Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/860
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Digoxin (Injection)
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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:<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 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-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 atwice-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: 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/>Rapid
Digitalization with a Loading Dose: Digoxin Injection is frequently used to achieve rapid
digitalization, with conversion to digoxin tablets or
digoxin 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 amount actually given. A
single initial intravenous dose of 400 to 600 mcg (0.4
to 0.6 mg) of Digoxin Injection 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
that a 70-kg patient requires to achieve 8- to 12-mcg/kg
peak body stores is 600 to 1000 mcg (0.6 to 1
mg).<br/>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 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 1800 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 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 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 ��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. If no loading dose is
administered, steady-state serum concentrations in this
patient should be anticipated at approximately 11
days<br/>Infants and
Children: See the
full prescribing information for pediatric digoxin injection
(not available from Baxter Healthcare) 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.<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
difference in bioavailability between injectable digoxin and
oral digoxin must be considered when changing patients from one
dosage form to another (see Table
1 in CLINICAL
PHARMACOLOGY, Pharmacokinetics). Intramuscular
injection of digoxin is extremely painful and offers no
advantage unless other routes of administration are
contraindicated. Parenteral drug products should be
inspected visually for particulate matter and discoloration
prior to administration, whenever solution and container
permit.
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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 ofDigitalis 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 has the
chemical name: 3��-[(O-2,6-Dideoxy-��-D-ribo-hexopyranosyl-(1���4)-O-2,6-dideoxy-��-D-ribo-hexopy��ranosyl-(1���4)-2,6-dideoxy-��-D-ribo-hexopyranosyl)oxy]-12��,14-dihydroxy-5��-card-20(22)-enolide,
and the following struc����tural formula: CHOMW 780.94 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 for slow intravenous or deep intramuscular
injection. Each mL contains digoxin 250 mcg (0.25 mg), alcohol 0.1 mL,
propylene glycol 0.4 mL, dibasic sodium phosphate, anhydrous 3 mg and
citric acid, anhydrous 0.8 mg in Water for Injection. pH 6.7-7.3; citric
acid and/or sodium phosphate added, if necessary, for pH adjustment.
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 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.<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 Digoxin Tablets equivalent to 125
mcg Digoxin Elixir Pediatric equivalent to 100 mcg
Digoxin Capsules equivalent to 100 mcg Digoxin
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 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 (seeDOSAGE 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 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. 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.<br/>Pharmacodynamic and
Clinical Effects: The times
to onset of pharmacologic effect and to peak effect of
preparations of digoxin 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)
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 de��veloping 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 , 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 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. *
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.<br/>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 available as: 500 mcg/2 mL (250
mcg/mL) DOSETTE ampuls packaged in 25s (NDC 0641-1410-35)<br/>Storage: Store at 20��-25��C (68��-77��F),
excursions permitted to 15��-30��C (59��-86��F) [see USP
Controlled Room Temperature]. Baxter and
Dosette are trademarks of Baxter International Inc., or its
subsidiaries. Manufactured by Baxter Healthcare
Corporation Deerfield,
IL 60015 USA For Product
Inquiry 1 800 ANA DRUG (1-800-262-3784) MLT-17/1.0
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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 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 theseelectrolytes 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 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) andtetracycline may
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. Rifampinmay 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:<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 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 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. Digoxin Immune Fab (Ovine) 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 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. Digoxin
Immune Fab (Ovine) should be used to reverse the toxic effects
of ingestion of a massive overdose. The decision to administer
Digoxin Immune Fab (Ovine) 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 Digoxin Immune Fab (Ovine); 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)
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dailymed-instance:adverseRe... |
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 hasdecreased 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.<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
.<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 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 serumdigoxin 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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dailymed-instance:warning |
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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dailymed-instance:indicatio... |
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.<br/>Atrial Fibrillation: Digoxin is
indicated for the control of ventricular response rate in
patients with chronic atrial fibrillation.
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dailymed-instance:name |
Digoxin
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