DIGOXIN
DESCRIPTION:
LANOXIN (digoxin) is one of the cardiac (or digitalis) glycosides, a closely
related group of drugs having in common specific effects on the myocardium.
These drugs are found in a number of plants. Digoxin is extracted from the
leaves of Digitalis Lanata. The term "digitalis" is used to designate the whole
group of glycosides. The glycosides are composed of two portions: a sugar and a
cardenolide (hence "glycosides"). Digoxin is described chemically as (3 beta,5
beta,12 beta)-3-((O-2,6-dideoxy-beta-D-Ribo- hexopyranosyl- (1 right arrow 4)-O-
2,6-dideoxy- beta-D-Ribo-hexopyranosyl-(1 right arrow 4)-2,6-dideoxy-beta -D-
Ribo- hexopyranosyl)oxy)-12,14-dihydroxy-card- 20(22)-enolide. Its molecular
formula is C41H64O14, and its molecular weight is 780.95.
Digoxin exists as odorless white crystals that melt with decomposition above 230
deg C. The drug is practically insoluble in water and in ether; slightly soluble
in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine.
LANOXIN is supplied as 125-mcg (0.125-mg) or 250-mcg (0.25-mg) tablets for oral
administration. Each tablet contains the labeled amount of digoxin USP and the
following inactive ingredients: corn and potato starches, lactose, and magnesium
stearate. In addition, the dyes used in the 125-mcg (0.125-mg) tablets are D&C
Yellow No. 10 and FD&C Yellow No. 6.
ACTIONS/CLINICAL PHARMACOLOGY:
MECHANISM OF ACTION: Digoxin inhibits sodium- potassium ATPase, an enzyme that
regulates the quantity of sodium and potassium inside cells. Inhibition of the
enzyme leads to an increase in the intracellular concentration of sodium and
thus (by stimulation of sodium-calcium exchange) an increase in the
intracellular concentration of calcium. The beneficial effects of digoxin result
from direct actions on cardiac muscle, as well as indirect actions on the
cardiovascular system mediated by effects on the autonomic nervous system. The
autonomic effects include: (1) a vagomimetic action, which is responsible for
the effects of digoxin on the sinoatrial and atrioventricular (AV) nodes; and
(2) baroreceptor sensitization, which results in increased afferent inhibitory
activity and reduced activity of the sympathetic nervous system and renin-
angiotensin system for any given increment in mean arterial pressure. The
pharmacologic consequences of these direct and indirect effects are: (1) an
increase in the force and velocity of myocardial systolic contraction (positive
inotropic action); (2) a decrease in the degree of activation of the sympathetic
nervous system and renin-angiotensin system (neurohormonal deactivating effect);
and (3) slowing of the heart rate and decreased conduction velocity through the
AV node (vagomimetic effect). The effects of digoxin in heart failure are
mediated by its positive inotropic and neurohormonal deactivating effects,
whereas the effects of the drug in atrial arrhythmias are related to its
vagomimetic actions. In high doses, digoxin increases sympathetic outflow from
the central nervous system (CNS). This increase in sympathetic activity may be
an important factor in digitalis toxicity.
PHARMACOKINETICS: ABSORPTION: Following oral administration, peak serum
concentrations of digoxin occur at 1 to 3 hours. Absorption of digoxin from
LANOXIN Tablets has been demonstrated to be 60% to 80% complete compared to an
identical intravenous dose of digoxin (absolute bioavailability) or
LANOXICAPS(R) (relative bioavailability). When LANOXIN 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. Comparisons of
the systemic availability and equivalent doses for oral preparations of LANOXIN
are shown in Table 1:
TABLE 1: COMPARISONS OF THE SYSTEMIC AVAILABILITY AND EQUIVALENT
DOSES FOR ORAL PREPARATIONS OF LANOXIN
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Absolute Equivalent Doses (mcg)(*)
Product Bioavailability Among Dosage Forms
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LANOXIN Tablets 60 - 80% 62.5 125 250 500
LANOXIN Elixir Pediatric 70 - 85% 62.5 125 250 500
LANOXICAPS(R) 90 - 100% 50 100 200 400
LANOXIN Injection/IV 100% 50 100 200 400
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* For example, 125-mcg LANOXIN Tablets equivalent to 125 mcg LANOXIN Elixir
Pediatric equivalent to 100 mcg LANOXICAPS equivalent to 100 mcg LANOXIN
Injection/IV.
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In some patients, orally administered digoxin is converted to inactive 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. As a result, certain antibiotics may increase the
absorption of digoxin in such patients. 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 in
serum digoxin concentration relates to the extent of bacterial inactivation, and
may be as much as two-fold in some cases.
DISTRIBUTION: Following drug administration, a 6-to 8-hour tissue distribution
phase is observed. This is followed by a much more gradual decline in the serum
concentration of the drug, which is dependent on the elimination of digoxin from
the body. The peak height and slope of the early portion
(absorption/distribution phases) of the serum concentration-time curve are
dependent upon the route of administration and the absorption characteristics of
the formulation. Clinical evidence indicates that the early high serum
concentrations do not reflect the concentration of digoxin at its site of
action, but that with chronic use, the steady-state post- distribution serum
concentrations are in equilibrium with tissue concentrations and correlate with
pharmacologic effects. In individual patients, these post-distribution serum
concentrations may be useful in evaluating therapeutic and toxic effects (see
DOSAGE AND ADMINISTRATION: Serum Digoxin Concentrations).
Digoxin is concentrated in tissues and therefore has a large apparent volume of
distribution. Digoxin crosses both the blood-brain barrier and the placenta. At
delivery, the serum digoxin concentration in the newborn is similar to the serum
concentration in the mother. Approximately 25% of digoxin in the plasma is bound
to protein. Serum digoxin concentrations are not significantly altered by large
changes in fat tissue weight, so that its distribution space correlates best
with lean (i.e., ideal) body weight, not total body weight.
METABOLISM: Only a small percentage (16%) of a dose of digoxin is metabolized.
The end metabolites, which include 3 beta-digoxigenin, 3-keto-digoxigenin, and
their glucuronide and sulfate conjugates, are polar in nature and are postulated
to be formed via hydrolysis, oxidation, and conjugation. The metabolism of
digoxin is not dependent upon the cytochrome P- 450 system, and digoxin is not
known to induce or inhibit the cytochrome P-450 system.
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 healthy volunteers, 50% to 70%
of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin
is proportional to glomerular filtration rate and is largely independent of
urine flow. In healthy volunteers with normal renal function, digoxin has a
half- life of 1.5 to 2.0 days. The half-life in anuric patients is prolonged to
3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis,
exchange transfusion, or during cardiopulmonary bypass because most of the drug
is bound to tissue and does not circulate in the blood.
SPECIAL POPULATIONS: Race differences in digoxin pharmacokinetics have not been
formally studied. Because digoxin is primarily eliminated as unchanged drug via
the kidney and because there are no important differences in creatinine
clearance among races, pharmacokinetic differences due to race are not expected.
The clearance of digoxin can be primarily correlated with renal function as
indicated by creatinine clearance. The Cockcroft and Gault formula for
estimation of creatinine clearance includes age, body weight, and gender. A
table that provides the usual daily maintenance dose requirements of LANOXIN
Tablets based on creatinine clearance (per 70 kg) is presented in the DOSAGE AND
ADMINISTRATION section.
Plasma digoxin concentration profiles in patients with acute hepatitis generally
fell within the range of profiles in a group of healthy subjects.
PHARMACODYNAMIC AND CLINICAL EFFECTS: The times to onset of pharmacologic effect
and to peak effect of preparations of LANOXIN are shown in Table 2:
TABLE 2: TIMES TO ONSET OF PHARMACOLOGIC EFFECT AND TO PEAK EFFECT
OF PREPARATIONS OF LANOXIN
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Product Time to Onset of Effect(*) Time to Peak Effect(*)
LANOXIN Tablets 0.5 - 2 hours 2 - 6 hours
LANOXIN Elixir Pediatric 0.5 - 2 hours 2 - 6 hours
LANOXICAPS 0.5 - 2 hours 2 - 6 hours
LANOXIN Injection/IV 5 - 30 minutes(**/*) 1 - 4 hours
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* Documented for ventricular response rate in atrial fibrillation, inotropic
effects and electrocardiographic changes.
**/* Depending upon rate of infusion.
HEMODYNAMIC EFFECTS: Digoxin produces hemodynamic improvement in patients with
heart failure. Short- and long-term therapy with the drug increases cardiac
output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure,
and systemic vascular resistance. These hemodynamic effects are accompanied by
an increase in the left ventricular ejection fraction and a decrease in end-
systolic and end- diastolic dimensions.
CHRONIC HEART FAILURE: Two 12-week, double-blind, placebo-controlled studies
enrolled 178 (RADIANCE trial) and 88 (PROVED trial) patients with NYHA class II
or III heart failure previously treated with digoxin, a diuretic, and an ACE
inhibitor (RADIANCE only) and randomized them to placebo or treatment with
LANOXIN. Both trials demonstrated better preservation of exercise capacity in
patients randomized to LANOXIN. Continued treatment with LANOXIN reduced the
risk of developing worsening heart failure, as evidenced by heart failure-
related hospitalizations and emergency care and the need for concomitant heart
failure therapy. The larger study also showed treatment-related benefits in NYHA
class and patients' global assessment. In the smaller trial, these trended in
favor of a treatment benefit. The Digitalis Investigation Group (DIG) main trial
was a multicenter, randomized, double- blind, placebo-controlled mortality study
of 6,801 patients with heart failure and left ventricular ejection fraction
(=)0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure
of ischemic etiology, 44% had been receiving digoxin, and most were receiving
concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to
placebo or LANOXIN, the dose of which was adjusted for the patient's age, sex,
lean body weight, and serum creatinine (see DOSAGE AND ADMINISTRATION), and
followed for up to 58 months (median 37 months). The median daily dose
prescribed was 0.25 mg. Overall all-cause mortality was 35% with no difference
between groups (95% confidence limits for relative risk of 0.91 to 1.07).
LANOXIN was associated with a 25% reduction in the number of hospitalizations
for heart failure, a 28% reduction in the risk of a patient having at least one
hospitalization for heart failure, and a 6.5% reduction in total
hospitalizations (for any cause).
Use of LANOXIN was associated with a trend in reduction in time to all-cause
death or hospitalization. The trend was evident in subgroups of patients with
mild heart failure as well as more severe disease, as shown in Table 3. Although
the effect on all-cause death or hospitalization was not statistically
significant, much of the apparent benefit derived from effects on mortality and
hospitalization attributed to heart failure.
TABLE 3: SUBGROUP ANALYSES OF MORTALITY AND HOSPITALIZATION
DURING THE FIRST TWO YEARS FOLLOWING RANDOMIZATION
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Risk of All-Cause Mortality or
All-Cause Hospitalization(*)
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n Placebo LANOXIN Relative risk(**/*)
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All patients 0.94
(EF =0.45) 6801 604 593 (0.88-1.00)
0.96
NYHA I / II 4571 549 541 (0.89-1.04)
0.99
EF 0.25-0.45 4543 568 571 (0.91-1.07)
0.98
CTR =0.55 4455 561 563 (0.91-1.06)
0.88
NYHA III / IV 2224 719 696 (0.80-0.97)
0.84
EF <0.25 2258 677 637 (0.76-0.93)
0.85
CTR >0.55 2346 687 650 (0.77-0.94)
1.04
EF >0.45(+) 987 571 585 (0.88-1.23)
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* Number of patients with an event during the first 2 years per 1000
randomized patients.
**/* Relative risk (95% confidence interval).
(+) DIG Ancillary Study.
TABLE 3 Con't
TABLE 3: SUBGROUP ANALYSES OF MORTALITY AND HOSPITALIZATION
DURING THE FIRST TWO YEARS FOLLOWING RANDOMIZATION
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Risk of HF-Related Mortality or
HF-Related Hospitalization(*)
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n Placebo LANOXIN Relative risk(**/*)
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All patients 0.69
(EF =0.45) 6801 294 217 (0.63-0.76)
0.70
NYHA I / II 4571 242 178 (0.62-0.80)
0.74
EF 0.25-0.45 4543 244 190 (0.66-0.84)
0.71
CTR =0.55 4455 239 180 (0.63-0.81)
0.65
NYHA III / IV 2224 402 295 (0.57-0.75)
0.61
EF <0.25 2258 394 270 (0.53-0.71)
0.65
CTR >0.55 2346 398 287 (0.57-0.75)
0.72
EF >0.45(+) 987 179 136 (0.53-0.99)
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* Number of patients with an event during the first 2 years per 1000
randomized patients.
**/* Relative risk (95% confidence interval).
(+) DIG Ancillary Study.
In situations where there is no statistically significant benefit of treatment
evident from a trial's primary endpoint, results pertaining to a secondary
endpoint should be interpreted cautiously.
CHRONIC ATRIAL FIBRILLATION: In patients with chronic atrial fibrillation,
digoxin slows rapid ventricular response rate in a linear dose- response fashion
from 0.25 to 0.75 mg/day. Digoxin should not be used for the treatment of
multifocal atrial tachycardia.
INDICATIONS AND USAGE:
1. Heart failure with atrial fibrillation. It is not very
effective in controlling ventricular rate during exercise.
Patients of thyrotoxicosis are sensitive to
digitalis toxicity and digoxin alone is not effective in
controlling ventricular rate in these patients. Atrial fib-
rillation with a ventricular rate of 250/min or more
could be due to fast conduction over accessory path-
way. Digoxin should not be tried in these cases as it
can increase conduction over accessory pathway and
precipitate ventricular fibrillation.
2. Heart failure in sinus rhythm
A) Digoxin has no role in following circumstances-
(i) Diastolic heart failure due to left ventricular hy-
pertrophy, restrictive cardiomyopathy, pericardial
constriction and cardiac tamponade : In these condi-
tions, systolic function of myocardium is normal and
problem is with diastolic filling which is not affected
by digoxin. Digoxin may worsen diastolic dysfunction
by increasing intracellular calcium levels.4
(ii) Acute systolic failure due to viral myocarditis or
acute myocardial infarction : In these situations part of
the myocardium is damaged and the remaining healthy
myocardium has normal systolic function. These patients
are also susceptible to digoxin induced
arrhythmias. Digoxin does not have any effect on
damaged or ischemic myocardium. Patients with acute
aortic or mitral regurgitation, acute rupture of Sinus of
valsalva or acute rupture of interventricular septum
also not benefited because systolic functions of myocardium
are normal and problem is of acute increase in preload.
(iii) Chronic syslolic failure without symptom;
systemic or pulmonary congestion : These patients are
not likely to experience any symptomatic benefits.
(iv) Heart failure secondary to thyrotoxicosis or
arterio-venous fistula is not likely to benefit as cardiac
contractility is more than normal.
(v) Patients of isolated mitral stenosis in normal si-
nus rhythm without right ventricular failure also
not have any advantage because myocardial function
is normal.
(vi) Digoxin has no role in prevention of aerial fib-
rillation. On the contrary it increases the risk of onset
of atrial fibrillation by decreasing refractory period of
atrial muscle.
(vii) Due to impaired clearance, digoxin is not
recommended routinely in premature infants with patent
ductus arteriosus and heart failure.
B) Mild chronic systolic heart failure - These
patients can be better managed with angiotensin
converting enzyme (ACE) inhibitors rather than with
digoxin because ACE inhibitors have been shown to
provide survival benefit. If symptoms are not control
led with ACE inhibitors and vasodilators, addition of
digoxin does provide symptomatic relief through
neurohormonal effects.Withdrawal of digoxin has
also been shown to worsen patients with mild heart
failure.
C) Moderate to severe chronic heart failure -
Digoxin should be added if symptoms are not controlled
with ACE inhibitors and diuretics. In these patients
digoxin reduces breathlessness, improves exercise
tolerance and reduces freauency of hospitalization due to worsening of heart failure.
HEART FAILURE: LANOXIN is indicated for the treatment of mild to moderate heart
failure. LANOXIN 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, LANOXIN should be used with a diuretic and an angiotensin-converting
enzyme inhibitor, but an optimal order for starting these three drugs cannot be
specified.
ATRIAL FIBRILLATION: LANOXIN is indicated for the control of ventricular
response rate in patients with chronic atrial fibrillation.
D) Digoxin should be used cautiously in patients of
cor pulmonale specially during acute respiratory in-
sufficiency.These patients with hypoxia and
acidosis have higher risk of cardiac arrhythmias.
Digoxin is concentrated in amyloid tissue. Patients of
amyloid heart disease are, therefore, more susceptible
to digitalis toxicity. Digoxin should be used very cau-
tiously in heart failure accompanying acute
glomerulonephritis because of impaired renal excre-
tion.
Dose : Recommended daily dose is 0.125 to 0.35
mg/day. Beneficial neurohumoral effects are seen
even at lower dose. In some cases, higher dose (up
to 0.5 mg/day) may provide more benefit if used cau-
tiously. Infants require higher dose as compared to
their body weight, due to higher apparent volume of
distribution. Elderly persons need relatively lower
dose due to decreased lean body mass and glomerular
filtration rate. Most of the drug is excreted through
kidneys. Patients with impaired renal functions, there-
fore, need lower dose. Creatinine clearance is more
reliable in judging renal functions than serum creat-
inine as the later is also influenced by muscle mass.
Direct measurement of creatinine clearance is, how-
ever, impractical. Roughly, the dose of digoxin should
be reduced to half with serum creatinine value about 3
mg/dl. In some patients, intestinal flora converts
digoxin to an inactive compound. Such patients re-
quire higher dose to attain adequate serum levels.
Digoxin can be used safely during pregnancy and
lactation. There is no justification of giving digoxin
for five days a week. Serum half life is 1.5 days.
Discontinuing digoxin for two days may reduce serum
levels below effective range on second and third day
of omission. Lower maintenance dose is better than in-
termittent therapy. Electrocardiogram is significantly
affected by underlying disease and is, therefore, not
reliable injudging adequacy of digoxin dose. Facili-
ties for estimation of serum concentration are not
routinely available. Further, the cellular effects of
digoxin are influenced by several factors other than
serum concentration. Old age, hypokalemia, hypo-
magnesemia, hypercalcemia, acidosis, hypoxia,
hyperthyroidism and catecholamine excess increase
sensitivity to digoxin.' Overall clinical assessment
is more reliable.
CONTRAINDICATIONS:
Digitalis glycosides are contraindicated in patients with ventricular
fibrillation or in patients with a known hypersensitivity to digoxin. A
hypersensitivity reaction to other digitalis preparations usually constitutes a
contraindication to digoxin.
WARNINGS:
SINUS NODE DISEASE AND AV BLOCK: Because digoxin slows sinoatrial and AV
conduction, the drug commonly prolongs the PR interval. The drug may cause
severe sinus bradycardia or sinoatrial block in patients with pre-existing sinus
node disease and may cause advanced or complete heart block in patients with
pre-existing incomplete AV block. In such patients consideration should be given
to the insertion of a pacemaker before treatment with digoxin.
ACCESSORY AV PATHWAY (WOLFF-PARKINSON-WHITE SYNDROME): After intravenous digoxin
therapy, some patients with paroxysmal atrial fibrillation or flutter and a
coexisting accessory AV pathway have developed increased antegrade conduction
across the accessory pathway bypassing the AV node, leading to a very rapid
ventricular response or ventricular fibrillation. Unless conduction down the
accessory pathway has been blocked (either pharmacologically or by surgery),
digoxin should not be used in such patients. The treatment of paroxysmal
supraventricular tachycardia in such patients is usually direct- current
cardioversion.
USE IN PATIENTS WITH PRESERVED LEFT VENTRICULAR SYSTOLIC FUNCTION: Patients with
certain disorders involving heart failure associated with preserved left
ventricular ejection fraction may be particularly susceptible to toxicity of the
drug. Such disorders include restrictive cardiomyopathy, constrictive
pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with
idiopathic hypertrophic subaortic stenosis may have worsening of the outflow
obstruction due to the inotropic effects of digoxin.
PRECAUTIONS:
USE IN PATIENTS WITH IMPAIRED RENAL FUNCTION: Digoxin is primarily excreted by
the kidneys; therefore, patients with impaired renal function require smaller
than usual maintenance doses of digoxin (see DOSAGE AND ADMINISTRATION). Because
of the prolonged elimination half-life, a longer period of time is required to
achieve an initial or new steady-state serum concentration in patients with
renal impairment than in patients with normal renal function. If appropriate
care is not taken to reduce the dose of digoxin, such patients are at high risk
for toxicity, and toxic effects will last longer in such patients than in
patients with normal renal function.
USE IN PATIENTS WITH ELECTROLYTE DISORDERS: In patients with hypokalemia or
hypomagnesemia, toxicity may occur despite serum digoxin concentrations below
2.0 ng/mL, because potassium or magnesium depletion sensitizes the myocardium to
digoxin. Therefore, it is desirable to maintain normal serum potassium and
magnesium concentrations in patients being treated with digoxin. Deficiencies of
these electrolytes may result from malnutrition, diarrhea, or prolonged
vomiting, as well as the use of the following drugs or procedures: diuretics,
amphotericin B, corticosteroids, antacids, dialysis, and mechanical suction of
gastrointestinal secretions.
Hypercalcemia from any cause predisposes the patient to digitalis toxicity.
Calcium, particularly when administered rapidly by the intravenous route, may
produce serious arrhythmias in digitalized patients. On the other hand,
hypocalcemia can nullify the effects of digoxin in humans; thus, digoxin may be
ineffective until serum calcium is restored to normal. These interactions are
related to the fact that digoxin affects contractility and excitability of the
heart in a manner similar to that of calcium.
USE IN THYROID DISORDERS AND HYPERMETABOLIC STATES: Hypothyroidism may reduce
the requirements for digoxin. Heart failure and/or atrial arrhythmias resulting
from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or
arteriovenous shunt) are best treated by addressing the underlying condition.
Atrial arrhythmias associated with hypermetabolic states are particularly
resistant to digoxin treatment. Care must be taken to avoid toxicity if digoxin
is used.
USE IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION: Digoxin should be used with
caution in patients with acute myocardial infarction. The use of inotropic drugs
in some patients in this setting may result in undesirable increases in
myocardial oxygen demand and ischemia.
USE DURING ELECTRICAL CARDIOVERSION: It may be desirable to reduce the dose of
digoxin for 1 to 2 days prior to electrical cardioversion of atrial fibrillation
to avoid the induction of ventricular arrhythmias, but physicians must consider
the consequences of increasing the ventricular response if digoxin is withdrawn.
If digitalis toxicity is suspected, elective cardioversion should be delayed. If
it is not prudent to delay cardioversion, the lowest possible energy level
should be selected to avoid provoking ventricular arrhythmias.
LABORATORY TEST MONITORING: Patients receiving digoxin should have their serum
electrolytes and renal function (serum creatinine concentrations) assessed
periodically; the frequency of assessments will depend on the clinical setting.
For discussion of serum digoxin concentrations, see DOSAGE AND ADMINISTRATION
section.
DRUG INTERACTIONS: Potassium-depleting Diuretics are a major contributing factor
to digitalis toxicity. Calcium, particularly if administered rapidly by the
intravenous route, may produce serious arrhythmias in digitalized patients.
Quinidine, Verapamil, Amiodarone, Propafenone, Indomethacin, Itraconazole,
Alprazolam, and Spironolactone raise the serum digoxin concentration due to a
reduction in clearance and/or in volume of distribution of the drug, with the
implication that digitalis intoxication may result. Erythromycin and
Clarithromycin (and possibly other Macrolide Antibiotics) and Tetracycline may
increase digoxin absorption in patients who inactivate digoxin by bacterial
metabolism in the lower intestine, so that digitalis intoxication may result
(see ACTIONS/CLINICAL PHARMACOLOGY: Absorption). Propantheline and
Diphenoxylate, by decreasing gut motility, may increase digoxin absorption.
Antacids, Kaolin-Pectin, Sulfasalazine, Neomycin, Cholestyramine, certain
Anticancer Drugs, and Metoclopramide may interfere with intestinal digoxin
absorption, resulting in unexpectedly low serum concentrations. Rifampin may
decrease serum digoxin concentration, especially in patients with renal
dysfunction, by increasing the non- renal clearance of digoxin. There have been
inconsistent reports regarding the effects of other drugs (e.g., Quinine,
Penicillamine) on serum digoxin concentration. Thyroid administration to a
digitalized, hypothyroid patient may increase the dose requirement of digoxin.
Concomitant use of digoxin and Sympathomimetics increases the risk of cardiac
arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from
muscle cells, and may thereby cause arrhythmias in digitalized patients.
Although beta-adrenergic blockers or calcium channel blockers and digoxin may be
useful in combination to control atrial fibrillation, their additive effects on
AV node conduction can result in advanced or complete heart block.
Due to the considerable variability of these interactions, the dosage of digoxin
should be individualized when patients receive these medications concurrently.
Furthermore, caution should be exercised when combining digoxin with any drug
that may cause a significant deterioration in renal function, since a decline in
glomerular filtration or tubular secretion may impair the excretion of digoxin.
DRUG/LABORATORY TEST INTERACTIONS: The use of therapeutic doses of digoxin may
cause prolongation of the PR interval and depression of the ST segment on the
electrocardiogram. Digoxin may produce false positive ST-T changes on the
electrocardiogram during exercise testing. These electrophysiologic effects
reflect an expected effect of the drug and are not indicative of toxicity.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: There have been no long-
term studies performed in animals to evaluate carcinogenic potential, nor have
studies been conducted to assess the mutagenic potential of digoxin or its
potential to affect fertility.
PREGNANCY: 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
reproductive capacity. Digoxin should be given to a pregnant woman only if
clearly needed.
NURSING MOTHERS: Studies have shown that digoxin concentrations in the mother's
serum and milk are similar. However, the estimated exposure of a nursing infant
to digoxin via breast feeding will be far below the usual infant maintenance
dose. Therefore, this amount should have no pharmacologic effect upon the
infant. Nevertheless, caution should be exercised when digoxin is administered
to a nursing woman.
PEDIATRIC USE: Newborn infants display considerable variability in their
tolerance to digoxin. Premature and immature infants are particularly sensitive
to the effects of digoxin, and the dosage of the drug must not only be reduced
but must be individualized according to their degree of maturity. Digitalis
glycosides can cause poisoning in children due to accidental ingestion.
GERIATRIC USE: The majority of clinical experience gained with digoxin has been
in the elderly population. This experience has not identified differences in
response or adverse effects between the elderly and younger patients. However,
this drug is known to be substantially excreted by the kidney, and the risk of
toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection, which should be based on renal
function, and it may be useful to monitor renal function (see DOSAGE AND
ADMINISTRATION).
DRUG INTERACTIONS:
DRUG INTERACTIONS: Potassium-depleting Diuretics are a major contributing factor
to digitalis toxicity. Calcium, particularly if administered rapidly by the
intravenous route, may produce serious arrhythmias in digitalized patients.
Quinidine, Verapamil, Amiodarone, Propafenone, Indomethacin, Itraconazole,
Alprazolam, and Spironolactone raise the serum digoxin concentration due to a
reduction in clearance and/or in volume of distribution of the drug, with the
implication that digitalis intoxication may result. Erythromycin and
Clarithromycin (and possibly other Macrolide Antibiotics) and Tetracycline may
increase digoxin absorption in patients who inactivate digoxin by bacterial
metabolism in the lower intestine, so that digitalis intoxication may result
(see ACTIONS/CLINICAL PHARMACOLOGY: Absorption). Propantheline and
Diphenoxylate, by decreasing gut motility, may increase digoxin absorption.
Acarbose can reduce serum levels of digoxin.
Antacids, Kaolin-Pectin, Sulfasalazine, Neomycin, Cholestyramine, certain
Anticancer Drugs, and Metoclopramide may interfere with intestinal digoxin
absorption, resulting in unexpectedly low serum concentrations. Rifampin may
decrease serum digoxin concentration, especially in patients with renal
dysfunction, by increasing the non- renal clearance of digoxin. There have been
inconsistent reports regarding the effects of other drugs (e.g., Quinine,
Penicillamine) on serum digoxin concentration. Thyroid administration to a
digitalized, hypothyroid patient may increase the dose requirement of digoxin.
Concomitant use of digoxin and Sympathomimetics increases the risk of cardiac
arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from
muscle cells, and may thereby cause arrhythmias in digitalized patients.
Although beta-adrenergic blockers or calcium channel blockers and digoxin may be
useful in combination to control atrial fibrillation, their additive effects on
AV node conduction can result in advanced or complete heart block.
Due to the considerable variability of these interactions, the dosage of digoxin
should be individualized when patients receive these medications concurrently.
Furthermore, caution should be exercised when combining digoxin with any drug
that may cause a significant deterioration in renal function, since a decline in
glomerular filtration or tubular secretion may impair the excretion of digoxin.
DRUG/LABORATORY TEST INTERACTIONS: The use of therapeutic doses of digoxin may
cause prolongation of the PR interval and depression of the ST segment on the
electrocardiogram. Digoxin may produce false positive ST-T changes on the
electrocardiogram during exercise testing. These electrophysiologic effects
reflect an expected effect of the drug and are not indicative of toxicity.
(See also PRECAUTIONS)
ADVERSE REACTIONS:
In general, the adverse reactions of digoxin are dose-dependent and occur at
doses higher than those needed to achieve a therapeutic effect. Hence, adverse
reactions are less common when digoxin is used within the recommended dose range
or therapeutic serum concentration range and when there is careful attention to
concurrent medications and conditions.
Because some patients may be particularly susceptible to side effects with
digoxin, the dosage of the drug should always be selected carefully and adjusted
as the clinical condition of the patient warrants. In the past, when high doses
of digoxin were used and little attention was paid to clinical status or
concurrent medications, adverse reactions to digoxin were more frequent and
severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal
disturbances for about one- fourth, and CNS and other toxicity for about one-
fourth of these adverse reactions. However, available evidence suggests that the
incidence and severity of digoxin toxicity has decreased substantially in recent
years. In recent controlled clinical trials, in patients with predominantly mild
to moderate heart failure, the incidence of adverse experiences was comparable
in patients taking digoxin and in those taking placebo. In a large mortality
trial, the incidence of hospitalization for suspected digoxin toxicity was 2% in
patients taking LANOXIN compared to 0.9% in patients taking placebo. In this
trial, the most common manifestations of digoxin toxicity included
gastrointestinal and cardiac disturbances; CNS manifestations were less common.
ADULTS: CARDIAC: Therapeutic doses of digoxin may cause heart block in patients
with pre-existing sinoatrial or AV conduction disorders; heart block can be
avoided by adjusting the dose of digoxin. Prophylactic use of a cardiac
pacemaker may be considered if the risk of heart block is considered
unacceptable. High doses of digoxin may produce a variety of rhythm
disturbances, such as first-degree, second-degree (Wenckebach), or third-degree
heart block (including asystole); atrial tachycardia with block; AV
dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform
ventricular premature contractions (especially bigeminy or trigeminy);
ventricular tachycardia; and ventricular fibrillation. Digoxin produces PR
prolongation and ST segment depression which should not by themselves be
considered digoxin toxicity. Cardiac toxicity can also occur at therapeutic
doses in patients who have conditions which may alter their sensitivity to
digoxin (see WARNINGS and PRECAUTIONS).
GASTROINTESTINAL: Digoxin may cause anorexia, nausea, vomiting, and diarrhea.
Rarely, the use of digoxin has been associated with abdominal pain, intestinal
ischemia, and hemorrhagic necrosis of the intestines.
CNS: Digoxin can produce visual disturbances (blurred or yellow vision),
headache, weakness, dizziness, apathy, confusion, and mental disturbances (such
as anxiety, depression, delirium, and hallucination).
OTHER: Gynecomastia has been occasionally observed following the prolonged use
of digoxin. Thrombocytopenia and maculopapular rash and other skin reactions
have been rarely observed. The following table summarizes the incidence of those
adverse experiences listed above for patients treated with LANOXIN Tablets or
placebo from two randomized, double-blind, placebo-controlled withdrawal trials.
Patients in these trials were also receiving diuretics with or without
angiotensin-converting enzyme inhibitors. These patients had been stable on
digoxin, and were randomized to digoxin or placebo. The results shown in Table 4
reflect the experience in patients following dosage titration with the use of
serum digoxin concentrations and careful follow-up. These adverse experiences
are consistent with results from a large, placebo- controlled mortality trial
(DIG trial) wherein over half the patients were not receiving digoxin prior to
enrollment.
TABLE 4: ADVERSE EXPERIENCES IN TWO PARALLEL,
DOUBLE-BLIND, PLACEBO-CONTROLLED WITHDRAWAL TRIALS
(NUMBER OF PATIENTS REPORTING)
-----------------------------------------------------------------------------------------------------------------------------------------------
Digoxin Placebo
Patients Patients
Adverse Experience (n = 123) (n = 125)
-----------------------------------------------------------------------------------------------------------------------------------------------
Cardiac
Palpitation 1 4
Ventricular extrasystole 1 1
Tachycardia 2 1
Heart arrest 1 1
Gastrointestinal
Anorexia 1 4
Nausea 4 2
Vomiting 2 1
Diarrhea 4 1
Abdominal pain 0 6
CNS
Headache 4 4
Dizziness 6 5
Mental disturbances 5 1
Other
Rash 2 1
Death 4 3
INFANTS AND CHILDREN: The side effects of digoxin in infants and children differ
from those seen in adults in several respects. Although digoxin may produce
anorexia, nausea, vomiting, diarrhea, and CNS disturbances in young patients,
these are rarely the initial symptoms of overdosage. Rather, the earliest and
most frequent manifestation of excessive dosing with digoxin in infants and
children is the appearance of cardiac arrhythmias, including sinus bradycardia.
In children, the use of digoxin may produce any arrhythmia. The most common are
conduction disturbances or supraventricular tachyarrhythmias, such as atrial
tachycardia (with or without block) and junctional (nodal) tachycardia.
Ventricular arrhythmias are less common. Sinus bradycardia may 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 develops in a child taking digoxin should be assumed to be caused by
digoxin, until further evaluation proves otherwise.
OVERDOSAGE:
TREATMENT OF ADVERSE REACTIONS PRODUCED BY OVERDOSAGE: Digoxin should be
temporarily discontinued until the adverse reaction resolves. Every effort
should also be made to correct factors that may contribute to the adverse
reaction (such as electrolyte disturbances or concurrent medications). Once the
adverse reaction has resolved, therapy with digoxin may be reinstituted,
following a careful reassessment of dose.
Withdrawal of digoxin may be all that is required to treat the adverse reaction.
However, when the primary manifestation of digoxin overdosage is a cardiac
arrhythmia, additional therapy may be needed. If the rhythm disturbance is a
symptomatic bradyarrhythmia or heart block, consideration should be given to the
reversal of toxicity with DIGIBIND(R) (Digoxin Immune Fab (Ovine)) (see below),
the use of atropine, or the insertion of a temporary cardiac pacemaker. However,
asymptomatic bradycardia or heart block related to digoxin may require only
temporary withdrawal of the drug and cardiac monitoring of the patient.
If the rhythm disturbance is a ventricular arrhythmia, consideration should be
given to the correction of electrolyte disorders, particularly if hypokalemia
(see below) or hypomagnesemia is present. DIGIBIND is a specific antidote for
digoxin and may be used to reverse potentially life-threatening ventricular
arrhythmias due to digoxin overdosage.
ADMINISTRATION OF POTASSIUM: Every effort should be made to maintain the serum
potassium concentration between 4.0 and 5.5 mmol/L. Potassium is usually
administered orally, but when correction of the arrhythmia is urgent and the
serum potassium concentration is low, potassium may be administered cautiously
by the intravenous route. The electrocardiogram should be monitored for any
evidence of potassium toxicity (e.g., peaking of T waves) and to observe the
effect on the arrhythmia. Potassium salts may be dangerous in patients who
manifest bradycardia or heart block due to digoxin (unless primarily related to
supraventricular tachycardia) and in the setting of massive digitalis overdosage
(see Massive Digitalis Overdosage) subsection).
MASSIVE DIGITALIS OVERDOSAGE: Manifestations of life-threatening toxicity
include ventricular tachycardia or ventricular fibrillation, or progressive
bradyarrhythmias, or heart block. The administration of more than 10 mg of
digoxin in a previously healthy adult, or more than 4 mg in a previously healthy
child, or a steady-state serum concentration greater than 10 ng/mL often results
in cardiac arrest.
DIGIBIND should be used to reverse the toxic effects of ingestion of a massive
overdose. The decision to administer DIGIBIND to a patient who has ingested a
massive dose of digoxin but who has not yet manifested life-threatening toxicity
should 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 the 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 manifestations, it may be unsafe to induce vomiting or attempt passage of
a gastric tube, because such maneuvers may induce an acute vagal episode that
can worsen digitalis-related arrhythmias.
Severe digitalis intoxication can cause a massive shift of potassium from inside
to outside the cell, leading to life-threatening hyperkalemia. The
administration of potassium supplements in the setting of massive intoxication
may be hazardous and should be avoided. Hyperkalemia caused by massive digitalis
toxicity is best treated with DIGIBIND; initial treatment with glucose and
insulin may also be required if hyperkalemia itself is acutely life-threatening.
DOSAGE AND ADMINISTRATION:
GENERAL: Recommended dosages of digoxin may require considerable modification
because of individual sensitivity of the patient to the drug, the presence of
associated conditions, or the use of concurrent medications. In selecting a dose
of digoxin, the following factors must be considered:
1. The body weight of the patient. Doses should be calculated based upon lean
(i.e., ideal) body weight.
2. The patient's renal function, preferably evaluated on the basis of estimated
creatinine clearance.
3. The patient's age. Infants and children require different doses of digoxin
than adults. Also, advanced age may be indicative of diminished renal function
even in patients with normal serum creatinine concentration (i.e., below 1.5
mg/dL).
4. Concomitant disease states, concurrent medications, or other factors likely
to alter the pharmacokinetic or pharmacodynamic profile of digoxin (see
PRECAUTIONS).
SERUM DIGOXIN CONCENTRATIONS: In general, the dose of digoxin used should be
determined on clinical grounds. However, measurement of serum digoxin
concentrations can be helpful to the clinician in determining the adequacy of
digoxin therapy and in assigning certain probabilities to the likelihood of
digoxin intoxication. About two-thirds of adults considered adequately
digitalized (without evidence of toxicity) have serum digoxin concentrations
ranging from 0.8 to 2.0 ng/mL. However, digoxin may produce clinical benefits
even at serum concentrations below this range. About two-thirds of adult
patients with clinical toxicity have serum digoxin concentrations greater than
2.0 ng/mL. However, since one-third of patients with clinical toxicity have
concentrations less than 2.0 ng/mL, values below 2.0 ng/mL do not rule out the
possibility that a certain sign or symptom is related to digoxin therapy.
Rarely, there are patients who are unable to tolerate digoxin at serum
concentrations below 0.8 ng/mL. Consequently, the serum concentration of digoxin
should always be interpreted in the overall clinical context, and an isolated
measurement should not be used alone as the basis for increasing or decreasing
the dose of the drug.
To allow adequate time for equilibration of digoxin between serum and tissue,
sampling of serum concentrations should be done just before the next scheduled
dose of the drug. If this is not possible, sampling should be done at least 6 to
8 hours after the last dose, regardless of the route of administration or the
formulation used. On a once-daily dosing schedule, the concentration of digoxin
will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the
patient's renal function. 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.
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. Serum digoxin concentration may decrease acutely during periods of exercise
without any associated change in clinical efficacy due to increased binding of
digoxin to skeletal muscle.
HEART FAILURE: ADULTS: 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. If rapid digitalization is considered medically appropriate, it may be
achieved by administering a loading dose based upon projected peak digoxin
body stores. Maintenance dose can be calculated as a percentage of the loading
dose.
2. More gradual digitalization may be obtained by beginning an appropriate
maintenance dose, thus allowing digoxin body stores to accumulate slowly.
Steady-state serum digoxin concentrations will be achieved in approximately five
half-lives of the drug for the individual patient. Depending upon the
patient's renal function, this will take between 1 and 3 weeks.
RAPID DIGITALIZATION WITH A LOADING DOSE: Peak digoxin body stores of 8 to 12
mcg/kg should provide therapeutic effect with minimum risk of toxicity in most
patients with heart failure and normal sinus rhythm. Because of altered digoxin
distribution and elimination, projected peak body stores for patients with renal
insufficiency should be conservative (i.e., 6 to 10 mcg/kg) (see PRECAUTIONS).
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
loading dose of digoxin, then calculation of the maintenance dose should be
based upon the amount actually given.
A single initial dose of 500 to 750 mcg (0.5 to 0.75 mg) of LANOXIN Tablets
usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2
to 6 hours. Additional doses of 125 to 375 mcg (0.125 to 0.375 mg) may be given
cautiously 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 12 mcg/kg peak body stores is 750 to 1,250 mcg (0.75 to
1.25 mg).
LANOXIN Injection is frequently used 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, ACTIONS/CLINICAL PHARMACOLOGY).
MAINTENANCE DOSING: The doses of digoxin used in controlled trials in patients
with heart failure have ranged from 125 to 500 mcg (0.125 to 0.5 mg) once daily.
In these studies, the digoxin dose has been generally titrated according to the
patient's age, lean body weight, and renal function. Therapy is generally
initiated at a dose of 250 mcg (0.25 mg) once daily in patients under age 70
with good renal function, at a dose of 125 mcg (0.125 mg) once daily in patients
over age 70 or with impaired renal function, and at a dose of 62.5 mcg (0.0625
mg) in patients with marked renal impairment. Doses may be increased every 2
weeks according to clinical response.
In a subset of approximately 1,800 patients enrolled in the DIG trial (wherein
dosing was based on an algorithm similar to that in Table 5) the mean (+/- SD)
serum digoxin concentrations at 1 month and 12 months were 1.01 +/- 0.47 ng/mL
and 0.97 +/- 0.43 ng/mL, respectively.
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 Dose) * % Daily Loss/100
Where: % Daily Loss = 14 + Ccr/5
(Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m(squared)
body surface area)
Table 5 provides average daily maintenance dose requirements of LANOXIN Tablets
for patients with heart failure based upon lean body weight and renal function:
TABLE 5: USUAL DAILY MAINTENANCE DOSE REQUIREMENTS (MCG) OF LANOXIN
FOR ESTIMATED PEAK BODY STORES OF 10 MCG/KG
-------------------------------------------------------------------------------------------------------------------------------
Lean Body Weight
Number of
Corrected Ccr kg 50 60 70 80 90 100 Days Before
(mL/min per Steady State
70 kg)* lb 110 132 154 176 198 198 Achieved**
-------------------------------------------------------------------------------------------------------------------------------
0 62.5+ 125 125 125 187.5 187.5 22
10 125 125 125 187.5 187.5 187.5 19
20 125 125 187.5 187.5 187.5 250 16
30 125 187.5 187.5 187.5 250 250 14
40 125 187.5 187.5 250 250 250 13
50 187.5 187.5 250 250 250 250 12
60 187.5 187.5 250 250 250 375 11
70 187.5 250 250 250 250 375 10
80 187.5 250 250 250 375 375 9
90 187.5 250 250 250 375 500 8
100 250 250 250 375 375 500 7
--------------------------------------------------------------------------------------------------------------------------------
* Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73
m(squared) body surface area. For Adults, if only 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
multiplied by 0.85. Note: This equation cannot be used for estimating
creatinine clearance in infants or children.
** If no loading dose administered.
+ 62.5 mcg = 0.0625 mg
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 dose of 250
mcg (0.25 mg) daily of LANOXIN Tablets, usually taken after the morning meal. If
no loading dose is administered, steady-state serum concentrations in this
patient should be anticipated at approximately 11 days.
INFANTS AND CHILDREN: In general, divided daily dosing is recommended for
infants and young children (under age 10). 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. Children over 10
years of age require adult dosages in proportion to their body weight. Some
researchers have suggested that infants and young children tolerate slightly
higher serum concentrations than do adults.
Daily maintenance doses for each age group are given in Table 6 and should
provide therapeutic effects with minimum risk of toxicity in most patients with
heart failure and normal sinus rhythm. These recommendations assume the presence
of normal renal function:
TABLE 6: DAILY MAINTENANCE DOSES IN CHILDREN WITH NORMAL RENAL FUNCTION
---------------------------------------------------------------------------------------------------------------------------------------------------------
Daily Maintenance Dose
Age (mcg/kg)
---------------------------------------------------------------------------------------------------------------------------------------------------------
2 to 5 Years 10 to 15
5 to 10 Years 7 to 10
Over 10 Years 3 to 5
In children with renal disease, digoxin must be carefully titrated based upon
clinical response. 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.
ATRIAL FIBRILLATION: Peak digoxin body stores larger than the 8 to 12 mcg/kg
required for most patients with heart failure and normal sinus rhythm have been
used for control of ventricular rate in patients with atrial fibrillation. Doses
of digoxin used for the treatment of chronic atrial fibrillation should be
titrated to the minimum dose that achieves the desired ventricular rate control
without causing undesirable side effects. Data are not available to establish
the appropriate resting or exercise target rates that should be achieved.
DOSAGE ADJUSTMENT WHEN CHANGING PREPARATIONS: The difference in bioavailability
between LANOXIN Injection or LANOXICAPS and LANOXIN Elixir Pediatric or LANOXIN
Tablets must be considered when changing patients from one dosage form to
another.
Doses of 100 mcg (0.1 mg) and 200 mcg (0.2 mg) of LANOXICAPS are approximately
equivalent to 125-mcg (0.125-mg) and 250-mcg (0.25-mg) doses of LANOXIN Tablets
and Elixir Pediatric, respectively (see table in ACTIONS/CLINICAL PHARMACOLOGY:
Pharmacokinetics).
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