Lanoxin®


(digoxin)
Tablets

125 g (0.125 mg) Scored I.D. Imprint Y3B (yellow)
250 g (0.25 mg) Scored I.D. Imprint X3A (white)
500 g (0.5 mg) Scored I.D. Imprint T9A (green)

DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED

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 levels of Digitalis lanata. The term "digitalis" is used to designate the whole group. The glycosides are composed of two portions: a sugar and cardenolide (hence "glycosides").

Digoxin has the molecular formula C41H64O14, a molecular weight of 780.95 and melting and decomposition points above 235oC. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chlorform; and freely soluble in pyridine. Digoxin powder is composed of odorless white crystals.

Digoxin has the chemical name: (3Beta,5B,12B)-3-[(0-2,6-dideoxy-B-D-ribo-hexopyranosyl-(1 to 4)-0- 2,6-dideoxy-B-D-ribo-hexopyranosyl-(1 to 4)-2,6 dideoxy-B D-ribo-hexopyranosyl)oxy]-12,14-dihydroxycard-20(22)-enolide, and the structure shown:

LANOXIN tablets with 125 g (0.125 mg) 250 g (0.25 mg) or 500 g (0.5 mg) digoxin USP are intended for oral use. Each tablet contains the labeled amount of digoxin USP and the inactive ingredients: 0.125 mg tablet-corn and potato starch, D&C Yellow No. 10, FD&C Yellow No.6, lactose , and magnesium stearate; 0.25 mg tablet corn and potato starch lactose, magnesium stearate, and steric acid; 0.5 mg tablet corn and potato starch, D&C Green No.5, and Yellow No.10, FD&C Red No.40, lactose, magnesium stearate, and stearic acid.

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CLINICAL PHARMACOLOGY

Mechanism of Action: The influence of digitalis glycosides on the myocardium is dose-related, and involves both a direct action on cardiac muscle and the specialized conduction system and indirect actions on the cardiovascular system medicated by the autonomic nervous system. The indirect actions mediated by the autonomic nervous system involve a vagomimetic action, which is responsible for the effects of digitalis on the sino-atrial (SA) and atrioventricular (AV) nodes; and also baroreceptor sensitization which results in increased carotid sinus nerve activity and enhanced sympathetic withdrawal 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 slowing of heart rate (negative chronotropic effect); and 3) decreased conduction velocity through the AV node. In higher doses, digitalis increases sympathetic outflow from the central nervous system (CNS) to both cardiac and peripheral sympathetic nerves. This increase in sympathetic activity may be an important factor in digitalis cardiac toxicity. Most of the extracardiac manifestations of digitalis toxicity are also mediated by the CNS.

Pharmacokinetics:
Absorption: Gastrointestinal absorption of digoxin is a passive process. Absorption of dioxin from the LANOXIN tablet formulation has been demonstrated to be 60% to 80% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When digoxin tablets are taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Comparison of the systemic availability and equivalent doses for digoxin preparations are shown in the following table:


PRODUCT ABSOLUTE BIOAVAILABILITY EQUIVALENT DOSES (IN MG)*
LANOXIN® Tablets 60-80% 0.125 0.25 0.5 LANOXIN Elixir 70-85% 0.125 0.25 0.5 LANOXIN Injection/I.M. 70-85% 0.125 0.25 0.5 LANOXIN Injection I.V. 100% 0.1 0.2 0.4 LANOXICAPS® Capsules 90-100% 0.1 0.2 0.4
*1 mg =1000 g

In some patients, orally administered digoxin is converted to cardioinactive reduction products (e.g dihydrodigoxin) by colonic bacteria in the gut. Data suggest that one in ten patients treated with digoxin tablets will degrade 40% or more of the ingested dose.

Distribution: Following drug administration, a 6 to 8 hour distribution phase is observed. This is followed by a much more gradual serum concentration decline, which is dependent on digoxin elimination 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 levels are in equilibrium with tissue levels and correlate with pharmacologic effects. In individual patients, these post distrubution serum concentrations are linearly related to maintenance dosage and maybe 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, serum digoxin concentration in the newborn is similar to the serum level in the mother. Approximately 20% to 25% of plasma digoxin 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 (ideal) body weight, not total body weight.

Pharmacologic Response: The approximate times to onset of effect and to peak effect of all the LANOXIN preparations are given in the following table:


PRODUCT TIME ON ONSET OF EFFECT* TIME TO PEAK EFFECT*
LANOXIN® Tablets 0.5 to 2 hours 2 to 6 hours LANOXIN Elixir 0.5 to 2 hours 2 to 6 hours LANOXIN Injection/I.M. 0.5 to 2 hours 2 to 6 hours LANOXIN Injection/I.V. 5 to 30 minutesT 1 to 4 hours LANOXICAPS® Capsules 0.5 to 2 hours 2 to 6 hours
*Documented for ventricular response rate in atrial fibrillation, inotropic effect and electrocardiographic changes. TDepending upon rate of infusion.

Excretion: 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 normal subjects, 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 subjects with normal renal function, digoxin has a half-life of 1.5 to 2.0 days. The half-life in anuric patients is prolonged to 4 to 6 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion or during cardiopulmonary by-pass because most of the drug is in tissue rather than circulating in the blood.

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INDICATIONS AND USAGE

Heart Failure: The increased cardiac output resulting from the inotropic action of digoxin ameliorates the disturbances characteristic of heart failure (venous congestion, edema, dyspnea, orthopnea and cardiac asthma).

Digoxin is more effective in "low output" (pump) failure than in "high output" heart failure secondary to arteriovenous fistula, anemia, infection or hyperthyroidsm.

Digoxin is usually continued after failure is controlled, unless some known precipitating factor is corrected. Studies have shown, however that even though hemodynamic effects can be demonstrated in almost all patients, corresponding improvement in the signs and symptoms of heart failure is not necessarily apparent. Therefore, in patients in whom digoxin may be difficult to regulate, or in whom the risk of toxicity may be great (e.g patients with unstable renal function or whose potassium levels tend to fluctuate) a cautious withdrawal of digoxin may be considered. If digoxin is discontinued, the patient should be regularly monitored for clinical evidence of recurrent heart failure.

Atrial Fibraillation: Digoxin reduced ventricular rate and thereby improves hemodynamics. Palpitation, precorring distress or weakness are relieved and concomitant congestive failure ameliorated. Digoxin should be continued in doses necessary to maintain the desired ventricular rate.

Atrial Flutter: Digoxin slows the heart and regular sinus rhythm may appear. Frequently the flutter is converted to atrial fibrillation with controlled ventricular response. Digoxin treatment should be maintained if atrial fibrillation persists. (Electrical cardioversion is often the treatment of choice for atrial flutter. See discussion of cardioversion in PRECAUTIONS.)

Paroxysmal Atrial Tachycardia (PAT): Digoxin may convert PAT to sinus rhythm by slowing conduction through the AV node. If heart failure has ensued or paroxyms recur frequently, digoxin should be continued. In infants, digoxin is usually continued for 3 to 6 months after a single episode of PAT to prevent recurrence.

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CONTRAINDICATIONS

Digitalis glycosides are contraindicated in ventricular fibrillation.

In a given patient, an untoward effect requiring permanent discontinuation of other digitalis preparations usually constitutes a contraindication to digoxin. Hypersensitivity to digoxin itself is a contraindictation to its use. Allergy to dioxin, though rare, does occur. It may not extend to all such preparations, and another digitalis glycoside may be tried with caution.

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WARNINGS

Digitalis alone or with other drugs has been used in the treatment of obesity. This use of digoxin or other digitalis glycosides is unwarranted. Moreover, since they may cause potentially fatal arrhythmias or other adverse effects, the use of these drugs solely for the treatment of obesity is dangerous.

Anorexia, nausea, vomiting and arrhythmias may accompany heart failure or may be indications of digitalis intoxication. Clinical evaluation of the cause of these symptoms should be attempted before further digitalis administration. In such circumstances determination of the serum digoxin concentration may be an aid in deciding whether or not digitalis toxicity is likely to be present. If the possibility of digitalis intoxication cannot be excluded, cardiac glycosides should be temporarily withheld, if permitted by the clinical situation.

Patients with renal insufficiency require smaller than usual maintenance doses of digoxin (see DOSAGE AND ADMINISTRATION).

Heart failure accompanying acute glomerulonephritis requires extreme care in digitalization. Relatively low loading and maintenance doses and concomitant use of antihypertensive drugs may be necessary and careful monitoring is essential. Digoxin should be discontinued as soon as possible.

Patients with severe carditis, such as carditis associated with rheumatic fever or viral myocarditis, are especially sensitive to digoxin-induced disturbances of rhythm.

Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive, and dosage must not only be reduced but must be individualized according to their degree of maturity.

Note: Digitalis glycosides are an important cause of accidental poisoning in children.

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PRECAUTIONS

General: Digoxin toxcity develops more frequently and lasts longer in patients with renal impairment because of the decreased excretion of digoxin. Therefore, it should be anticipated that dosage requirements will be decreased in patients with moderate to severe renal disease (see DOSAGE AND ADMINISTRATION). Because of the prolonged half-life, a longer period of time is required to achieve an initial or new steady-state concentration in patients with renal impairment than in patients with normal renal function.

Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Hypercalcemia from any cause predisposes the patient to digitalis toxcity. 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 calcium affects contractility and excitability of the heart in a manner similar to digoxin.

Hypomagnesemia may predispose to digitalis toxicity. If low magnesium levels are detected in a patient on digoxin, replacement therapy should be instituted

Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, and alprazolam may cause a rise in serum digoxin concentration, with the implication that digitalis intoxication may result. This rise appears to be proportional to the dose. The effect is mediated by a reduction in the digoxin clearance and, in the case of quinidine, decreased volume of distribution as well.

Tectracycline and erythromycin (and possibly other macrolide antibiotics) may increase digoxin absorption in patients who convert digoxin to inactive metabolites in the gut (see CLINICAL PHARMACOLOGY: Pharmacokinetics). Recent studies have shown that specific colonic bacteria in the lower gastrointestinal tract convert digoxin to cardioinactive reduction products, thereby reducing its bioavailability. Although inactivation of these bacteria by antibiotics is rapid, the serum digoxin concentration will rise at a rate consistent with the elimination half-life of digoxin. The magnitude of rise of serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as two-fold in some cases.

Patients with acute myocardial infarction or severe pulmonary disease may be unusually sensitive to dogoxin-induced disturbances of rhythm.

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 hypothyroidsm, the digoxin requirements are reduced. Digoxin responses in patients with compensated thyroid disease are normal.

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 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.

Incomplete AV block, especially in patients with Stokes-Adams attacks, may progress to advanced or complete heart block if digoxin is given.

In some patients with sinus node disease (i.e. Sick Sinus Syndrome) digoxin may worsen sinus bradycardia or sinoatrial block.

In patients with Wolff-Parkinson-White Syndrome and atrial fibrillation, digoxin can enhance transmission of impulses through the accessory pathway. This effect may result in extremely rapid ventricular rates and even ventriucular fibrillation.

Digoxin may worsen the outflow obstruction in patients with idiopathic hypertrophic subaortic stenosis (IHSS). Unless cardiac failure is severe, it is doubtful whether digoxin should be employed.

Patients with chronic constrictive pericarditis may fail to respond to digoxin. In addition, slowing of the heart rate by digoxin in some patients may further decrease cardiac output.

Patients with heart failure from amyloid heart disease or constrictive cardiomyopathies respond poorly to treatment with digoxin.

Digoxin is is not indicated for the treatment of sinus tachycardia unless it is associated with heart failure.

Digoxin may produce false positive ST-T changes in the electrocardiogram during exercise testing.

Intramuscular injection of digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.

Laboratory Tests: Patients receiving digoxin should have their serum electrolytes and renal function(BUN and/or serum creatinine) 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 corticosteroids and diuretics may be major contributing factors 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, and alprazolam may cause a rise in serum digoxin concentration, with the implication that digitalis intoxication may result. Serum levels of digoxin may be increased by concomitant administration of tetracycline and erythromycin (and possibly other macrolide antibiotics). Propantheline and diphenoxylate, by decreasing gut motility, may increase digoxin absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs, and metoclopramide may reduce intestinal digoxin absorption, resulting in unexpectedly low serum concentrations. There have been inconsistent reports regarding the effects of other drugs on the 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 because both enhance ectopic pacemaker activity. 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 complete heart block.

Due to the considerable variability of these interactions, digoxin should be carefully individualized when patients receive coadministered medications. Furthermore, caution should be exercised when combining digoxin with any drug that may cause a significant deterioration in renal function, since this may impair the excretion of digoxin.

Carcinogenesis, Mutagenesis, Impairment of Fertility: There have been no long-term studies performed in animals to evaluate carcinogenic potential.

Pregnancy: Teratogenic Effects: Pregnancy Category C. 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 daily dose to a nursing infant 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.

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ADVERSE REACTIONS

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 and DOSAGE AND ADMINISTRATION: (Serum Digoxin Concentrations). 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.

Adults:
Cardiac: Unifocal or multiform ventricular premature contraction, especially in bigeminal or trigeminal patters, are the most common arrhythmias associated with digoxin toxicity in adults with heart disease.

Ventricular tachycardia may result from digitalis toxicity. Atrioventricular (AV) dissociation, accelerated junctional (nodal) rhythm and atrial tachycardia with block are also common arrhythmias caused by digoxin overdosage.

Excessive slowing of the pulse is a clinical sign of digoxin overdosage. AV block (Wenckebach) of increasing degree may proceed to complete heart block.

Note: The electrocardiogram is fundamental in determining the presence and nature of these cardiac disturbances. Digoxin may also induce other charges in the ECG (e.g. PR prolongation, ST depression), which represent digoxin effect and may or may not be associated with digitalis toxicity.

Gastrointestinal: Anorexia, nausea, vomiting and less commonly diarrhea are common early symptoms of overdosage. However, uncontrolled heart failure may also produce such symptoms. Digitalis toxicity very rarely may cause abdominal pain and hemmorrhagic necrosis of the intestines.

CNS: Visual disturbances (blurred or yellow vision), headache, weakness, dizziness, apathy and psychosis occur.

Other: Gynecomastia is occasionally observed. Maculopapular rash or other skin reactions are rarely observed.

Infants and Children: Toxicity differs from the adult in a number of respects. Anorexia, nausea, vomiting, diarrhea and CNS disturbances may be present but are rare as initial symptoms in infants. Cardiac arrhythmias are more reliable signs of toxcicty. Digoxin in children may produce any arrhythmia. The most commonly encountered are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia with or without block, and junctional (nodal) tachycardia. Ventricular arrhythmias are less commmon. Sinus bradycardia may also be a sign of impending digoxin intoxication, especially in infants, even in the absence of first degree heart block. Any arrhythmia or alteration in cardiac conduction that developes in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication.

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OVERDOSAGE

Treatment of Arrhythmias Produced by overdosage:
Adults: 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.

Correction of factors that may contribute to toxicity such as electrolyte distrubances, hypoxia, acid-base distrubances and removal of aggravating agents such as catecholamines, should also be considered. Potassium salts may be indicated, particularly if hypokalemia is present. Potassium administration may be dangerious in the setting of massive digitalis over dosage (see Massive Digitalis Overdosage subsection below). Potassium chloride in divided oral doses totaling 3 to 6 grams of the salt (40 to 80mEq K+) for adults may be given provided renal function is adequate (see infants and Children subsection below for potassium recommendations).

When correction of the arrhythmia is urgent and the serum potassium concentration is low or normal, potassium should be administered intravenously in 5% dextrose injection. For adults, a total of 40 to 80 mEq (diluted to a concentration of 40mEq per kmL) may be given at a rate not exceeding 20 mEq per hour, or slower if limited by pain due to a local irritation. Additional amounts may be given if the arrhythmia is uncontrolled and potassium well-tolerated. 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.

Other agents that have been used for the treatment of digoxin intoxication include lidocaine, procainamide, propranolol, and phenytoin, although use of the latter must be considered experimental. In advanced heart block, atropine and/or temporary ventricular pacing may be beneficial. DIGIBIND®, Digoxin Immune Fab (Ovine), can be used to reverse potentially life- threatining digoxin (or digitoxin) intoxication. Improvement in sign and symtoms of digitalis toxicty usually begins within 1/2 hour of DIGIBIND® administration. Each 38 mg vial of DIGIBIND® will neutralize 0.5 mg of digoxin (which is a usual body store of an adequately digitalized 70 kg patient).

Infants and Children: See Adults section for general recommendations for the treatment of arrhythmias produced by overdosage and for cautions regarding the use of potassium.

If a potassium preparation is used to treat toxicity, it may be given orally in divided doses totaling 1 to 1.5 mEq K+ per kilogram (kg) body weight (1 gram of potassium chloride contains 13.4 mEq K+).

When correction of the arrhythmia with potassium is urgent, approximately 0.56 mEq/Kg of potassium per hour may be given intravenously, with careful ECG monitoring. 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.

Massive Digitalis Overdosage: Manifestations of life-threatening toxicity include severe ventricular arrhythmias such as ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias such as severe sinus bradycardia or second or third degree heart block not responsive to atropine. An overdosage of more than 10 mg of digoxin in previously healthy adults or 4 mg in previously healthy children or overdosage resulting in steady-state serum concentrations greater than 10 ng/mL, often results in cardiac arrest.

Severe digitalis intoxication can cause life-threatening elevation in serum potassium concentrations by shifting potassium for inside to outside the cell resulting in hyperkalemia. Administration of potassium supplements in the setting of massive intoxication may be hazardous.

DIGIBIND®, Digoxin Immune Fab (Ovine), may be used at a dose equimolar to digoxin in the body to reverse the effects of ingestion of a massive overdose. The decision to administer DIGIBIND® before the onset of toxic manifestations will depend on the likelihood that life-threatening toxicity will occur (see above).

Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation. Emesis or gastric lavage may be indicated especially if ingestion has occurred within 30 minutes of patient's presentation at the hospital. Emesis should not be induced in patients who are obtunded. If a patient presents more than 2 hours after ingestion or already has toxic manifestation, it may be unsafe to induce vomiting or attempt passage of a gastric tube, because such maneuvers may induce an acute vaginal episode that can worsen digitalis-toxic arrhythmias.

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DOSAGE AND ADMINISTRATION

Recommended dosages are average values that may require considerable modification because of individual sensitivity or associated conditions. Diminished renal function is the most important factor requiring modification of recommended doses.

In deciding the dose of digoxin, several factors must be considered:
1. The disease being treated. Atrial arrhythmias may require larger doses than heart failure.
2. The body weight of the patient. Doses should be calculated based upon lean or ideal body weight.
3. The patient's renal function, preferably evaluated on the basis of creatinine clearance.
4 Age is an important factor in infants and children.
5. Concomitant disease states, drugs or other factors likely to alter the expected clinical response to digoxin (see PRECAUTIONS and Drug interactions subsection).

Digitalization may be accomplished by either of two general approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount of digoxin accumulated in the body.

1. Rapid digitalization may be achieved by administering a loading dose based upon projected peak body dioxin then calculating the maintenance dose as a percentage of the loading dose.
2. More gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing dioxgoxin body stores to accumulate slowly. Stead-state serum digoxin concentrations will be achieved in approximately 5 half-lives of the drug for the individual patient. Depending upon the patient's renal function, this will take between one and three weeks.

Adults: Rapid Digitalization with a Loading Dose: Peak body digoxin stores of 8 to 12 g/kg should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Larger stores (10 to 15 are often required for adequate control of ventricular rate in patients with atrial flutter or fibrillation. Because of altered digoxin distrubution and elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e, 6 to 10 g/kg) (see PRECAUTIONS).

The loading dose should be based on the projected peak body stores and administered in several portions with roughly half the total given as the first dose. Additional fraction of this planned total dose may be given at 6 to 8 hour intervals with careful assessment of clinical response before each additional dose.

If the patient's clinical response necessitates a change from the calculated dose of digoxin, then the calculation of the maintenance dose should be based on the amount actually given.

In previously undigitalized patients, a single initial LANOXIN Tablet dose of 500 to 750 g (0.5 to 0.75 mg) usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2 to 5 hours. Additional doses of 125 to 375 mg (0.125 to 0.375 mg) may be given cԉously at 6 to 8 hour intervals until clinical evidence of an adequate effect is noted. The usual amount of LANOXIN Tablets that a 70 kg patient requires to achieve 8 to 15 g/kg per peak body stores is 750 to 1250 g (0.75 to 1.25 mg).

Although peak body stores are mathematically related to loading doses and are utilized to calculate maintenance doses do not correlate with measured serum concentrations. This discrepancy is caused by digoxin distribution within the body during the first 6 to 8 hours following a dose. Serum concentrations drawn during this time are usually not interpretable.

The maintenance dose should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use:

Maintenance Dose=Peak Body Stores (i.e, Loading Doses) x % Daily Loss / 100

Where: % Daily Loss=14 + Ccr/5

Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body surface area. For adults, only if serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg body weight) may be estimated in men as 140- Age) /Scr. For women, this result should be a multiplied by 0.85.

Note: This equation cannot be used for estimating creatinine clearance in infants or children.

A common practice involves the use of LANOXIN injection to achieve rapid digitalization, with conversion to LANOXIN Tablets or Lanoxicaps for maintenance therapy. If patients are switched from intravenous to oral digoxin formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages (see table CLINICAL PHARMACOLOGY).

Adults: Gradual Digitalization with a Maintenance Dose: The following table provides average LANOXIN Tablet daily maintenance dose requirements for patients with heart failure based upon lean body weight and renal function:

Usual LANOXIN® Daily Maintenance Dose Requirements (g)
For Estimated Peak Body Stores of 10 g/kg


                             Lean Body Weight (kg/lbs)
               50/110   60/132   70/154   80/176   90/198  100/220

0 | 63*+ 125 125 125 188++ 188 | 22 10 | 125 125 125 188 188 188 | 19 Corrected 20 | 125 125 188 188 188 250 | 16 Ccr 30 | 125 188 188 188 250 250 | 14 # of (mL/min 40 | 125 188 188 250 250 250 | 13 Days per 70kg) 50 | 188 188 250 250 250 250 | 12 Before 60 | 188 188 250 250 250 375 | 11 Steady- 70 | 188 250 250 250 250 375 | 10 State 80 | 188 250 250 250 375 375 | 9 Achieved 90 | 188 250 250 250 375 500 | 8 100 | 250 250 250 375 375 500 | 7

*63 g=0.063 mg.
+1/2 of 125 g tablet or 125 g every other day.
++1/1/2 of 125 g tablet.

Example: Based on the above table, a patient in heart failure with an estimated lean body weight of 70 kg and a Ccr of 60 mL/min, should be given a 250 g (0.25 mg) LANOXIN Tablet each day, usually taken after the morning meal. Steady-state serum concentrations should not be anticipated before 11 days.

Infants and Children: Digitalization must be individualized. Dividend daily dosing is recommended for infants and young children. Children over 10 years of age require adult dosages in proportion to their body weight.

In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area.

LANOXIN Injection Pediatric can be used to achieve rapid digitalization, with conversion to an oral LANOXIN formulation for maintenance therapy. If patients are switched from intravenous to oral digoxin tablets or elixir, allowances must be made for differences in bioavailability when calculating maintenance dosages (see bioavailability table in CLINICAL PHARMACOLOGY and dosing table below).

Intramuscular injection digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.

Digitalizing and daily maintenance doses for each age group are given below and should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Larger doses are often required for adequate control of ventricular rate in patients with atrial flutter or fibrillation.

The loading dose should be administered in several portions, with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 6 to 8 hour intervals, with careful assessment of clinical response before each additional dose. If the patient's clinical response necessitates a change from the calculated dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given.

Usual Digitalizing and Maintenance Dosages for LANOXIN® Tablets
in Children with Normal Renal Function Based on Lean Body Weight
    Age     Digitalizing* Dose (mg/kg)   Daily+ Maintenance Dose(g/kg)
2-5 years           30 to 40
5-10 years          20 to 35             25% to 35% of oral loading dose++
Over 10 years       10 to 15

*I.V. digitalizing doses are 80% of oral digitalizing doses.
+Divided daily dosing is recommended for children under 10 years of age.
++Projected or actual digitalizing dose providing clinical response.

More gradual digitalization can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided above can be used in calculating this dose for patients with normal renal function. In children with renal disease, digoxin dosing must be carefully titrated based upon clinical response.

Long-term use of digoxin is indicated in many children who have been digitalized for acute heart failure, unless the cause is transient. Children with severe congenital heart disease, even after surgery, may require digoxin for prolonged periods.

It cannot be overemphasized that both the adult and pediatric dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, ultimate dosage selection must be based upon clinical assessment of the patient.

Serum Digoxin Concentrations: Measurement of serum digoxin concentrations can be helpful to the clinician in determining the state of digitalization and in assigning certain probabilities to the likelihood of digoxin intoxication. Studies in adults considered adequately digitalized (without evidence of toxicity) show that about two-thirds of such patients have serum digoxin levels ranging from 0.8 to 2.0 ng/mL. Patients with atrial fibrillation or atrial flutter require and appear to tolerate higher levels than do patients with other indications. On the other hand, in adult patients with clinical evidence of digoxin toxicity, about two-thirds will have serum digoxin levels greater than 2.0 ng/mL. Thus, whereas levels less than 0.8 ng/mL are infrequently associated with toxicity, levels greater than 2.0 ng/mL are often associated with toxicity. Values in between are not very helpful in deciding whether a certain sign or symptom is more likely caused by digoxin toxicity or by something else. There are rare patients who are unable to tolerate digoxin even at serum concentrations below 0.8 ng/mL. Some researchers suggest that infants and young children tolerate slightly higher serum concentrations than do adults.

To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations for clinical use should be at least 6 to 8 hours after the last dose , regardless of the route of administration or formulation used. On a twice daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. After a single daily dose, the concentration will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient's renal function. Ideally, sampling for assessment of steady-state concentrations should be done just before the next dose.

If a discrepancy exists between the reported serum concentration and the observed clinical response, the clinician should consider the following possibilities:

1. Analytical problems in the assay procedure.
2. Inappropriate serum sampling time.
3. Administration of a digitalis glycoside other than digoxin.
4. Conditions (described in WARNINGS and PRECAUTIONS) causing an alteration in the sensitivity of the patient to digoxin.
5. The patient falls outside the norm in his response to or handling of digoxin. This decision should only be reached after exclusion of the other possibilities and generally should be confirmed by additional correlations of clinical observations with serum digoxin concentrations.

The serum concentration data should always be interpreted in the overall clinical context and an isolated serum concentration value should not be used alone as a basis for increasing or decreasing digoxin dosage.

Adjustment of Maintenance Dose in Previously Digitalized Patients: LANOXIN Tablet maintenance doses in individual patients on steady-state digoxin can be adjusted upward or downward in proportion to the ratio of the desired versus the measured serum concentration. For example, a patient at steady-state on 125 g (0.125 mg) per day, with a measured serum concentration of 0.7 ng/mL, should have the dose increased to 250 g (0.25 mg) per day to achieve a steady-state serum concentration of 1.4 ng/mL, assuming the serum digoxin concentration measurement is correct, renal function remains stable during this time and the needed adjustment is not the result of a problem with compliance.

Dosage Adjustment When Changing Preparations: The difference in bioavailability between injectable LANOXIN or LANOXICAPS and LANOXIN Elixir Pediatric or LANOXIN Tablets must be considered when changing patients from one dosage form to another.

LANOXIN Injection and LANOXICAPS doses of 100 g (0.1 mg) and 200 g (0.2 mg) are approximately equivalent to 125 g (0.125 mg) and 250 g (0.25 mg) doses of LANOXIN Tablets and Elixir Pediatric (see Table CLINICAL PHARMACOLOGY). Intramuscular injection o f digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.

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HOW SUPPLIED

LANOXIN (digoxin) Tablets, Scored 125 mg (0.125 mg): Bottles of 30 with child-resistant cap (NDC 0081-0242-30),100 (NDC 0081-0242-55) and 1000 (NDC 0081-0242-75); unit dose pack of 100 (NDC 0081-0242-56) imprinted with LANOXIN and Y3B (yellow). Store at 15 to 25 C (59- 77F) in a dry place and protect from light. LANOXIN (digoxin) Tablets, Scored 250 g (0.25mg): Bottles of 30 with child-resistant cap (NDC 0081-0242-30), 100 (NDC 0081-0242-55) and 1000 (NDC 0081-0242-75); unit dose pack of 100 (NDC 0081-0242-56). Imprinted with LANOXIN and Y3B (yellow). Store a t 15o to 25oC (59o to 77oF) in a dry place and protect from light.

LANOXIN (digoxin) Tablets, Scored 250 g (0.25 mg): Bottles of 30 with child-resistant cap (NDC 0081-0249-30), 100 (NDC 0081-0249-55), package of 12 bottles x 100 with child-resistant cap (NDC 0081-0249-01), 1000 (NDC 0081-0249-75) and 5000 (NDC 0081-0249-80); unit dose pack of 100 (NDC 0081-0249-56). Imprinted with LANOXIN X3A (white). Store at 15o to 25oC (59o-77oF) in a dry place.

LANOXIN (digoxin) Tablets, Scored 500 g (0.5 mg): Bottle of 100 (NDC 0081-0253-55). Imprinted with LANOXIN and T9A (green). Store at 15o to 25oC (59o to 77oF) in a dry place and protect from light.

Also Available:
LANOXIN (digoxin) Elixir Pediatric, 50 g (0.05 mg) per mL; bottle of 60 mL with calibrated dropper.

LANOXIN (digoxin) Injection, 500 g (0.5 mg) in 2 mL (250 g[0.25mg] per mL); boxes of 10 and 50 ampuls.

LANOXIN (digoxin) Injection Pediatric, 100 g (0.1 mg) in 1 mL; box of 10 ampuls.

LANOXICAPS (digoxin solution in capsules). 50 g (0.05 mg) bottle of 100; 100 g (0.1 mg) bottles of 30 (with child-resistant cap) and 100; 200 g (0.2 mg) bottles of 30 (with child-resistant cap) and 100.

GlaxoWellcome

Glaxo Wellcome Inc.
Research Triangle Park, NC 27709

February 1995

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