DIGOXIN Oral Solution, USP
50 mcg (0.05 mg) per mL

Rx only

Digoxin is one of the cardiac glycosides, a closely-related group of plant-derived drugs with shared pharmacological effects. The term "digitalis" is used to designate the whole group. Digoxin is extracted from the leaves of the common foxglove, Digitalis lanata. Like each of the other cardiac glycosides, digoxin consists of a polycyclic core and a sugar side chain. Digoxin’s chemical name is 3β-[0-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-0-2, 6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2, 6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-12β, 14-dihydroxy-5β-card-20(22)-enolide; its structural formula is:

Its molecular formula is C₄₁H₆₄O₁₄, and its molecular weight is 780.95. Digoxin is practically insoluble in water and in ether, slightly soluble in 50% ethanol and in chloroform, and freely soluble in pyridine. Digoxin powder consists of odorless white crystals.

Digoxin Oral Solution, USP is formulated for oral administration, and each mL contains 50 mcg (0.05 mg digoxin). The lime-flavored solution contains the following inactive ingredients: alcohol 10% (by volume at 60°F), glycerin, lime (imitation), methylparaben 0.1%, propylparaben 0.02%, purified water, sodium citrate, and sorbitol solution.

All of digoxin’s actions are mediated through its effects on NaK–ATPase. This enzyme, the “sodium pump,” is responsible for maintaining the intracellular milieu throughout the body by moving sodium ions out of and potassium ions into cells. By inhibiting NaK–ATPase, digoxin

• causes increased availability of intracellular calcium in the myocardium and conduction system, with consequent increased inotropy, increased automaticity, and reduced conduction velocity;
• indirectly causes parasympathetic stimulation of the autonomic nervous system, with consequent effects on the sino-atrial (SA) and atrioventricular (AV) nodes;
• reduces catecholamine reuptake at nerve terminals, rendering blood vessels more sensitive to endogenous or exogenous catecholamines;
• increases baroreceptor sensitization, with consequent increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increment in mean arterial pressure;
• increases (at higher concentrations) sympathetic outflow from the central nervous system (CNS) to both cardiac and peripheral sympathetic nerves; and
• allows (at higher concentrations) progressive efflux of intracellular potassium, with consequent increase in serum potassium levels.

The cardiologic consequences of these direct and indirect effects are an increase in the force and velocity of myocardial systolic contraction (positive inotropic action), a slowing of the heart rate (negative chronotropic effect), and decreased conduction velocity through the AV node.

In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggested that one in ten patients treated with digoxin will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. The magnitude of rise in serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as two-fold in some cases.

Digoxin Oral Solution, USP 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.

Digoxin increases myocardial contractility in children with congestive heart failure.

Digoxin Oral Solution, USP is indicated for the control of resting ventricular response rate in patients with chronic atrial fibrillation.

There are no controlled randomized studies of digoxin in children with atrial tachyarrhythmias.

Allergy to digoxin is rare. In such patients (who may or may not have similar reactions to other forms of digitalis), the use of digoxin is contraindicated. Digitalis glycosides are contraindicated in ventricular fibrillation.

Patients with Wolff-Parkinson-White syndrome who develop atrial fibrillation are at high risk of ventricular fibrillation. Treatment of these patients with digoxin leads to greater slowing of conduction in the atrioventricular node than in accessory pathways, and the risks of rapid ventricular response leading to ventricular fibrillation are thereby increased.

By slowing conduction in nodal tissue, digoxin administration can exacerbate Sick Sinus Syndrome and can cause a greater degree of atrioventricular block.

Some signs and symptoms (anorexia, nausea, vomiting, and certain arrhythmias) can equally result from digoxin toxicity as from congestive heart failure. Misidentification of their etiology might lead the clinician to continue or increase digoxin dosing, when dosing should actually be suspended. When the etiology of these signs and symptoms is not obvious, measurement of serum digoxin levels may be helpful.

In patients with hypertrophic cardiomyopathy (formerly called idiopathic hypertrophic subaortic stenosis), the positive inotropic effect of digoxin leads to an increased subvalvular outflow gradient. Digoxin is rarely beneficial in patients with this condition.

Chronic constrictive pericarditis is not generally associated with any inotropic defect, so heart failure of this etiology is unlikely to respond to treatment with digoxin. By slowing the resting heart rate, digoxin may actually decrease cardiac output in these patients.

Patients with amyloid heart disease may be more susceptible to toxicity from digoxin.

Digoxin is of limited value in patients with restrictive cardiomyopathies, although it has been used for rate control in the subgroup of patients with atrial fibrillation.

Even at serum levels of digoxin within the conventional therapeutic range (0.5 to 2 ng/mL), the risk of digoxin toxicity is increased by hypokalemia. Serum potassium levels should be carefully monitored when digoxin is given to patients at high risk of hypokalemia (e.g., those receiving diuretics, corticosteroids, or other drugs that commonly lead to potassium loss; those with gastrointestinal losses through diarrhea, vomiting, or nasogastric suction; or those with potassium-losing endocrinopathies or nephropathies).

Digoxin toxicity is also more likely in the presence of hypomagnesemia. Hypomagnesemia is common in most of the same conditions in which hypokalemia appears. It is also commonly seen in alcoholics and in patients with diabetes mellitus or hypercalcemia.

Because digoxin’s therapeutic and toxic effects are all largely mediated by intracellular calcium distribution, they are affected by abnormalities in serum calcium levels. Hypercalcemia increases the risk of digoxin toxicity, while digoxin may be therapeutically ineffective in the presence of hypocalcemia.

Reduction of digoxin dosage may be desirable prior to electrical cardioversion to avoid induction of ventricular arrhythmias, but the physician must consider the consequences of a rapid increase in ventricular response to atrial fibrillation if digoxin is withheld 1 to 2 days prior to cardioversion. If there is a suspicion that digitalis toxicity exists, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the energy level selected should be minimal at first and carefully increased in an attempt to avoid precipitating ventricular arrhythmias.

Atrial arrhythmias associated with hypermetabolic states (e.g., hyperthyroidism) are particularly resistant to digoxin treatment. Large doses of digoxin are not recommended as the only treatment of these arrhythmias and care must be taken to avoid toxicity if large doses of digoxin are required. In hypothyroidism, the digoxin requirements are reduced. Digoxin responses are normal in patients with compensated thyroid disease.

At normal heart rates, therapeutic levels of digoxin are associated with characteristic “scooping” changes in the S–T segment of the electrocardiogram; these changes are unlikely to be misinterpreted. During exercise, however, the same serum levels of digoxin can lead to changes that may be indistinguishable from those of ischemia.

Assays of serum digoxin levels are described in CLINICAL PHARMACOLOGY, and their use in patient monitoring is described in DOSAGE AND ADMINISTRATION.

Drugs that induce/inhibit P-glycoprotein in intestine or kidney have the potential to alter digoxin pharmacokinetics.

There have been no long-term studies performed in animals to evaluate carcinogenic potential.

Digoxin levels in human milk are lower than those in maternal serum. A human infant ingesting plausible quantities of such milk will receive much less than therapeutic doses of digoxin, even when the mother’s levels are well into the toxic range.

Clinical studies of digoxin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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, and it may be useful to monitor renal function.

Digoxin increases myocardial contractility in children with congestive heart failure. There are no controlled randomized studies of digoxin in children with atrial tachyarrhythmias. See: CLINICAL PHARMACOLOGY: Clinical Trials, INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.

The frequency and severity of adverse reactions to digoxin depend on the dose and route of administration, as well as on the patient's underlying disease or concomitant therapies (see PRECAUTIONS). The overall incidence of adverse reactions has been reported as 5 to 20%, with 15 to 20% of them being considered serious (one to four percent of patients receiving digoxin). Evidence suggests that the incidence of toxicity has decreased since the introduction of the serum digoxin assay and improved standardization of digoxin tablets. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions.

Conduction disturbances or supraventricular tachyarrhythmias, such as atrioventricular (AV) block, atrial tachycardia with or without block and junctional (nodal) tachycardia are the most common arrhythmias associated with digoxin toxicity in children. Ventricular arrhythmias, such as unifocal or multiform ventricular premature contractions, especially in bigeminal or trigeminal patterns, are less common. Ventricular tachycardia may result from digitalis toxicity. Sinus bradycardia may also be a sign of impending digoxin intoxication, especially in infants, even in the absence of first degree heart block. Any arrhythmias or alteration in cardiac conduction that develops in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication.

Anorexia, nausea, vomiting and diarrhea may be early symptoms of overdosage. However, uncontrolled heart failure may also produce such symptoms.

Visual disturbances (blurred or yellow vision), headache, weakness, apathy and psychosis can occur. These may be difficult to recognize in infants and children. In one reported case, asymmetric chorea was seen at high digoxin levels, and reappeared when similar levels were inadvertently re-achieved.

Gynecomastia is occasionally observed.

Digoxin should be discontinued until all signs of toxicity are gone. Discontinuation may be all that is necessary if toxic manifestations are not severe and appear only near the expected time for maximum effect of the drug.

Potassium salts may be used, particularly if hypokalemia is present. Potassium chloride in divided oral doses totaling 1 to 1.5 mEq K⁺ per kilogram (kg) body weight may be given provided renal function is adequate (1 gram of potassium chloride contains 13.4 mEq K⁺). When correction of the arrhythmia with potassium is urgent and the serum potassium concentration is low or normal, approximately 0.5 mEq/kg of potassium per hour may be given intravenously in 5% dextrose injection. The intravenous solution of potassium should be dilute enough to avoid local irritation; however, especially in infants care must be taken to avoid intravenous fluid overload. ECG monitoring should be performed to watch for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. The infusion may be stopped when the desired effect is achieved.

Note: Potassium should not be used and may be dangerous in heart block due to digoxin, unless primarily related to supraventricular tachycardia.

Because of its large extravascular volume of distribution, digoxin is not effectively removed from the body by dialysis, by exchange transfusion, or during cardiopulmonary bypass.

Multiple doses of activated charcoal have been found effective in at least 1 case report, and may be of use while the need for and availability of digoxin specific antibody fragments are being assessed. In advanced heart block, temporary ventricular pacing may be beneficial.

Digoxin Immune Fab (Ovine) [DIGIBIND®, DIGIFAB®] may be indicated for the treatment of patients with life-threatening or potentially life-threatening digoxin toxicity or overdose.

Because the pharmacokinetics of digoxin are complex, and because toxic levels of digoxin are only slightly higher than therapeutic levels, digoxin dosing can be difficult. The recommended approach is to

• estimate the patient’s daily maintenance dose;
• adjust the estimate to account for patient-specific factors;
• choose a dosing regimen;
• monitor the patient for toxicity and for therapeutic effect, if possible; and
• adjust the dose.

These doses will, in uncomplicated patients, tend to produce steady-state post-absorptive levels of 1 to 2 ng/mL, but the confidence limits around this range are wide.

As noted in CLINICAL PHARMACOLOGY, Pharmacokinetics and in WARNINGS: Drug Interactions, the body’s handling of digoxin can be affected by many different patient-specific factors. Some of the possible effects are usually small, so anticipatory dose adjustment might not be required, but others should be considered before initial dosing. Patients with abnormal renal function need to have their doses of digoxin proportionately reduced. Normal developmental changes in pediatric renal function were factored into the table given in the previous subsection, but age-related (or other) changes in adult renal function were not. The effects of renal function on recommended digoxin doses in adults is shown in Table 3 below. For children with known or suspected renal dysfunction, lower starting doses should be considered combined with frequent monitoring of digoxin levels.

Digoxin’s volume of distribution is proportional to lean body weight, and the table in the previous section assumes that patients are of average composition. The dose of digoxin must be reduced in patients whose lean body weight is — typically because of obesity or edema — an abnormally small fraction of their total body mass.

Concomitant drug use should be considered when adjusting the estimated digoxin dose (see PRECAUTIONS: Drug Interactions).

NOTE: The calibrated dropper supplied with the 60 mL bottle of digoxin oral solution is not appropriate to measure doses below 0.2 mL. Doses less than 0.2 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient.

Table 3 provides average daily maintenance dose requirements of digoxin for patients with heart failure based upon lean body weight and renal function.

On the left side of the chart, locate the patient’s weight in kilograms. At the top of the chart, identify which dose in mcg/kg/day will be used for this patient. The block on the chart at which the two rows (weight and target dose) intersect is the milliliter amount that should be given to the patient.

Dosing as described above may need to be increased or decreased, depending upon the patient’s response, so patients must be monitored for signs of efficacy and toxicity.

When the purpose of digoxin therapy is reduction of resting ventricular response to atrial tachyarrhythmia, a therapeutic digoxin effect may be obvious. In other settings, however, the therapeutic effect of digoxin may be difficult to separate from other developments in the course of the underlying disease.

Similarly, digoxin toxicity may be easily identified when there are pathognomonic findings of new atrioventricular block, or of yellow/green discoloration of vision. Other manifestations of digoxin toxicity (e.g., nausea) might have alternative explanations, and symptoms of toxicity may be difficult to evaluate in small children and other inarticulate patients. It will therefore often be necessary to monitor digoxin therapy by means of serum digoxin levels.

Because hypokalemia or hypomagnesia can greatly increase the risk of digoxin toxicity, it is appropriate to monitor these levels whenever digoxin levels are measured. These assays are widely available.

Digoxin should be allowed to distribute into its volume of distribution before measurement, so specimens for these assays should not be collected until 6 to 8 hours after the time of administration. In general, serum levels below 0.5 ng/mL are unlikely to be beneficial, while levels above 2 ng/mL are associated with increased toxicity without increased benefit. Within the 0.5 to 2 ng/mL range, the inotropic effects of digoxin tend to appear at lower concentrations than the electrophysiological effects.

When decision-making is to be guided by serum digoxin levels, the clinician must consider the possibility of reported concentrations that have been falsely elevated by endogenous digoxin-like immunoreactive substances (see CLINICAL PHARMACOLOGY: Assays). If the assay being used is sensitive to these substances, it may be prudent to obtain a baseline measurement before digoxin therapy is started, and correct later values by the reported baseline level.

The monitoring described above may suggest increases or decreases in digoxin doses. Additional monitoring, and in some cases anticipatory dose adjustment, may be indicated around the time of various changes in the patient’s internal milieu, including

• normal development through childhood;
• concomitant drug use should be considered when adjusting the estimated digoxin dose (see PRECAUTIONS: Drug Interactions);
• new co-administration of an antibiotic, especially if the patient had required high doses of digoxin in order to achieve modest serum concentrations, raising the suspicion that a substantial fraction of administered digoxin was being destroyed by colonic bacteria; and
• changes in renal function (see Table 3 above).

Digoxin Oral Solution, USP [50 mcg (0.05 mg) per mL] is available in two forms of packaging: as unit-dose Patient Cups™ and as bottles with child-resistant closures. Once open, the bottles are used with graduated droppers provided in the carton. Starting at 0.2 mL, this 1 mL dropper is marked in divisions of 0.1 mL, corresponding to 5 mcg or 0.005 mg of digoxin.

Each bottle contains 60 mL of solution (3 mg of digoxin), and Patient Cups are each filled to deliver 2.5 mL of solution (0.125 mg of digoxin) or 5 mL of solution (0.25 mg of digoxin). There are 10 Patient Cups in each shelf pack, and 4 shelf packs in each shipping package. The National Drug Code designations of the various packages are

NDC 0054-0057-16 2.5 mL Patient Cups

NDC 0054-0057-55 5 mL Patient Cups

NDC 0054-0057-46 60 mL bottle

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] and protect from light.

10001143/02

Rev March 2005

© RLI, 2005