 59 kg: 170 mcg IV twice daily.
LBW 60 to 69 kg: 204 mcg IV twice daily.

CrCl 90 to 99 mL/minute/1.73m2:
LBW 5 to 9 kg: 16 mcg IV twice daily.
LBW 10 to 19 kg: 32 mcg IV twice daily.
LBW 20 to 29 kg: 64 mcg IV twice daily.
LBW 30 to 39 kg: 96 mcg IV twice daily.
LBW 40 to 49 kg: 128 mcg IV twice daily.
LBW 50 to 59 kg: 160 mcg IV twice daily.
LBW 60 to 69 kg: 192 mcg IV twice daily.

CrCl 80 to 89 mL/minute/1.73m2:
LBW 5 to 9 kg: 15 mcg IV twice daily.
LBW 10 to 19 kg: 30 mcg IV twice daily.
LBW 20 to 29 kg: 60 mcg IV twice daily.
LBW 30 to 39 kg: 90 mcg IV twice daily.
LBW 40 to 49 kg: 120 mcg IV twice daily.
LBW 50 to 59 kg: 150 mcg IV twice daily.
LBW 60 to 69 kg: 180 mcg IV twice daily.

CrCl 70 to 79 mL/minute/1.73m2:
LBW 5 to 9 kg: 14 mcg IV twice daily.
LBW 10 to 19 kg: 28 mcg IV twice daily.
LBW 20 to 29 kg: 56 mcg IV twice daily.
LBW 30 to 39 kg: 84 mcg IV twice daily.
LBW 40 to 49 kg: 112 mcg IV twice daily.
LBW 50 to 59 kg: 140 mcg IV twice daily.
LBW 60 to 69 kg: 168 mcg IV twice daily.

CrCl 60 to 69 mL/minute/1.73m2:
LBW 5 to 9 kg: 13 mcg IV twice daily.
LBW 10 to 19 kg: 26 mcg IV twice daily.
LBW 20 to 29 kg: 52 mcg IV twice daily.
LBW 30 to 39 kg: 78 mcg IV twice daily.
LBW 40 to 49 kg: 104 mcg IV twice daily.
LBW 50 to 59 kg: 130 mcg IV twice daily.
LBW 60 to 69 kg: 156 mcg IV twice daily.

CrCl 50 to 59 mL/minute/1.73m2:
LBW 5 to 9 kg: 12 mcg IV twice daily.
LBW 10 to 19 kg: 24 mcg IV twice daily.
LBW 20 to 29 kg: 48 mcg IV twice daily.
LBW 30 to 39 kg: 72 mcg IV twice daily.
LBW 40 to 49 kg: 96 mcg IV twice daily.
LBW 50 to 59 kg: 120 mcg IV twice daily.
LBW 60 to 69 kg: 144 mcg IV twice daily.

CrCl 40 to 49 mL/minute/1.73m2:
LBW 5 to 9 kg: 11 mcg IV twice daily.
LBW 10 to 19 kg: 22 mcg IV twice daily.
LBW 20 to 29 kg: 44 mcg IV twice daily.
LBW 30 to 39 kg: 66 mcg IV twice daily.
LBW 40 to 49 kg: 88 mcg IV twice daily.
LBW 50 to 59 kg: 110 mcg IV twice daily.
LBW 60 to 69 kg: 132 mcg IV twice daily.

CrCl 30 to 39 mL/minute/1.73m2:
LBW 5 to 9 kg: 10 mcg IV twice daily.
LBW 10 to 19 kg: 20 mcg IV twice daily.
LBW 20 to 29 kg: 40 mcg IV twice daily.
LBW 30 to 39 kg: 60 mcg IV twice daily.
LBW 40 to 49 kg: 80 mcg IV twice daily.
LBW 50 to 59 kg: 100 mcg IV twice daily.
LBW 60 to 69 kg: 120 mcg IV twice daily.

CrCl 20 to 29 mL/minute/1.73m2:
LBW 5 to 9 kg: 9 mcg IV twice daily.
LBW 10 to 19 kg: 18 mcg IV twice daily.
LBW 20 to 29 kg: 36 mcg IV twice daily.
LBW 30 to 39 kg: 54 mcg IV twice daily.
LBW 40 to 49 kg: 72 mcg IV twice daily.
LBW 50 to 59 kg: 90 mcg IV twice daily.
LBW 60 to 69 kg: 108 mcg IV twice daily.

CrCl 10 to 19 mL/minute/1.73m2:
LBW 5 to 9 kg: 8 mcg IV twice daily.
LBW 10 to 19 kg: 16 mcg IV twice daily.
LBW 20 to 29 kg: 32 mcg IV twice daily.
LBW 30 to 39 kg: 48 mcg IV twice daily.
LBW 40 to 49 kg: 64 mcg IV twice daily.
LBW 50 to 59 kg: 80 mcg IV twice daily.
LBW 60 to 69 kg: 96 mcg IV twice daily.

Intravenous dosage: Children older than 10 years and Adolescents
CrCl 100 mL/minute/1.73m2 or more:
LBW 40 to 49 kg: 136 mcg IV once daily.
LBW 50 to 59 kg: 170 mcg IV once daily.
LBW 60 to 69 kg: 204 mcg IV once daily.
LBW 70 to 79 kg: 238 mcg IV once daily.
LBW 80 to 89 kg: 272 mcg IV once daily.
LBW 90 to 99 kg: 306 mcg IV once daily.
LBW 100 kg or more: 340 mcg IV once daily.

CrCl 90 to 99 mL/minute/1.73m2:
LBW 40 to 49 kg: 128 mcg IV once daily.
LBW 50 to 59 kg: 160 mcg IV once daily.
LBW 60 to 69 kg: 192 mcg IV once daily.
LBW 70 to 79 kg: 224 mcg IV once daily.
LBW 80 to 89 kg: 256 mcg IV once daily.
LBW 90 to 99 kg: 288 mcg IV once daily.
LBW 100 kg or more: 320 mcg IV once daily.

CrCl 80 to 89 mL/minute/1.73m2:
LBW 40 to 49 kg: 120 mcg IV once daily.
LBW 50 to 59 kg: 150 mcg IV once daily.
LBW 60 to 69 kg: 180 mcg IV once daily.
LBW 70 to 79 kg: 210 mcg IV once daily.
LBW 80 to 89 kg: 240 mcg IV once daily.
LBW 90 to 99 kg: 270 mcg IV once daily.
LBW 100 kg or more: 300 mcg IV once daily.

CrCl 70 to 79 mL/minute/1.73m2:
LBW 40 to 49 kg: 112 mcg IV once daily.
LBW 50 to 59 kg: 140 mcg IV once daily.
LBW 60 to 69 kg: 168 mcg IV once daily.
LBW 70 to 79 kg: 196 mcg IV once daily.
LBW 80 to 89 kg: 224 mcg IV once daily.
LBW 90 to 99 kg: 252 mcg IV once daily.
LBW 100 kg or more: 280 mcg IV once daily.

CrCl 60 to 69 mL/minute/1.73m2:
LBW 40 to 49 kg: 104 mcg IV once daily.
LBW 50 to 59 kg: 130 mcg IV once daily.
LBW 60 to 69 kg: 156 mcg IV once daily.
LBW 70 to 79 kg: 182 mcg IV once daily.
LBW 80 to 89 kg: 208 mcg IV once daily.
LBW 90 to 99 kg: 234 mcg IV once daily.
LBW 100 kg or more: 260 mcg IV once daily.

CrCl 50 to 59 mL/minute/1.73m2:
LBW 40 to 49 kg: 96 mcg IV once daily.
LBW 50 to 59 kg: 120 mcg IV once daily.
LBW 60 to 69 kg: 144 mcg IV once daily.
LBW 70 to 79 kg: 168 mcg IV once daily.
LBW 80 to 89 kg: 192 mcg IV once daily.
LBW 90 to 99 kg: 216 mcg IV once daily.
LBW 100 kg or more: 240 mcg IV once daily.

CrCl 40 to 49 mL/minute/1.73m2:
LBW 40 to 49 kg: 88 mcg IV once daily.
LBW 50 to 59 kg: 110 mcg IV once daily.
LBW 60 to 69 kg: 132 mcg IV once daily.
LBW 70 to 79 kg: 154 mcg IV once daily.
LBW 80 to 89 kg: 176 mcg IV once daily.
LBW 90 to 99 kg: 198 mcg IV once daily.
LBW 100 kg or more: 220 mcg IV once daily.

CrCl 30 to 39 mL/minute/1.73m2:
LBW 40 to 49 kg: 80 mcg IV once daily.
LBW 50 to 59 kg: 100 mcg IV once daily.
LBW 60 to 69 kg: 120 mcg IV once daily.
LBW 70 to 79 kg: 140 mcg IV once daily.
LBW 80 to 89 kg: 160 mcg IV once daily.
LBW 90 to 99 kg: 180 mcg IV once daily.
LBW 100 kg or more: 200 mcg IV once daily.

CrCl 20 to 29 mL/minute/1.73m2:
LBW 40 to 49 kg: 72 mcg IV once daily.
LBW 50 to 59 kg: 90 mcg IV once daily.
LBW 60 to 69 kg: 108 mcg IV once daily.
LBW 70 to 79 kg: 126 mcg IV once daily.
LBW 80 to 89 kg: 144 mcg IV once daily.
LBW 90 to 99 kg: 162 mcg IV once daily.
LBW 100 kg or more: 180 mcg IV once daily.

CrCl 10 to 19 mL/minute/1.73m2:
LBW 40 to 49 kg: 64 mcg IV once daily.
LBW 50 to 59 kg: 80 mcg IV once daily.
LBW 60 to 69 kg: 96 mcg IV once daily.
LBW 70 to 79 kg: 112 mcg IV once daily.
LBW 80 to 89 kg: 128 mcg IV once daily.
LBW 90 to 99 kg: 144 mcg IV once daily.
LBW 100 kg or more: 160 mcg IV once daily.

Oral dosage (liquid): Infants and Children 10 years and younger
CrCl 100 mL/minute/1.73m2 or more:
LBW 5 to 9 kg: 21 mcg PO twice daily.
LBW 10 to 19 kg: 43 mcg PO twice daily.
LBW 20 to 29 kg: 85 mcg PO twice daily.
LBW 30 to 39 kg: 128 mcg PO twice daily.
LBW 40 to 49 kg: 170 mcg PO twice daily.
LBW 50 to 59 kg: 213 mcg PO twice daily.
LBW 60 to 69 kg: 255 mcg PO twice daily.

CrCl 90 to 99 mL/minute/1.73m2:
LBW 5 to 9 kg: 20 mcg PO twice daily.
LBW 10 to 19 kg: 40 mcg PO twice daily.
LBW 20 to 29 kg: 80 mcg PO twice daily.
LBW 30 to 39 kg: 120 mcg PO twice daily.
LBW 40 to 49 kg: 160 mcg PO twice daily.
LBW 50 to 59 kg: 200 mcg PO twice daily.
LBW 60 to 69 kg: 240 mcg PO twice daily.

CrCl 80 to 89 mL/minute/1.73m2:
LBW 5 to 9 kg: 19 mcg PO twice daily.
LBW 10 to 19 kg: 38 mcg PO twice daily.
LBW 20 to 29 kg: 75 mcg PO twice daily.
LBW 30 to 39 kg: 113 mcg PO twice daily.
LBW 40 to 49 kg: 150 mcg PO twice daily.
LBW 50 to 59 kg: 188 mcg PO twice daily.
LBW 60 to 69 kg: 225 mcg PO twice daily.

CrCl 70 to 79 mL/minute/1.73m2:
LBW 5 to 9 kg: 18 mcg PO twice daily.
LBW 10 to 19 kg: 35 mcg PO twice daily.
LBW 20 to 29 kg: 70 mcg PO twice daily.
LBW 30 to 39 kg: 105 mcg PO twice daily.
LBW 40 to 49 kg: 140 mcg PO twice daily.
LBW 50 to 59 kg: 175 mcg PO twice daily.
LBW 60 to 69 kg: 210 mcg PO twice daily.

CrCl 60 to 69 mL/minute/1.73m2:
LBW 5 to 9 kg: 16 mcg PO twice daily.
LBW 10 to 19 kg: 33 mcg PO twice daily.
LBW 20 to 29 kg: 65 mcg PO twice daily.
LBW 30 to 39 kg: 98 mcg PO twice daily.
LBW 40 to 49 kg: 130 mcg PO twice daily.
LBW 50 to 59 kg: 163 mcg PO twice daily.
LBW 60 to 69 kg: 195 mcg PO twice daily.

CrCl 50 to 59 mL/minute/1.73m2:
LBW 5 to 9 kg: 15 mcg PO twice daily.
LBW 10 to 19 kg: 30 mcg PO twice daily.
LBW 20 to 29 kg: 60 mcg PO twice daily.
LBW 30 to 39 kg: 90 mcg PO twice daily.
LBW 40 to 49 kg: 120 mcg PO twice daily.
LBW 50 to 59 kg: 150 mcg PO twice daily.
LBW 60 to 69 kg: 180 mcg PO twice daily.

CrCl 40 to 49 mL/minute/1.73m2:
LBW 5 to 9 kg: 14 mcg PO twice daily.
LBW 10 to 19 kg: 28 mcg PO twice daily.
LBW 20 to 29 kg: 55 mcg PO twice daily.
LBW 30 to 39 kg: 83 mcg PO twice daily.
LBW 40 to 49 kg: 110 mcg PO twice daily.
LBW 50 to 59 kg: 138 mcg PO twice daily.
LBW 60 to 69 kg: 165 mcg PO twice daily.

CrCl 30 to 39 mL/minute/1.73m2:
LBW 5 to 9 kg: 13 mcg PO twice daily.
LBW 10 to 19 kg: 25 mcg PO twice daily.
LBW 20 to 29 kg: 50 mcg PO twice daily.
LBW 30 to 39 kg: 75 mcg PO twice daily.
LBW 40 to 49 kg: 100 mcg PO twice daily.
LBW 50 to 59 kg: 125 mcg PO twice daily.
LBW 60 to 69 kg: 150 mcg PO twice daily.

CrCl 20 to 29 mL/minute/1.73m2:
LBW 5 to 9 kg: 11 mcg PO twice daily.
LBW 10 to 19 kg: 23 mcg PO twice daily.
LBW 20 to 29 kg: 45 mcg PO twice daily.
LBW 30 to 39 kg: 68 mcg PO twice daily.
LBW 40 to 49 kg: 90 mcg PO twice daily.
LBW 50 to 59 kg: 113 mcg PO twice daily.
LBW 60 to 69 kg: 135 mcg PO twice daily.

CrCl less than 20 mL/minute/1.73m2:
LBW 5 to 9 kg: 10 mcg PO twice daily.
LBW 10 to 19 kg: 20 mcg PO twice daily.
LBW 20 to 29 kg: 40 mcg PO twice daily.
LBW 30 to 39 kg: 60 mcg PO twice daily.
LBW 40 to 49 kg: 80 mcg PO twice daily.
LBW 50 to 59 kg: 100 mcg PO twice daily.
LBW 60 to 69 kg: 120 mcg PO twice daily.

Oral dosage (liquid): Children older than 10 years and Adolescents
CrCl 100 mL/minute/1.73m2 or more:
LBW 40 to 49 kg: 170 mcg PO once daily.
LBW 50 to 59 kg: 213 mcg PO once daily.
LBW 60 to 69 kg: 255 mcg PO once daily.
LBW 70 to 79 kg: 298 mcg PO once daily.
LBW 80 to 89 kg: 340 mcg PO once daily.
LBW 90 to 99 kg: 383 mcg PO once daily.
LBW 100 kg or more: 425 mcg PO once daily.

CrCl 90 to 99 mL/minute/1.73m2:
LBW 40 to 49 kg: 160 mcg PO once daily.
LBW 50 to 59 kg: 200 mcg PO once daily.
LBW 60 to 69 kg: 240 mcg PO once daily.
LBW 70 to 79 kg: 280 mcg PO once daily.
LBW 80 to 89 kg: 320 mcg PO once daily.
LBW 90 to 99 kg: 360 mcg PO once daily.
LBW 100 kg or more: 400 mcg PO once daily.

CrCl 80 to 89 mL/minute/1.73m2:
LBW 40 to 49 kg: 150 mcg PO once daily.
LBW 50 to 59 kg: 188 mcg PO once daily.
LBW 60 to 69 kg: 225 mcg PO once daily.
LBW 70 to 79 kg: 263 mcg PO once daily.
LBW 80 to 89 kg: 300 mcg PO once daily.
LBW 90 to 99 kg: 338 mcg PO once daily.
LBW 100 kg or more: 375 mcg PO once daily.

CrCl 70 to 79 mL/minute/1.73m2:
LBW 40 to 49 kg: 140 mcg PO once daily.
LBW 50 to 59 kg: 175 mcg PO once daily.
LBW 60 to 69 kg: 210 mcg PO once daily.
LBW 70 to 79 kg: 245 mcg PO once daily.
LBW 80 to 89 kg: 280 mcg PO once daily.
LBW 90 to 99 kg: 315 mcg PO once daily.
LBW 100 kg or more: 350 mcg PO once daily.

CrCl 60 to 69 mL/minute/1.73m2:
LBW 40 to 49 kg: 130 mcg PO once daily.
LBW 50 to 59 kg: 163 mcg PO once daily.
LBW 60 to 69 kg: 195 mcg PO once daily.
LBW 70 to 79 kg: 228 mcg PO once daily.
LBW 80 to 89 kg: 260 mcg PO once daily.
LBW 90 to 99 kg: 293 mcg PO once daily.
LBW 100 kg or more: 325 mcg PO once daily.

CrCl 50 to 59 mL/minute/1.73m2:
LBW 40 to 49 kg: 120 mcg PO once daily.
LBW 50 to 59 kg: 150 mcg PO once daily.
LBW 60 to 69 kg: 180 mcg PO once daily.
LBW 70 to 79 kg: 210 mcg PO once daily.
LBW 80 to 89 kg: 240 mcg PO once daily.
LBW 90 to 99 kg: 270 mcg PO once daily.
LBW 100 kg or more: 300 mcg PO once daily.

CrCl 40 to 49 mL/minute/1.73m2:
LBW 40 to 49 kg: 110 mcg PO once daily.
LBW 50 to 59 kg: 138 mcg PO once daily.
LBW 60 to 69 kg: 165 mcg PO once daily.
LBW 70 to 79 kg: 193 mcg PO once daily.
LBW 80 to 89 kg: 220 mcg PO once daily.
LBW 90 to 99 kg: 248 mcg PO once daily.
LBW 100 kg or more: 275 mcg PO once daily.

CrCl 30 to 39 mL/minute/1.73m2:
LBW 40 to 49 kg: 100 mcg PO once daily.
LBW 50 to 59 kg: 125 mcg PO once daily.
LBW 60 to 69 kg: 150 mcg PO once daily.
LBW 70 to 79 kg: 175 mcg PO once daily.
LBW 80 to 89 kg: 200 mcg PO once daily.
LBW 90 to 99 kg: 225 mcg PO once daily.
LBW 100 kg or more: 250 mcg PO once daily.

CrCl 20 to 29 mL/minute/1.73m2:
LBW 40 to 49 kg: 90 mcg PO once daily.
LBW 50 to 59 kg: 113 mcg PO once daily.
LBW 60 to 69 kg: 135 mcg PO once daily.
LBW 70 to 79 kg: 158 mcg PO once daily.
LBW 80 to 89 kg: 180 mcg PO once daily.
LBW 90 to 99 kg: 203 mcg PO once daily.
LBW 100 kg or more: 225 mcg PO once daily.

CrCl less than 20 mL/minute/1.73m2:
LBW 40 to 49 kg: 80 mcg PO once daily.
LBW 50 to 59 kg: 100 mcg PO once daily.
LBW 60 to 69 kg: 120 mcg PO once daily.
LBW 70 to 79 kg: 140 mcg PO once daily.
LBW 80 to 89 kg: 160 mcg PO once daily.
LBW 90 to 99 kg: 180 mcg PO once daily.
LBW 100 kg or more: 200 mcg PO once daily.

Oral dosage (tablets): Children 10 years and younger
NOTE: Doses are rounded to the nearest whole/half tablet
CrCl 100 mL/minute/1.73m2 or more:
LBW 20 to 29 kg: 62.5 mcg PO twice daily.
LBW 30 to 39 kg: 125 mcg PO twice daily.
LBW 40 to 49 kg: 187.5 mcg PO twice daily.
LBW 50 to 59 kg: 250 mcg PO twice daily.
LBW 60 to 69 kg: 312.5 mcg PO twice daily.

CrCl 90 to 99 mL/minute/1.73m2:
LBW 20 to 29 kg: 62.5 mcg PO twice daily.
LBW 30 to 39 kg: 125 mcg PO twice daily.
LBW 40 to 49 kg: 187.5 mcg PO twice daily.
LBW 50 to 69 kg: 250 mcg PO twice daily.

CrCl 80 to 89 mL/minute/1.73m2:
LBW 20 to 29 kg: 62.5 mcg PO twice daily.
LBW 30 to 39 kg: 125 mcg PO twice daily.
LBW 40 to 59 kg: 187.5 mcg PO twice daily.
LBW 60 to 69 kg: 250 mcg PO twice daily.

CrCl 70 to 79 mL/minute/1.73m2:
LBW 20 to 29 kg: 62.5 mcg PO twice daily.
LBW 30 to 39 kg: 125 mcg PO twice daily.
LBW 40 to 59 kg: 187.5 mcg PO twice daily.
LBW 60 to 69 kg: 250 mcg PO twice daily.

CrCl 60 to 69 mL/minute/1.73m2:
LBW 20 to 29 kg: 62.5 mcg PO twice daily.
LBW 30 to 49 kg: 125 mcg PO twice daily.
LBW 50 to 59 kg: 187.5 mcg PO twice daily.
LBW 60 to 69 kg: 250 mcg PO twice daily.

CrCl 50 to 59 mL/minute/1.73m2:
LBW 20 to 29 kg: 62.5 mcg PO twice daily.
LBW 30 to 49 kg: 125 mcg PO twice daily.
LBW 50 to 69 kg: 187.5 mcg PO twice daily.

CrCl 40 to 49 mL/minute/1.73m2:
LBW 20 to 39 kg: 62.5 mcg PO twice daily.
LBW 40 to 49 kg: 125 mcg PO twice daily.
LBW 50 to 69 kg: 187.5 mcg PO twice daily.

CrCl 30 to 39 mL/minute/1.73m2:
LBW 20 to 39 kg: 62.5 mcg PO twice daily.
LBW 40 to 59 kg: 125 mcg PO twice daily.
LBW 60 to 69 kg: 187.5 mcg PO twice daily.

CrCl 20 to 29 mL/minute/1.73m2:
LBW 20 to 39 kg: 62.5 mcg PO twice daily.
LBW 40 to 69 kg: 125 mcg PO twice daily.

CrCl less than 20 mL/minute/1.73m2:
LBW 30 to 49 kg: 62.5 mcg PO twice daily.
LBW 50 to 69 kg: 125 mcg PO twice daily.

Oral dosage (tablets): Children older than 10 years and Adolescents
CrCl 100 mL/minute/1.73m2 or more:
LBW 40 to 49 kg: 187.5 mcg PO once daily.
LBW 50 to 59 kg: 250 mcg PO once daily.
LBW 60 to 79 kg: 312.5 mcg PO once daily.
LBW 80 to 89 kg: 375 mcg PO once daily.
LBW 90 to 99 kg: 437.5 mcg PO once daily.
LBW 100 kg or more: 500 mcg PO once daily.

CrCl 90 to 99 mL/minute/1.73m2:
LBW 40 to 49 kg: 187.5 mcg PO once daily.
LBW 50 to 69 kg: 250 mcg PO once daily.
LBW 70 to 79 kg: 312.5 mcg PO once daily.
LBW 80 to 89 kg: 375 mcg PO once daily.
LBW 90 kg or more: 437.5 mcg PO once daily.

CrCl 80 to 89 mL/minute/1.73m2:
LBW 40 to 59 kg: 187.5 mcg PO once daily.
LBW 60 to 69 kg: 250 mcg PO once daily.
LBW 70 to 89 kg: 312.5 mcg PO once daily.
LBW 90 to 99 kg: 375 mcg PO once daily.
LBW 100 kg or more: 437.5 mcg PO once daily.

CrCl 70 to 79 mL/minute/1.73m2:
LBW 40 to 59 kg: 187.5 mcg PO once daily.
LBW 60 to 79 kg: 250 mcg PO once daily.
LBW 80 to 89 kg: 312.5 mcg PO once daily.
LBW 90 kg or more: 375 mcg PO once daily.

CrCl 60 to 69 mL/minute/1.73m2:
LBW 40 to 49 kg: 125 mcg PO once daily.
LBW 50 to 59 kg: 187.5 mcg PO once daily.
LBW 60 to 79 kg: 250 mcg PO once daily.
LBW 80 to 99 kg: 312.5 mcg PO once daily.
LBW 100 kg or more: 375 mcg PO once daily.

CrCl 40 to 59 mL/minute/1.73m2:
LBW 40 to 49 kg: 125 mcg PO once daily.
LBW 50 to 69 kg: 187.5 mcg PO once daily.
LBW 70 to 89 kg: 250 mcg PO once daily.
LBW 90 kg or more: 312.5 mcg PO once daily.

CrCl 30 to 39 mL/minute/1.73m2:
LBW 40 to 59 kg: 125 mcg PO once daily.
LBW 60 to 79 kg: 187.5 mcg PO once daily.
LBW 80 to 99 kg: 250 mcg PO once daily.
LBW 100 kg or more: 312.5 mcg PO once daily.

CrCl 20 to 29 mL/minute/1.73m2:
LBW 40 to 69 kg: 125 mcg PO once daily.
LBW 70 to 89 kg: 187.5 mcg PO once daily.
LBW 90 kg or more: 250 mcg PO once daily.

CrCl less than 20 mL/minute/1.73m2:
LBW 40 to 49 kg: 62.5 mcg PO once daily.
LBW 50 to 69 kg: 125 mcg PO once daily.
LBW 70 to 99 kg: 187.5 mcg PO once daily.
LBW 100 kg or more: 250 mcg PO once daily.

Intermittent hemodialysis
Administer 25% of usual dose at usual intervals, or usual dose every 48 hours. Digoxin is not effectively removed by dialysis because of its large extravascular volume of distribution.

Peritoneal dialysis
Administer 25% of usual dose at usual intervals, or usual dose every 48 hours.

Continuous renal replacement therapy
Administer 75% of usual dose at usual intervals; monitor serum concentrations and titrate to effect.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Digoxin inhibits the Na-K-ATPase membrane pump. Na-K-ATPase regulates intracellular sodium and potassium. Inhibition of this enzyme leads to an increase in intracellular sodium concentration (i.e., decreased outward transport) and ultimately to an increase in intracellular calcium as sodium-calcium exchange is stimulated by high intracellular sodium concentrations. It is believed that increased intracellular concentrations of calcium allow for greater activation of contractile proteins (e.g., actin, myosin). While the contractile proteins and the troponin-tropomysin system are directly involved in muscular contraction, it is not clear how digoxin augments their action. Digoxin does not directly affect these proteins or the cellular mechanisms that provide energy for contraction, nor does it affect contraction in skeletal muscle. Digoxin also increases sympathetic tone, however, this does not account for the positive inotropic effect which persists even in the presence of beta-adrenergic blockade.

Digoxin directly increases the force and velocity of myocardial contraction in both healthy and failing hearts. In the failing heart, an increased force of contraction raises cardiac output, resulting in greater systolic emptying and a smaller diastolic heart size. End-diastolic pressures decrease, leading to a reduction in pulmonary and systemic venous pressures. In patients with normal hearts, however, cardiac output remains unchanged. Digoxin also possesses direct vasoconstrictive properties and reflex CNS-mediated peripheral vasoconstriction. Although this increases vascular resistance, in patients with failing hearts, increased myocardial contractility predominates and total peripheral resistance drops. In patients with congestive heart failure, an increased cardiac output will decrease sympathetic tone, thereby reducing the heart rate and causing diuresis in edematous patients and improving coronary blood flow.

In addition to its inotropic effects, digoxin also possesses significant actions on the electrical activity of the heart. It increases the slope of phase 4 depolarization, shortens the action potential duration, and decreases the maximal diastolic potential. The increase in vagal activity mediated by cardiac glycosides decreases conduction velocity through the atrioventricular (AV) node, prolonging its effective refractory period. In atrial flutter or fibrillation, digoxin decreases the number of atrial depolarizations that reach the ventricle, thereby slowing ventricular rate. Sympathetic stimulation, however, easily overrides the beneficial inhibitory effects of digoxin on AV nodal conduction.

Pharmacokinetics: Digoxin is administered orally, intravenously, or intramuscularly. After administration, digoxin undergoes a 6- to 8-hour distribution phase in which serum concentrations fall more rapidly followed by a slower elimination phase. Digoxin distributes throughout the body tissues, with the highest concentrations found in the heart, kidneys, intestine, liver, stomach, and skeletal muscle. Small amounts can be found in the brain. Since digoxin concentrates in the tissues, it has a large volume of distribution. Early serum concentrations do not represent digoxin concentrations at the sites of action; however, an equilibrium is obtained between serum and tissue concentrations at steady-state, post-distribution with chronic digoxin therapy. The presence of congestive heart failure slows the rate at which steady-state distribution is achieved. Approximately 25% of the drug is plasma protein-bound. Digoxin crosses the placenta, and maternal and fetal plasma concentrations of the drug are equal.

A small amount of digoxin (approximately 13 to 16%) is metabolized in the liver via hydrolysis, oxidation, and conjugation; the cytochrome P450 system is not involved in the metabolism of digoxin. Fifty to 70% of an intravenous dose is excreted unchanged in the urine. The elimination half-life of digoxin in adults is normally 36 to 48 hours, but heart failure or renal impairment can prolong digoxin elimination.

Affected cytochrome P450 isoenzymes and drug transporters: P-glycoprotein (P-gp)
Digoxin is a substrate for P-glycoprotein transport; drug-drug interactions may occur with drugs that are P-gp inducers or inhibitors.


-Route-Specific Pharmacokinetics
Oral Route
In general, digoxin is rapidly absorbed from the GI tract after an oral dose. In approximately 10% of patients, 40% or more of an orally ingested digoxin is converted to inactive metabolites, such as dihydrodigoxin, in the gut by colonic bacteria.
-Oral Tablets: Peak serum concentrations occur within 1 to 3 hours after oral digoxin administration. Bioavailability is approximately 60 to 80% from oral tablets. Onset of therapeutic effects generally occurs within 30 minutes to 2 hours and peak effect within 2 to 6 hours after oral administration of a dose. The rate of digoxin absorption is slower, but the amount absorbed is usually unchanged when digoxin tablets are taken after meals. However, when digoxin tablet are administered with a high fiber meal, digoxin absorption is reduced.
-Oral Solution: Peak serum concentrations occur within 30 to 90 minutes after oral digoxin administration. Bioavailability is approximately 70 to 85% from the oral solution. Peak serum concentrations increase by 20% and total absorption increases by 43% when the digoxin solution is taken after meals, but absorption rate is unchanged. Administration after a high fiber meal reduces digoxin absorption.

Intravenous Route
Onset of therapeutic effects generally occurs within 5 to 30 minutes and peak effect within 1 to 4 hours after IV administration.


-Special Populations
Pediatrics
The elimination half-life of digoxin is longest in premature neonates and shortest in infants and the total body clearance lowest in premature neonates and highest in infants. These values approach adult values in children.

Premature Neonates
Digoxin elimination by premature neonates is significantly slower than that of term neonates, which is due at least in part to immature renal function. The elimination half-life and total body clearance in premature neonates receiving digoxin has been reported as 56 to 170 hours and 6.5 ml/min/m2.

Neonates
The mean elimination half-life, total body clearance, and volume of distribution in neonates receiving digoxin has been reported as 34 to 44 hours, 29 to 38 ml/min/m2, and 7.5 L/kg, respectively. The mean renal clearance of digoxin in neonates 1 week of age was estimated as 33 ml/min/1.73m2.

Infants
Digoxin clearance changes dramatically during infancy from slow during the newborn period to more rapid than adults by the end of the first year. The mean elimination half-life, clearance, and volume of distribution in infants receiving digoxin has been reported as 18 to 25 hours, 136 to 187 ml/min/m2, and 16 L/kg, respectively. The mean renal clearance of digoxin in infants 3 months of age was estimated as 89 ml/min/1.73m2.

Children
The mean elimination half-life, total body clearance, volume of distribution in children receiving digoxin has been reported as 35 to 37 hours, 133 ml/min/m2, and 16 L/kg, respectively. Compared to adults, children have a significantly larger volume of distribution but comparable half-life. The mean renal clearance of digoxin in children 1.5 years of age was estimated as 144 ml/min/1.73m2.

Hepatic Impairment
Hepatic impairment does not have a clinically meaningful effect on the pharmacokinetics of digoxin.

Renal Impairment
Renal impairment prolongs digoxin elimination. In adult patients with renal impairment, the half-life is extended to as long as 3.5 to 5 days. Renal excretion of digoxin is proportional to creatinine clearance. Dialysis does not effectively remove digoxin from the body.