Label: DIGOXIN - digoxin tablet

  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated 11/09

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  • CLINICAL PHARMACOLOGY


    MECHANISM OF ACTION

    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 neu-rohormonal 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.

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  • PHARMACOKINETICS SECTION: ABSORPTION

    Pharmacokinetics:Absorption: Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours.
    Absorption of digoxin from digoxin tablets has been demonstrated to be 60% to 80% complete compared to an identical intravenous
    dose of digoxin (absolute bioavailability) or LANOXICAPS® [Digoxin Solution in Capsules] (relative bioavailability). When digoxin
    tablets are taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When
    taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Comparisons of the systemic
    availability and equivalent doses for oral preparations of digoxin are shown in Table 1.




    Table 1: Comparisons of the Systemic Availability and Equivalent Doses for Oral Preparations of Digoxin
    Product
    Absolute
    Bioavailability
    Equivalent Doses (mcg)*
    Amoung Dosage Forms



    Digoxin Tablets
    60-80%
    62.5             125         250        500
    Digoxin Elixir Pediatric
    70-85%
    62.5             125         250        500
    Digoxin Solution in Capsules
    90-100%
    50                100         200        400
    Digoxin Injection/IV
    100%
    50                100         200        400
    In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in
    the gut. Data suggest that one in ten patients treated with digoxin tablets will degrade 40% or more of the ingested dose. As a result,
    certain antibiotics may increase the absorption of digoxin in such patients. Although inactivation of these bacteria by antibiotics is
    rapid, the serum digoxin concentration will rise at a rate consistent with the elimination half-life of digoxin. The magnitude of rise in
    serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as two-fold in some cases.
    Distribution: Following drug administration, a 6- to 8-hour tissue distribution phase is observed. This is followed by a much more
    gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak
    height and slope of the early portion, (absorption/distribution phases) of the serum concentration-time curve are dependent upon the
    route of administration and the absorption characteristics of the formulation.
    Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action,
    but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and
    correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating
    therapeutic and toxic effects (see Dosage and Administration: Serum Digoxin Concentrations).
    Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution. Digoxin crosses both the blood-brain
    barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the
    mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered
    by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body
    weight.
    Metabolism: Only a small percentage (16%) of a dose of digoxin is metabolized. The end metabolites, which include 3b-digoxigenin;
    3-keto-digoxigenin, and their glucuronide and sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis,
    oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known
    to induce or inhibit the cytochrome P-450 system.
    Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional
    to the total body content). Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted
    unchanged in the urine. Renal excretion of digoxin is proportional to glomerular filtration rate and is largely independent of urine
    flow. In healthy volunteers with normal renal function, digoxin has a half-life of 1.5 to 2.0 days. The half-life in anuric patients
    is prolonged to 3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during
    cardiopulmonary bypass because most of the drug is bound to tissue and does not circulate in the blood.
    Special Populations: Race differences in digoxin pharmacokinetics have not been formally studied. Because digoxin is primarily
    eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races,
    pharmacokinetic differences due to race are not expected.
    The clearance of digoxin can be primarily correlated with renal function as indicated by creatinine clearance. The Cockcroft and
    Gault formula for estimation of creatinine clearance includes age, body weight, and gender. Table 5 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.
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  • PHARMACODYNAMICS SECTION

    Pharmacodynamic and Clinical Effects: The times to onset of pharmacologic effect and to peak effect of preparations of digoxin
    tablets are shown in Table 2.


    Table 2: Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of Digoxin
    Product
    Time to
    Onset of Effect*
    Time to
    Peak Effect



    Digoxin Tablets
    0.5 - 2 hours
    2 - 6 hours
    Digoxin Elixir Pediatric
    0.5 - 2 hours
    2 - 6 hours
    Digoxin Soultion in Capsules
    0.5 - 2 hours
    2 - 6 hours
    Digoxin Injection/IV
    5-30 minutes
    1 - 4 hours
    * Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes.
    † Depending upon rate of infusion.
    Hemodynamic Effects: Digoxin produces hemodynamic improvement in patients with heart failure. Short- and long-term therapy
    with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic
    vascular resistance. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease
    in end-systolic and end-diastolic dimensions.


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  • INDICATIONS AND USAGE

    INDICATIONS AND USAGE:
    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 angiotensinconverting
    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 Close
  • CONTRAINDICATIONS:

    CONTRAINDICATIONS:
    Digitalis glycosides are contraindicated in patients with ventricular fibrillation or in patients with a known hypersensitivity to digoxin.
    A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin. Close
  • WARNINGS

    WARNINGS:
    Sinus Node Disease and AV Block: Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR
    interval. The drug may cause severe sinus bradycardia or sinoatrial block in patients with preexisting sinus node disease and may
    cause advanced or complete heart block in patients with preexisting 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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  • PRECAUTIONS

    PRECAUTIONS:
    Use in Patients with Impaired Renal Function: Digoxin is primarily excreted by the kidneys; therefore, patients with impaired
    renal function require smaller than usual maintenance doses of digoxin (see DOSAGE AND ADMINISTRATION). Because of
    the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration
    in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of
    digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal
    function.
    Use in Patients with Electrolyte Disorders: In patients with hypokalemia or hypomagnesemia, toxicity may occur despite serum
    digoxin concentrations below 2 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 nullity the effects of
    digoxin in humans; thus, digoxin may be ineffective until serum calcium is restored to normal. These interactions are related to the
    fact that digoxin affects contractility and excitability of the heart in a manner similar to that of calcium.

    Use in Thyroid Disorders and Hypermetabolic States: Hypothyroidism may reduce the requirements for digoxin. Heart failure and/
    or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia or arteriovenous shunt) are
    best, treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly resistant
    to digoxin treatment. Care must be taken to avoid toxicity if digoxin is used.
    Use in Patients with Acute Myocardial Infarction: Digoxin should be used with caution in patients with acute myocardial
    infarction. The use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand
    and ischemia.
    Use During Electrical Cardioversion: It may be desirable to reduce the dose of digoxin for 1 to 2 days prior to electrical
    cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequences
    of increasing the ventricular response if digoxin is withdrawn. If digitalis toxicity is suspected, elective cardioversion should be
    delayed. If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular
    arrhythmias.
    Laboratory Test Monitoring: Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine
    concentrations) assessed periodically; the frequency of assessments will depend on the clinical setting. For discussion of serum
    digoxin concentrations; see DOSAGE AND ADMINISTRATION section.
    Drug Interactions: Potassium-depleting diuretics are a major contributing factor to digitalis toxicity. Calcium, particularly if
    administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Quinidine, verapamil,
    amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone raise the serum digox-in 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 tetracy-cline may increase digoxin absorption
    in patients who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication may result (see
    CLINICAL PHARMACOLOGY: Absorption). Propantheline and diphenoxylate, by decreasing gut motility, may increase digoxin
    absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine; certain anticancer drugs, and metoclopramide may
    interfere with intestinal digoxin absorption, resulting in unexpectedly low serum concentrations. Rifampin may decrease serum
    digoxin concentration, especially in patients with renal dysfunction, by increasing the non-renal clearance of digoxin. There have
    been inconsistent reports regarding the effects of other drugs [e.g., quinine, penicillamine] on serum digoxin concentration. Thyroid
    administration to a digitalized, hypothyroid patient may increase the dose requirement of digoxin. Concomitant use of digoxin and
    sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from muscle
    cells, and may thereby cause arrhythmias in digitalized patients. Although beta-adrenergic blockers or calcium channel blockers and
    digoxin may be useful in combination to control atrial fibrillation, their additive effects on AV node conduction can result in advanced
    or complete heart block.
    Due to the considerable variability of these interactions; the dosage of digoxin should be individualized when patients receive
    these medications concurrently. Furthermore, caution should be exercised when combining digoxin with any drug that may cause
    a significant deterioration in renal function, since a decline in glomerular filtration or tubular secretion may impair the excretion of
    digoxin.
    Drug/Laboratory Test Interactions: The use of therapeutic doses of digoxin may cause prolongation of the PR interval and
    depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram
    during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.
    Carcinogenesis, Mutagenesis, Impairment of Fertility: There have been no long-term studies performed in animals to evaluate
    carcinogenic potential; nor have studies been conducted to assess the mutagenic potential of digoxin or its potential to affect fertility.
    Pregnancy: Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with digoxin. It
    is also not known whether digoxin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.
    Digoxin should be given to a pregnant woman only if clearly needed.
    Nursing Mothers: Studies have shown that digoxin concentrations in the mother's serum and milk are similar. However, the
    estimated exposure of a nursing infant to digoxin via breast feeding will be far below the usual infant maintenance dose. Therefore,
    this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is
    administered to a nursing woman.
    Pediatric Use: Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are
    particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized
    according to their degree of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion.
    Geriatric Use: The majority of clinical experience gained with digoxin has been in the elderly population. This experience has
    not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to
    be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal
    function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which
    should be based on renal function, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION).
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  • ADVERSE REACTION

    ADVERSE REACTIONS:
    In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic
    effect. Hence, adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum
    concentration range and when there is careful attention to concurrent medications and conditions. Because some patients may be particularly susceptible to side effects with digoxin, the dosage of the drug should always be selected
    carefully and adjusted as the clinical condition of the patient warrants. In the past, when high doses of digoxin were used and little
    attention was paid to clinical status or concurrent medications, adverse reactions to digoxin were more frequent and severe. Cardiac
    adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for
    about one-fourth of these adverse reactions. However, available evidence suggests that the incidence and severity of digoxin toxicity
    has decreased substantially in recent years. In recent controlled clinical trials, in patients with predominantly mild to moderate
    heart failure, the incidence of adverse experiences was comparable in patients taking digoxin and in those taking placebo. In a large
    mortality trial, the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking digoxin 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 firstdegree,
    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.
    Table 4 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 inpatients following dosage titration with the use of serum digoxin
    concentrations and careful follow-up. These adverse experiences are consistent with results from a large, placebo-controlled mortality
    trial (DIG trial) wherein over half the patients were not receiving digoxin prior to enrollment.

    Table 4: Adverse Experience in Two Parallel, Double-Blind, Placebo-Controlled Withdrawal Trials (number of Patients Reporting)
    Adverse Experience
    Digoxin Patients
    (n=123)
    Placebo Patients
    (n=125)



    Cardiac
       Palpitation
       Ventricular Extrasystole
       Tachycardia
       Heart Arrest
    1
    1
    2
    1
    4
    1
    1
    1
    Gastrointestional
       Anorexia
       Nausea
       Vomiting
       Diarrhea
       Abdominal pain
    1
    4
    2
    4
    0
    4
    2
    1
    1
    6
    CNS
       Headache
       Dizziness
       Mental Disturbances
    4
    6
    5
    4
    5
    1
    Other
       Rash
       Death
    2
    4
    1
    3
    Infants and Children: The side effects of digoxin in infants and children differ from those seen in adults in several respects.
    Although digoxin may produce anorexia, nausea, vomiting, diarrhea, and CNS disturbances in young patients, these are rarely the
    initial symptoms of overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with digoxin in infants
    and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are conduction disturbances of 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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  • OVERDOSE SECTION

    OVERDOSAGE:
    Treatment of Adverse Reactions Produced by Overdosage: Digoxin should be temporarily discontinued until the adverse
    reaction resolves. Every effort should also be made to correct factors that may contribute to the adverse reaction (such as electrolyte
    disturbances or concurrent medications). Once the adverse reaction has resolved, therapy with digoxin may be reinstituted, following a
    careful reassessment of dose.
    Withdrawal of digoxin may be all that is required to treat the adverse reaction. However, when the primary manifestation of digoxin
    overdosage is a cardiac arrhythmia, additional therapy may be needed.
    If the rhythm disturbance is a symptomatic bradyarrhythmia or heart block, consideration should be given to the reversal of toxicity
    with DIGIBIND® [Digoxin Immune Fab (Ovine)] (see Massive Digitalis Overdosage subsection), 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 hyperkalemia (see Administration of Potassium subsection) or hypomagnesemia is present. DIGIBIND is a specific
    antidote for digoxin and may be used to reverse potentially life-threatening ventricular arrhythmias due to digoxin overdosage.
    Administration of Potassium: Every effort should be made to maintain the serum potassium concentration between 4.0 and
    5.5 mmol/L. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and the serum potassium
    concentration is low, potassium may be administered cautiously by the intravenous route. The electrocardiogram should be monitored
    for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. Potassium salts may be
    dangerous in patients who manifest bradycardia or heart block due to digoxin (unless primarily related to supraventricular tachycardia)
    and in the setting of massive digitalis overdosage (see Massive Digitalis Overdosage subsection).
    Massive Digitalis Overdosage: Manifestations of life-threatening toxicity include ventricular tachycardia or ventricular fibrillation,
    or progressive bradyarrhythmias, or heart block. The administration of more than 10 mg of digoxin in a previously healthy adult, or
    more than 4 mg in a previously healthy child, or a steady-state serum concentration greater than 10 ng/mL often results in cardiac
    arrest.
    DIGIBIND should be used to reverse the toxic effects of ingestion of a massive overdose. The decision to administer DIGIBIND to
    a patient who has ingested a massive dose of digoxin but who has not yet manifested life-threatening toxicity should depend on the
    likelihood that life-threatening toxicity will occur (see above).
    Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in
    the gut during enteroenteric recirculation. Emesis or gastric lavage may be indicated especially if ingestion has occurred within 30
    minutes of the patient's presentation at the hospital. Emesis should not be induced in patients who are obtunded. If a patient presents
    more than 2 hours after ingestion or already has toxic manifestations, it may be unsafe to induce vomiting or attempt passage of a
    gastric tube, because such maneuvers may induce an acute vagal episode that can worsen digitalis-related arrhythmias.
    Severe digitalis intoxication can cause a massive shift of potassium from inside to outside the cell, leading to life-threatening
    hyperkalemia. The administration of potassium supplements in the setting of massive intoxication may be hazardous and should be
    avoided. Hyperkalemia caused by massive digitalis toxicity is best treated with DIGIBIND; initial treatment with glucose and insulin
    may also be required if hyperkalemia itself is acutely life-threatening. Close
  • DOSAGE & ADMINISTRATION

    DOSAGE AND ADMINISTRATION:
    General: Recommended dosages of digoxin may require considerable modification because of individual sensitivity of the patient
    to the drug, the presence of associated conditions, or the use of concurrent medications. In selecting a dose of digoxin, the following
    factors must be considered:
    1. The body weight of the patient. Doses should be calculated based upon lean (i.e., ideal) body weight.
    2. The patient's renal function, preferably evaluated on the basis of estimated creatinine clearance.
    3. The patient's age. Infants and children require different doses of digoxin than adults. Also, advanced age may be indicative of
    diminished renal function even in patients with normal serum creatinine concentration (i.e., below 1.5 mg/dL).
    4. Concomitant disease states, concurrent medications, or other factors likely to alter the pharmacokinetic or pharma-codynamic
    profile of digoxin (see PRECAUTIONS).
    Serum Digoxin Concentrations: In general, the dose of digoxin used should be determined on clinical grounds. However,
    measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in
    assigning certain probabilities to the likelihood of digoxin intoxication. About two-thirds of adults considered adequately digitalized (without evidence of toxicity) have serum digoxin concentrations ranging from 0.8 to 2 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 a twice-daily dosing schedule,
    there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose.
    If a discrepancy exists between the reported serum concentration and the observed clinical response, the clinician should consider the
    following possibilities:
    1. Analytical problems in the assay procedure.
    2. Inappropriate serum sampling time.
    3. Administration of a digitalis glycoside other than digoxin.
    4. Conditions (described in WARNINGS and PRECAUTIONS) causing an alteration in the sensitivity of the patient to digoxin.
    5. Serum digoxin concentration may decrease acutely during periods of exercise without any associated change in clinical efficacy
    due to increased binding of digoxin to skeletal muscle.
    Heart Failure: Adults: Digitalization may be accomplished by either of two general approaches that vary in dosage and frequency of
    administration, but reach the same endpoint in terms of total amount of digoxin accumulated in the body.
    1. If rapid digitalization is considered medically appropriate, it may be achieved by administering a loading dose based upon
    projected peak digoxin body stores. Maintenance dose can be calculated as a percentage of the loading dose
    2. More gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to
    accumulate slowly. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives of the drug for the
    individual patient. Depending upon the patient's renal function, this will take between 1 and 3 weeks.

    Rapid Digitalization with a Loading Dose: Peak digoxin body stores of 8 to 12 mcg/kg should provide therapeutic effect with
    minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Because of altered digoxin distribution and
    elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e., 6 to 10 mcg/kg) [see
    PRECAUTIONS].
    The loading dose should be administered in several portions, with roughly half the total given as the first dose. Additional fractions of
    this planned total dose may be given at 6- to-8-hour intervals, with careful assessment of clinical response before each additional
    dose. If the patient's clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the
    maintenance dose should be based upon the amount actually given.
    A single initial dose of 500 to 750 mcg (0.5 to 0.75 mg) of digoxin tablets usually produces a detectable effect in 0.5 to 2 hours that
    becomes maximal in 2 to 6 hours. Additional doses of 125 to 375 mcg (0.125 to 0.375 mg) may be given cautiously at 6-to 8-hour
    intervals until clinical evidence of an adequate effect is noted. The usual amount of digoxin tablets that a 70 kg patient requires to
    achieve 8 to 12 mcg/kg peak body stores is 750 to 1250 mcg (0.75 to 1.25 mg).
    Digoxin Injection 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).
    Maintenance Dosing: The doses of digoxin used in controlled trials in patients with heart failure have ranged from 125 to 500 mcg
    (0.125 to 0.5 mg) once daily. In these studies, the digoxin dose has been generally titrated according to the patient's age, lean body
    weight, and renal function. Therapy is generally initiated at a dose of 250 mcg (0.25 mg) once daily in patients under age 70 with
    good renal function, at a dose of 125 mcg (0.125 mg) once daily in patients over age 70 or with impaired renal function, and at a
    dose of 62.5 mcg (0.0625 mg) in patients with marked renal impairment. Doses may be increased every 2 weeks according to clinical
    response.
    In a subset of approximately 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 m2 body surface area.)


    Example: Based on Table 5, a patient in heart failure with an estimated lean body weight of 70 kg and a Ccr of 60 mL/min should be
    given a dose of 250 mcg (0.25 mg) daily of digoxin tablets, usually taken after the morning meal. If no loading dose is administered,
    steady-state serum concentrations in this patient should be anticipated at approximately 11 days.
    Infants and Children: In general, divided daily dosing is recommended for infants and young children (under age 10). In the
    newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially
    pronounced in the premature infant. Beyond the immediate newborn period, children generally require proportionally larger doses
    than adults on the basis of body weight or body surface area. Children over 10 years of age require adult dosages in proportion to their
    body weight. Some researchers have suggested that infants and young children tolerate slightly higher serum concentrations than do
    adults.
    In children with renal disease, digoxin must be carefully; titrated; based upon clinical response.
    It cannot be overemphasized that both the adult and pediatric dosage guidelines provided are based upon average patient
    response and substantial individual variation can be expected. Accordingly, ultimate dosage selection must be based upon
    clinical assessment of the patient.
    Atrial Fibrillation: Peak digoxin body stores larger than the 8 to 12 mcg/kg required for most patients with heart failure and normal
    sinus rhythm have been used for control of ventricular rate in patients with atrial fibrillation. Doses of digox-in 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 or digoxin solution
    in capsules and digoxin pediatric elixir 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 digoxin pediatric elixir, respectively.

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  • How Supplied:

    HOW SUPPLIED:
    Digoxin Tablets USP, 0.125 mg are yellow, round, scored on one side with imprint "W 40" and are available in:
    Bottles of 100 tablets.
    Bottles of 1000 tablets.
    Bottles of 5000 tablets.
    Digoxin Tablets USP, 0.25 mg are white, round, scored on one side with imprint "WW 41" and are available in:
    Bottles of 100 tablets.
    Bottles of 1000 tablets.
    Bottles of 5000 tablets.
    Store at 20-25ºC (68-77ºF) [See USP Controlled Room Temperature] in a dry place.
    Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
    Lanoxicaps® is a registered trademark of GlaxoSmithKline.
    Manufactured By:
    West-ward Pharmaceutical Corp.
    Eatontown, NJ 07724
    Revised May 2008 Close
  • IMAGE FROM DRUG LABEL CONTENT
  • INGREDIENTS AND APPEARANCE
    DIGOXIN 
    digoxin tablet
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:53808-0165(NDC:00143-1240-01)
    Route of Administration ORAL DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    DIGOXIN (DIGOXIN) DIGOXIN 125 ug
    Inactive Ingredients
    Ingredient Name Strength
    ANHYDROUS LACTOSE  
    SILICON DIOXIDE  
    STARCH, CORN  
    D&C YELLOW NO. 10  
    FD&C YELLOW NO. 6  
    LACTOSE MONOHYDRATE  
    MAGNESIUM STEARATE  
    STARCH, CORN  
    Product Characteristics
    Color yellow Score 2 pieces
    Shape ROUND Size 6mm
    Flavor Imprint Code W;40
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:53808-0165-1 30 in 1 BLISTER PACK
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA077002 05/01/2008
    Labeler - DEPT HEALTH CENTRAL PHARMACY (829348114)
    Close