Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3264
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Digoxin (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 500 mcg (2
mL) should be injected into a single site. Digoxin
injection 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 digoxin injection 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 digoxin injection should probably be administered over a period
of 5 minutes or longer. Mixing of digoxin injection 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: 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 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 ng/mL. However, since one-third of patients
with clinical toxicity have concentrations less than 2 ng/mL, values below
2 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-dailydosing 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: 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. Rapid Digitalization with a
Loading Dose: Digoxin Injection, USP is frequently used to achieve
rapid digitalization, with conversion to Digoxin Tablets or Digoxin Solution
in Capsules 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 1, CLINICAL PHARMACOLOGY:
Pharmacokinetics and dosing Table 5 below). Intramuscular
injection of digoxin is extremely painful and offers no advantages unless
other routes of administration are contraindicated. 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 amountactually given. A single initial
intravenous dose of 400 to 600 mcg (0.4 to 0.6 mg) of Digoxin Injection, USP
usually produces a detectable effect in 5 to 30 minutes that becomes maximal
in 1 to 4 hours. Additional doses of 100 to 300 mcg (0.1 to 0.3 mg) may be
given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate
effect is noted. The usual amount of Digoxin Injection, USP that a 70-kg patient
requires to achieve 8 to 12 mcg/kg peak body stores is 600 to 1,000 mcg (0.6
to 1 mg). Maintenance Dosing: The doses of oral 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 inpatients 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) x % Daily Loss/100 Where: % Daily Loss = 14 +
Ccr/5 (Ccr is creatinine clearance, corrected to 70
kg body weight or 1.73 mbody surface area.) Table
5 provides average daily maintenance dose requirements of Digoxin Injection,
USP for patients with heart failure based upon lean body weight and renal
function: * Daily maintenance doses have been rounded to the nearest
25 mcg increment. Ccr is creatinine
clearance, corrected to 70 kg body weight or 1.73 mbody surface
area. For adults, if only serum creatinineconcentrations (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. 75 mcg = 0.075 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
175 mcg (0.175 mg) daily of Digoxin Injection, USP. If no loading dose is
administered, steady-state serum concentrations in this patient should be
anticipated at approximately 11 days. Infants
and Children: See the full prescribing information for Digoxin Injection
Pediatric for specific recommendations. It
cannot be overemphasized that 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 Digoxin Injection, USP or Digoxin Solution
in Capsules and Digoxin Elixir Pediatric or Digoxin 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 Digoxin Solution in Capsules are
approximately equivalent to 125 mcg (0.125 mg) and 250 mcg (0.25 mg) doses
of Digoxin Tablets and Elixir Pediatric, respectively (see Table 1 in CLINICAL
PHARMACOLOGY: Pharmacokinetics).
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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-[(0-2,6-dideoxy-��-D-ribo-hexopyranosyl-(1���4)-0-2,6-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. Digoxin
Injection is a sterile solution of digoxin for intravenous injection. The
vehicle contains 40% propylene glycol and 10% alcohol. The injection is buffered
to a pH of 6.8 to 7.2 with 0.18% sodium phosphate and 0.08% citric acid. Each
mL contains digoxin 250 mcg (0.25 mg). 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 inmean 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 byits 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: Note: The
following data are from studies performed in adults unless otherwise stated. Absorption���Comparisons of the systemic
availability and equivalent doses for digoxin preparations are shown in table
1: * For example, 125 mcg Digoxin Tablets equivalent to 125
mcg Digoxin Elixir Pediatric equivalent to 100 mcg Digoxin Solution in Capsules
equivalent to 100 mcg Digoxin Injection/IV. 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��-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 days. The half-life in anuricpatients 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 Digoxin 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 Digoxin Injection, USP are shown in
Table 2: * Documented for ventricular response rate in atrial fibrillation,
inotropic effect 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 oral digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized
them to placebo or treatment with digoxin tablets. Both trials demonstrated
better preservation of exercise capacity in patients randomized to digoxin.
Continued treatment with digoxin 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 6801 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 digoxin 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). Digoxin 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 digoxin 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. 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.
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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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Digoxin Injection, USP is supplied as follows: Store at 25��C (77��F);
excursions permitted to 15 to 30��C (59 to 86��F) [See USP] and protect
from light. HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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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. Use
in Patients with Electrolyte Disorders: In patients with hypokalemia
or hypomagnesemia, toxicity may occur despite serum digoxin concentrations
below 2 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.<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 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
bybacterial 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. 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.<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:: Teratogenic Effects: Pregnancy
Category C: Animal reproduction studies have not been conducted
with digoxin. It is also not known whether digoxin can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Digoxin
should be given to a pregnant woman only if clearly needed.<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 administered
to 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 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).
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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. Administration of Potassium: Every effort should
be made to maintain the serum potassium concentration between 4 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.
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Digoxin
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Digoxin (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 digoxin 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. 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 digoxin 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. 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 conductiondisturbances 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. 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.
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Heart Failure: Digoxin
is indicated for the treatment of mild to moderate heart failure. Digoxin
increases left ventricular ejection fraction and improves heart failure symptoms
as evidenced by exercise capacity and heart failure-related hospitalizations
and emergency care, while having no effect on mortality. Where possible, digoxin
should be used with a diuretic and an angiotensin-converting enzyme inhibitor,
but an optimal order for starting these three drugs cannot be specified. Atrial Fibrillation: Digoxin is indicated for the
control of ventricular response rate in patients with chronic atrial fibrillation.
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Digoxin
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