Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3723
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LANOXIN (Injection, Solution)
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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. Parenteral
administration of digoxin should be used only when the need for rapid digitalization
is urgent or when the drug cannot be taken orally. Intramuscular injection
can lead to severe pain at the injection site, thus intravenous administration
is preferred. If the drug must be administered by the intramuscular route,
it should be injected deep into the muscle followed by massage. No more than
200 mcg (2 mL) should be injected into a single site. LANOXIN
Injection Pediatric can be administered undiluted or diluted with a 4-fold
or greater volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection,
or 5% Dextrose Injection. The use of less than a 4-fold volume of diluent
could lead to precipitation of the digoxin. Immediate use of the diluted product
is recommended. If tuberculin syringes are used to
measure very small doses, one must be aware of the problem of inadvertent
overadministration of digoxin. The syringe should not be flushed with the parenteral solution after its contents are
expelled into an indwelling vascular catheter. Slow
infusion of LANOXIN Injection Pediatric is preferable to bolus administration.
Rapid infusion of digitalis glycosides has been shown to cause systemic and
coronary arteriolar constriction, which may be clinically undesirable. Caution
is thus advised and LANOXIN Injection Pediatric should probably be administered
over a period of 5 minutes or longer. Mixing of LANOXIN Injection Pediatric
with other drugs in the same container or simultaneous administration in the
same intravenous line is not recommended. In selecting
a dose of digoxin, the following factors must be considered:<br/>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:<br/>Heart Failure:<br/>Adults: See the full prescribing information for LANOXIN Injection
for specific recommendations.<br/>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. 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.<br/>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.<br/>Dosage Adjustment When Changing Preparations: The differences 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. 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 1 in CLINICAL PHARMACOLOGY: Pharmacokinetics).
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dailymed-instance:descripti... |
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��,5��,12��)-3-[(O-2,6-dideoxy-��-D-ribo-hexopyranosyl-(1���4)-O-2,6-dideoxy-��-D-ribo-hexopyranosyl-(1���4)-2,6-dideoxy-��-D-ribo-hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide.
Its molecular formula is CHO, its molecular
weight is 780.95, and its structural formula is: Digoxin
exists as odorless white crystals that melt with decomposition above 230��C.
The drug is practically insoluble in water and in ether; slightly soluble
in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine. LANOXIN
Injection Pediatric is a sterile solution of digoxin for intravenous or intramuscular
injection. The vehicle contains 40% propylene glycol and 10% alcohol. The
injection is buffered to a pH of 6.8 to 7.2 with 0.17% sodium phosphate and
0.08% anhydrous citric acid. Each 1-mL ampul contains 100 mcg (0.1 mg)
digoxin. Dilution is not required.
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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 myocardialsystolic 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.<br/>Pharmacokinetics: Note: The following data are from studies performed in adults,
unless otherwise stated.<br/>Absorption: Comparisons of
the systemic availability and equivalent doses for preparations of digoxin
are shown in Table 1. For example, 125 mcg
LANOXIN Tablets equivalent to 125 mcgLANOXIN
Elixir Pediatric equivalent to 100 mcg LANOXICAPS equivalent to 100 mcg
LANOXIN Injection/IV.<br/>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 uponthe 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.<br/>Metabolism: Only a small percentage (16%) of a dose of digoxin is metabolized.
The end metabolites, which include 3��-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.<br/>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.<br/>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. In children with renal disease, digoxin must be carefully
titrated based upon clinical response. Plasma digoxin
concentration profiles in patients with acute hepatitis generally fell within
the range of profiles in a group of healthy subjects.<br/>Pharmacodynamic and Clinical Effects: The times to onset of pharmacologic effect and to peak effect
of preparations of LANOXIN are shown in Table 2. Documented for ventricular
response rate in atrial fibrillation, inotropic effects and electrocardiographic
changes. Depending
upon rate of infusion.<br/>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.<br/>Chronic Heart Failure: Two 12-week, double-blind, placebo-controlled studies enrolled
178 (RADIANCE trial) and 88 (PROVED trial) adult patients with NYHA
class II or III heart failure previously treated with oral digoxin, a diuretic,
and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment
with LANOXIN Tablets. Both trials demonstrated better preservation of exercise
capacity in patients randomizedto 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 adult 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 Tablets, the dose of which was adjusted for the patient's
age, sex, lean body weight, and serum creatinine (see DOSAGE AND ADMINISTRATION),
and followed for up to 58 months (median 37 months). The median
daily dose prescribed was 0.25 mg. Overall all-cause mortality was 35%
with no difference between groups (95% confidence limits for relative risk
of 0.91 to 1.07). 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 to increase time to all-cause death or
hospitalization. The trend was evident in subgroups of patients with mild
heart failure as well as more severe disease, as shown in Table 3. Although
the effect on all-cause death or hospitalization was not statistically significant,
much of the apparent benefit derived from effects on mortality and hospitalization
attributed to heart failure. Number of patients with
an event during the first 2 years per 1,000 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.<br/>Chronic Atrial Fibrillation: In adult 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.
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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.
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LANOXIN (digoxin) Injection Pediatric, 100 mcg (0.1 mg)
in 1 mL; box of 10 ampuls (NDC 0173-0262-10). Store at 25��C (77��F); excursions permitted to 15
to 30��C (59 to 86��F) [see USP Controlled Room Temperature] and protect
from light. Manufactured by DSM
Pharmaceuticals, Inc. Greenville, NC 27834 for Glaxo
Wellcome Inc. Research Triangle Park, NC 27709 ��2002,GlaxoSmithKline.
All rights reserved. July2002 RL-1128
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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.<br/>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.<br/>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.<br/>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.<br/>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.<br/>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.<br/>Drug Interactions: Potassium-depleting diureticsare 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 volume of distribution of the drug, with the implication that digitalis
intoxication may result. Erythromycin and clarithromycin (and possibly other macrolide antibiotics) and tetracyclinemay increase digoxin absorption in patients who inactivate digoxin
by bacterial metabolism in the lower intestine, so that digitalis intoxication
may result. Propantheline and diphenoxylate, by decreasing gut motility, may
increase digoxin absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs,and metoclopramide may interfere with intestinal digoxin absorption, resulting in
unexpectedly low serum concentrations. 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. Thyroidadministration 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 advancedor complete heart block. Due
to the considerable variability of these interactions, 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.<br/>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.<br/>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.<br/>Pregnancy:<br/>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.<br/>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 administeredto a nursing woman.<br/>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.<br/>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 likelyto 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.
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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 [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.<br/>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).<br/>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.
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digoxin
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LANOXIN (Injection, Solution)
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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 Tablets compared to 0.9% in patients taking
placebo. In this trial, the most common manifestations of digoxin toxicity
included gastrointestinal and cardiac disturbances; CNS manifestations were
less common.<br/>Adults:<br/>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).<br/>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.<br/>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).<br/>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.<br/>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.
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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.<br/>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.<br/>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.
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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.<br/>Atrial Fibrillation: LANOXIN is indicated for the control of ventricular response
rate in patients with chronic atrial fibrillation.
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LANOXIN
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