125 µg (0.125 mg) Scored I.D. Imprint Y3B (yellow)
250 µg (0.25 mg) Scored I.D. Imprint X3A (white)
500 µg (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
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 µg (0.125 mg) 250 µg (0.25 mg) or 500 µg (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.
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 µg
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.
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.
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.
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.
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.
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¬²† 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.
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.
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 µg/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 µg/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 µg (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 cÔ‰˜ously 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 µg/kg per peak body stores is
750 to 1250 µg (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:
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 (µg)
For Estimated Peak Body Stores of 10 µg/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 µg=0.063 mg.
+1/2 of 125 µg tablet or 125 µg every other day.
++1/1/2 of 125 µg 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 µg (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.
in Children with Normal Renal Function Based on Lean Body Weight
Age Digitalizing* Dose (mg/kg) Daily+ Maintenance Dose(µg/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 µg (0.125 mg) per day, with a measured serum concentration of 0.7 ng/mL, should have the dose increased to 250 µg (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 µg (0.1 mg) and 200 µg (0.2 mg) are approximately equivalent to 125 µg (0.125 mg) and 250 µg (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.
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 µg (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 µg (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 µg (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 µg (0.05 mg) per mL; bottle of 60 mL with calibrated dropper.
LANOXIN (digoxin) Injection, 500 µg (0.5 mg) in 2 mL (250 µg[0.25mg] per mL); boxes of 10 and 50 ampuls.
LANOXIN (digoxin) Injection Pediatric, 100 µg (0.1 mg) in 1 mL; box of 10 ampuls.
LANOXICAPS (digoxin solution in capsules). 50 µg (0.05 mg) bottle of 100; 100 µg (0.1 mg) bottles of 30 (with child-resistant cap) and 100; 200 µg (0.2 mg) bottles of 30 (with child-resistant
cap) and 100.
GlaxoWellcome
Glaxo Wellcome Inc.
Research Triangle Park, NC 27709
February 1995