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Digoxin Description

Digoxin is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves ofDigitalis lanata. The term“digitalis” is used to designate the whole group of glycosides. The glycosides are composed of two portions: a sugar and a cardenolide (hence “glycosides”).

Digoxin has the chemical name: 3β - [(O - 2,6 - Dideoxy - β - D - ribo - hexopyranosyl - (1→4) - O - 2,6 - dideoxy - β - D - ribo - hexopy­ranosyl - (1→4) - 2,6 - dideoxy - β - D - ribo - hexopyranosyl)oxy] - 12β,14 - dihydroxy - 5β - card - 20(22) - enolide, and the following struc­­tural formula:

C41H64O14 MW 780.94

Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine.

Digoxin Injection is a sterile solution for slow intravenous or deep intramuscular injection. Each mL contains Digoxin 250 mcg (0.25 mg), alcohol 0.1 mL, propylene glycol 0.4 mL, dibasic sodium phosphate, anhydrous 3 mg and citric acid, anhydrous 0.8 mg in Water for Injection. pH 6.7-7.3; citric acid and/or sodium phosphate added, if necessary, for pH adjustment. Dilution is not required.

Digoxin - Clinical Pharmacology

Mechanism of Action

Digoxin inhibits sodium-potassium ATPase, an enzyme that regulates the quantity of sodium and potassium inside cells. Inhibition of the enzyme leads to an increase in the intracellular concentration of sodium and thus (by stimulation of sodium-calcium exchange) an increase in the intracellular concentration of calcium. The beneficial effects of Digoxin result from direct actions on cardiac muscle, as well as indirect actions on the cardiovascular system mediated by effects on the autonomic nervous system. The autonomic effects include: (1) a vagomimetic action, which is responsible for the effects of Digoxin on the sinoatrial and atrioventricular (AV) nodes; and (2) baroreceptor sensitization, which results in increased afferent inhibitory activity and reduced activity of the sympathetic nervous system and renin-angiotensin system for any given increment in mean arterial pressure. The pharmacologic consequences of these direct and indirect effects are: (1) an increase in the force and velocity of myocardial systolic contraction (positive inotropic action); (2) a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect); and (3) slowing of the heart rate and decreased conduction velocity through the AV node (vagomimetic effect). The effects of Digoxin in heart failure are mediated by its positive inotropic and neurohormonal deactivating effects, whereas the effects of the drug in atrial arrhythmias are related to its vagomimetic actions. In high doses, Digoxin increases sympathetic outflow from the central nervous system (CNS). This increase in sympathetic activity may be an important factor in digitalis toxicity.

Pharmacokinetics

Note–The following data are from studies performed in adults, unless otherwise stated.

Comparisons of the systemic availability and equivalent doses for preparations of Digoxin are shown in Table 1:

*For example, 125 mcg Digoxin Tablets equivalent to 125 mcg Digoxin Elixir Pediatric equivalent to 100 mcg Digoxin Capsules equivalent to 100 mcg Digoxin Injection/IV.

Following drug administration, a 6- to 8-hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of Digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of Digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects (see DOSAGE AND ADMINISTRATION, Serum Digoxin Concentrations).

Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum Digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of Digoxin in the plasma is bound to protein. Serum Digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight.

Only a small percentage (16%) of a dose of Digoxin is metabolized. The end metabolites, which include 3β-digoxigenin, 3-keto-digoxigenin, and their glucuronide and sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of Digoxin is not dependent upon the cytochrome P-450 system, and Digoxin is not known to induce or inhibit the cytochrome P-450 system.

Elimination of Digoxin follows first-order kinetics (that is, the quantity of Digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50% to 70% of a Digoxin dose is excreted unchanged in the urine. Renal excretion of Digoxin is proportional to glomerular filtration rate and is largely independent of urine flow. In healthy volunteers with normal renal function, Digoxin has a half-life of 1.5 to 2 days. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to tissue and does not circulate in the blood.

Race differences in Digoxin pharmacokinetics have not been formally studied. Because Digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected.

The clearance of Digoxin can be primarily correlated with renal function as indicated by creatinine clearance. The Cockcroft and Gault formula for estimation of creatinine clearance includes age, body weight, and gender. A table that provides the usual daily maintenance dose requirements of Digoxin tablets based on creatinine clearance (per 70 kg) is presented in the DOSAGE AND ADMINISTRATION section.

Plasma Digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects.

Pharmacodynamic and Clinical Effects

The times to onset of pharmacologic effect and to peak effect of preparations of Digoxin are shown in Table 2:

* Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes.

† Depending upon rate of infusion.

Digoxin produces hemodynamic improvement in patients with heart failure. Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions.

Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) patients with NYHA class II or III heart failure previously treated with oral Digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with Digoxin tablets. Both trials demonstrated better preservation of exercise capacity in patients randomized to Digoxin. Continued treatment with Digoxin reduced the risk of de­veloping worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy. The larger study also showed treatment-related benefits in NYHA class and patients’ global assessment. In the smaller trial, these trended in favor of a treatment benefit.

The Digitalis Investigation Group (DIG) main trial was a multicenter, randomized, double-blind, placebo-controlled mortality study of 6801 patients with heart failure and left ventricular ejection fraction ≤ 0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving Digoxin, and most were receiving concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to placebo or Digoxin tablets, the dose of which was adjusted for the patient’s age, sex, lean body weight, and serum creatinine (see DOSAGE AND ADMINISTRATION), and followed for up to 58 months (median 37 months). The median daily dose prescribed was 0.25 mg. Overall all-cause mortality was 35% with no difference between groups (95% confidence limits for relative risk of 0.91 to 1.07). Digoxin was associated with a 25% reduction in the number of hospitalizations for heart failure, a 28% reduction in the risk of a patient having at least one hospitalization for heart failure, and a 6.5% reduction in total hospitalizations (for any cause).

Use of Digoxin was associated with a trend in reduction in time to all-cause death or hospitalization. The trend was evident in subgroups of patients with mild heart failure as well as more severe disease, as shown in Table 3. Although the effect on all-cause death or hospitalization was not statistically significant, much of the apparent benefit derived from effects on mortality and hospitalization attributed to heart failure.

* Number of patients with an event during the first 2 years per 1000 randomized patients.

† Relative risk (95% confidence interval).

‡ DIG Ancillary Study.

In situations where there is no statistically significant benefit of treatment evident from a trial’s primary endpoint, results pertaining to a secondary endpoint should be interpreted cautiously.

In patients with chronic atrial fibrillation, Digoxin slows rapid ventricular response rate in a linear dose-response fashion from 0.25 to 0.75 mg/day. Digoxin should not be used for the treatment of multifocal atrial tachycardia.

Indications and Usage for Digoxin

Heart Failure

Digoxin is indicated for the treatment of mild to moderate heart failure. Digoxin increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by exercise capacity and heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, Digoxin should be used with a diuretic and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified.

Atrial Fibrillation

Digoxin is indicated for the control of ventricular response rate in patients with chronic atrial fibrillation.

Contraindications

Digitalis glycosides are contraindicated in patients with ventricular fibrillation or in patients with a known hypersensitivity to Digoxin. A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to Digoxin.

Warnings

Sinus Node Disease and AV Block

Because Digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. The drug may cause severe sinus bradycardia or sinoatrial block in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. In such patients consideration should be given to the insertion of a pacemaker before treatment with Digoxin.

Accessory AV Pathway (Wolff-Parkinson-White Syndrome)

After intravenous Digoxin therapy, some patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation. Unless conduction down the accessory pathway has been blocked (either pharmacologically or by surgery), Digoxin should not be used in such patients. The treatment of paroxysmal supraventricular tachycardia in such patients is usually direct-current cardioversion.

Use in Patients with Preserved Left Ventricular Systolic Function

Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may be particularly susceptible to toxicity of the drug. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of Digoxin.

Precautions

Use in Patients with Impaired Renal Function

Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of Digoxin (see DOSAGE AND ADMINISTRATION). Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of Digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function.

Use in Patients with Electrolyte Disorders

In patients with hypokalemia or hypomagnesemia, toxicity may occur despite serum Digoxin concentrations below 2 ng/mL, because potassium or magnesium depletion sensitizes the myocardium to Digoxin. Therefore, it is desirable to maintain normal serum potassium and magnesium concentrations in patients being treated with Digoxin. Deficiencies of these electrolytes may result from malnutrition, diarrhea, or prolonged vomiting, as well as the use of the following drugs or procedures: diuretics, amphotericin B, corticosteroids, antacids, dialysis, and mechanical suction of gastrointestinal secretions.

Hypercalcemia from any cause predisposes the patient to digitalis toxicity. Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. On the other hand, hypocalcemia can nullify the effects of Digoxin in humans; thus, Digoxin may be ineffective until serum calcium is restored to normal. These interactions are related to the fact that Digoxin affects contractility and excitability of the heart in a manner similar to that of calcium.

Use in Thyroid Disorders and Hypermetabolic States

Hypothyroidism may reduce the requirements for Digoxin. Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly resistant to Digoxin treatment. Care must be taken to avoid toxicity if Digoxin is used.

Use in Patients with Acute Myocardial Infarction

Digoxin should be used with caution in patients with acute myocardial infarction. The use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand and ischemia.

Use During Electrical Cardioversion

It may be desirable to reduce the dose of Digoxin for 1 to 2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequences of increasing the ventricular response if Digoxin is withdrawn. If digitalis toxicity is suspected, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias.

Laboratory Test Monitoring

Patients receiving Digoxin should have their serum electrolytes and renal function (serum creatinine concentrations) assessed periodically; the frequency of assessments will depend on the clinical setting. For discussion of serum Digoxin concentrations, see DOSAGE AND ADMINISTRATION.

Drug Interactions

Potassium-depleting diuretics are a major contributing factor to digitalis toxicity. Calcium, particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone raise the serum Digoxin concentration due to a reduction in clearance and/or in volume of distribution of the drug, with the implication that digitalis intoxication may result. Erythromycin and clarithromycin (and possibly other macrolide antibiotics) andtetracycline may increase Digoxin absorption in patients who inactivate Digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication may result. Propantheline and diphenoxylate, by decreasing gut motility, may increase Digoxin absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs, and metoclopramide may interfere with intestinal Digoxin absorption, resulting in unexpectedly low serum concentrations. Rifampinmay decrease serum Digoxin concentration, especially in patients with renal dysfunction, by increasing the non-renal clearance of Digoxin. There have been inconsistent reports regarding the effects of other drugs (e.g., quinine, penicillamine) on serum Digoxin concentration. Thyroid administration to a digitalized, hypothyroid patient may increase the dose requirement of Digoxin. Concomitant use of Digoxin and sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in digitalized patients. Although beta-adrenergic blockers or calcium channel blockers and Digoxin may be useful in combination to control atrial fibrillation, their additive effects on AV node conduction can result in advanced or complete heart block.

Due to the considerable variability of these interactions, the dosage of Digoxin should be individualized when patients receive these medications concurrently. Furthermore, caution should be exercised when combining Digoxin with any drug that may cause a significant deterioration in renal function, since a decline in glomerular filtration or tubular secretion may impair the excretion of Digoxin.

Drug/Laboratory Test Interactions

The use of therapeutic doses of Digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There have been no long-term studies performed in animals to evaluate carcinogenic potential, nor have studies been conducted to assess the mutagenic potential of Digoxin or its potential to affect fertility.

Pregnancy

Animal reproduction studies have not been conducted with Digoxin. It is also not known whether Digoxin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Digoxin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Studies have shown that Digoxin concentrations in the mother’s serum and milk are similar. However, the estimated exposure of a nursing infant to Digoxin via breast feeding will be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when Digoxin is administered to a nursing woman.

Pediatric Use

Newborn infants display considerable variability in their tolerance to Digoxin. Premature and immature infants 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. Digitalis glycosides can cause poisoning in children due to accidental ingestion.

Geriatric Use

The majority of clinical experience gained with Digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).

Adverse Reactions

In general, the adverse reactions of Digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when Digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions.

Because some patients may be particularly susceptible to side effects with Digoxin, the dosage of the drug should always be selected carefully and adjusted as the clinical condition of the patient warrants. In the past, when high doses of Digoxin were used and little attention was paid to clinical status or concurrent medications, adverse reactions to Digoxin were more frequent and severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. However, available evidence suggests that the incidence and severity of Digoxin toxicity has decreased substantially in recent years. In recent controlled clinical trials, in patients with predominantly mild to moderate heart failure, the incidence of adverse experiences was comparable in patients taking Digoxin and in those taking placebo. In a large mortality trial, the incidence of hospitalization for suspected Digoxin toxicity was 2% in patients taking Digoxin tablets compared to 0.9% in patients taking placebo. In this trial, the most common manifestations of Digoxin toxicity included gastrointestinal and cardiac disturbances; CNS manifestations were less common.

Adults

Therapeutic doses of Digoxin may cause heart block in patients with pre-existing sinoatrial or AV conduction disorders; heart block can be avoided by adjusting the dose of Digoxin. Prophylactic use of a cardiac pacemaker may be considered if the risk of heart block is considered unacceptable. High doses of Digoxin may produce a variety of rhythm disturbances, such as first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation. Digoxin produces PR prolongation and ST segment depression which should not by themselves be considered Digoxin toxicity. Cardiac toxicity can also occur at therapeutic doses in patients who have conditions which may alter their sensitivity to Digoxin (see WARNINGS and PRECAUTIONS).

Digoxin may cause anorexia, nausea, vomiting, and diarrhea. Rarely, the use of Digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines.

Digoxin can produce visual disturbances (blurred or yellow vision), headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination).

Gynecomastia has been occasionally observed following the prolonged use of Digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed.

The following table summarizes the incidence of those adverse experiences listed above for patients treated with Digoxin tablets or placebo from two randomized, double-blind, placebo-controlled withdrawal trials. Patients in these trials were also receiving diuretics with or without angiotensin-converting enzyme inhibitors. These patients had been stable on Digoxin, and were randomized to Digoxin or placebo. The results shown in Table 4 reflect the experience in patients following dosage titration with the use of serum Digoxin concentrations and careful follow-up. These adverse experiences are consistent with results from a large, placebo-controlled mortality trial (DIG trial) wherein over half the patients were not receiving Digoxin prior to enrollment.