Lanoxin

St. John’s wort (Hypericum perforatum) may interfere with intestinal digoxin absorption, resulting in unexpectedly low serum concentrations. Patients are advised to consult with their doctors before taking herbal products.

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.

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.

Digitalis glycosides have a narrow therapeutic range and changes in digoxin pharmacokinetics and/or pharmacodynamics caused by a digoxin-drug interaction can result in toxicity or underdigitalization. The presence of or a change in an underlying disease state also can cause changes in digoxin pharmacokinetics and/or pharmacodynamics and may complicate or contribute to a digoxin-drug interaction. Because a risk of digoxin toxicity exists, and the clinical significance of an interaction may be variable and not necessarily predictable, it is important that the addition or withdrawal of a drug to or from a therapeutic regimen that includes digoxin be carefully evaluated in the context of the patient and the clinical situation.

Potassium-depleting corticosteroids and diuretics may be major contributing factors 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, cause a rise in serum digoxin concentration, with the implication that digitalis intoxication may result. This rise appears to be proportional to the dose.

Certain antibiotics [erythromycin and clarithromycin (and possibly other macrolide antibiotics) and tetracycline] may increase digoxin absorption in patients who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication may result. Recent studies have shown that specific colonic bacteria in the lower gastrointestinal tract convert digoxin to cardioinactive reduction products, thereby reducing its bioavailability. 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 concentrations relates to the extent of bacterial inactivation, and may be as much as 2 fold in some cases.

Propantheline and diphenoxylate, by decreasing gut motility, may increase digoxin absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, phenytoin, St. John’s wort (Hypericum perforatum) and certain anticancer drugs may interfere with intestinal digoxin absorption, resulting in unexpectedly low serum concentrations. 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 because both enhance ectopic pacemaker activity. Succinylcholine may cause a sudden extrusion of potassium from muscle cells and may thereby cause arrhythmias in digitalized patients. Although α-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 complete heart block.

Due to the considerable variability of these interactions, digoxin dosage should be carefully individualized when patients receive coadministered medications. 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.

More gradual digitalization can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided in Table 5 can be used in calculating this dose for patients with normal renal function.

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.

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 the dose of digoxin, several 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 medication or other factors likely to alter the pharmacokinetic or pharmacodynamic profile of digoxin (see Warnings and Precautions).

   
   

5. To minimize toxic side effects, the lowest effective dose should be used as the maintenance dose.

Digoxin is usually administered orally as a single daily dose. Divided daily dosing is recommended in infants and young children.

If a dose is missed patients are advised to take the dose as soon as remembered if within 12 hours of scheduled dose and not taking if remembered later. Patients are advised not to double doses and to consult their doctor if a dose is missed for 2 days or more.

In children with renal disease, digoxin must be carefully titrated based upon clinical response.

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. Rapid digitalization may be achieved by administering a loading dose based upon projected peak body digoxin stores, then calculating the maintenance dose 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 5 half-lives of the drug for the individual patient. Depending upon the patient’s renal function, this will take between 1 and 3 weeks.

In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication. About two-thirds of adults considered adequately digitalized (without evidence of toxicity) have serum digoxin concentrations ranging from 0.8 to 2.0 ng/mL. However, digoxin may produce clinical benefits even at serum concentrations below this range. About two-thirds of adult patients with clinical toxicity have serum digoxin concentrations greater than 2.0 ng/mL. However, since one-third of patients with clinical toxicity have concentrations less than 2.0 ng/mL, values below 2.0 ng/mL do not rule out the possibility that a certain sign or symptom is related to digoxin therapy. Rarely, there are patients who are unable to tolerate digoxin at serum concentrations below 0.8 ng/mL. Consequently, the serum concentration of digoxin should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug.

To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations should be done just before the next scheduled dose of the drug. If this is not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of digoxin will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient's renal function. On a twice-daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose.

If a discrepancy exists between the reported serum concentration and the observed clinical response, the clinician should consider the following possibilities:

1. Analytical problems in the assay procedure.

   
   

2. Inappropriate serum sampling time.

   
   

3. Administration of a digitalis glycoside other man 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.

Rarely, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines.

Adverse reactions to digoxin are usually dose dependent and occur at dosages higher than those needed to achieve a therapeutic effect.

Adverse Experiences in Two Parallel, Double-blind, Placebo-controlled Withdrawal Trials with LANOXIN Tablets (Number of Patients Reporting)

In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions.

Because some patients may be particularly susceptible to side effects with digoxin, the dosage of the drug should always be selected carefully and adjusted as the clinical condition of the patient warrants. In the past, when high doses of digoxin were used and little attention was paid to clinical status or concurrent medications, adverse reactions to digoxin were more frequent and severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. However, available evidence suggests that the incidence and severity of digoxin toxicity has decreased substantially in-recent years. In recent controlled clinical trials, in patients with predominantly mild to moderate heart failure, the incidence of adverse experiences was comparable in patients taking digoxin and in those taking placebo. In a large mortality trial, the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking LANOXIN compared to 0.9% in patients taking placebo. In this trial, the most common manifestations of digoxin toxicity included gastrointestinal and cardiac disturbances; CNS manifestations were less common.

Toxicity differs from the adult in a number of respects. Anorexia, nausea, vomiting, diarrhea and CNS disturbances may be present but are rare as initial symptoms in infants. Cardiac arrhythmias are more reliable signs of toxicity. Digoxin in children may produce any arrhythmia. The most commonly encountered 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 also 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 initially be assumed to be a consequence of digoxin intoxication, until further evaluation proves otherwise.

Unifocal or multiform ventricular premature contractions, especially in bigeminal or trigeminal patterns, are the most common arrhythmias associated with digoxin toxicity in adults with heart disease. Persistent bigeminy at rest but not on exercise when the sinus rate increases has traditionally been acceptable in the management of some arrhythmias. Ventricular tachycardia and ventricular fibrillation may result from digitalis toxicity. Atrioventricular (AV) dissociation, accelerated junctional (nodal) rhythm and atrial tachycardia with block are also common arrhythmias caused by digoxin overdosage. Excessive slowing of the pulse is a clinical sign of digoxin overdosage. AV block (Wenckebach) of increasing degree may proceed to complete heart block (including asystole).

Note: The electrocardiogram is fundamental in determining the presence and nature of these cardiac disturbances.

Digoxin may also induce other changes in the ECG (e.g., PR prolongation, ST depression), which represent digoxin effect and may or may not be associated with digitalis 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).

Visual disturbances (blurred or yellow vision), headache, weakness, apathy, psychosis, and mental disturbances (such as anxiety, depression, delirium, and hallucination) can occur.

Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed.

LANOXIN is indicated for the treatment of mild to moderate heart failure. LANOXIN increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by exercise capacity and heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, LANOXIN should be used with a diuretic and angiotensin-converting enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified.

Digoxin is usually continued after failure is controlled unless some known precipitating factor is corrected. Studies have shown that withdrawal of digoxin may worsen functional status, exercise capacity, and the left ventricular ejection fraction in patients with heart failure. In patients in whom digoxin may be difficult to regulate, or in whom the risk of toxicity may be great (e.g., patients with unstable renal function or whose potassium levels tend to fluctuate) a cautious withdrawal of digoxin may be considered. If digoxin is discontinued, the patient should be regularly monitored for clinical evidence of recurrent heart failure.

Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effect of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. Digitalization in infants and children must be individualized (see Dosage and Administration).

LANOXIN is indicated for the control of ventricular response rate in patients with chronic atrial fibrillation.

Although appropriate studies on the relationship of age to the effects of digitalis glycosides have not been performed in the geriatric population, the majority of experience with digoxin is in this population. This drug is known to be substantially excreted by the kidneys, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients may be more likely to have age-related renal function impairment, which may significantly increase the elimination half-life of digoxin, 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).

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 maybe 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).

Manifestations of life-threatening toxicity include severe ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias or heart block. The administration of more than 10 mg of digoxin in a previously healthy adults, 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 effect 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 the 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.

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), 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 Administration of Potassium) 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.

Each round, peach, flat-faced, bevelled-edge tablet with code LANOXIN U3A, contains: digoxin 0.0625 mg (62.5 µg). Nonmedicinal ingredients: FD&C Yellow No. 6, lactose, magnesium stearate, pregelatinized starch and starch (corn). Tartrazine-free. Bottles of 250.

Each round, white, biconvex tablet, with code LANOXIN X3A on same side as score mark, contains: digoxin 0.25 mg (250 µg). Nonmedicinal ingredients: lactose, magnesium stearate, pregelatinized starch and starch (corn). Dye- and tartrazine-free. Bottles of 250 and 1000.

Each mL of clear, light-green colored liquid with a lime odor and taste, contains: digoxin 0.05 mg (50 µg). Nonmedicinal ingredients: alcohol, calcium diatomaceous earth, citric acid, D&C Green No. 5, D&C Yellow No. 10, lime flavour, methylparaben, propylene glycol, sodium phosphate, sucrose and water. Alcohol: 11.5 mL/100 mL. Tartrazine-free. Bottles of 115 mL with calibrated dropper.

Each round, yellow, flat-faced tablet, with code LANOXIN Y3B on the same side as score mark, contains: digoxin 0.125 mg (125 µg). Nonmedicinal ingredients: D&C Yellow No. 10, FD&C Yellow No. 6, lactose, magnesium stearate, pregelatinized starch and starch (corn). Tartrazine-free. Bottles of 250 and 1000.

In patients with hypokalemia, toxicity may occur despite serum digoxin concentrations within the normal range, because potassium depletion sensitizes the myocardium to digoxin. Therefore, it is desirable to maintain normal serum potassium levels in patients being treated with digoxin. Hypokalemia may result from diuretic, amphotericin B or corticosteroid therapy, and from peritoneal or hemodialysis or mechanical suction of gastrointestinal secretions. It may also accompany malnutrition, diarrhea, prolonged vomiting, old age, long-standing heart failure, long-standing wasting diseases and treatment with ion-exchange resins or carbenoxolone. In general, rapid changes in serum potassium or other electrolytes should be avoided, and i.v. treatment with potassium should be reserved for special circumstances as described below (see Overdosage).

Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Hypercalcemia from any cause predisposes the patient to digitalis toxicity. On the other hand, hypocalcemia can nullify the effects of digoxin in man; thus digoxin may be ineffective until serum calcium is restored to normal. These interactions are related to the fact that calcium affects contractility and excitability of the heart in a manner similar to digoxin.

Hypomagnesemia may predispose to digitalis toxicity. If low magnesium levels are detected in a patient on digoxin, replacement therapy should be instituted.

In hypothyroidism the digoxin requirements are reduced. Digoxin responses in patients with compensated thyroid disease are normal. 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.

No drug dependence has been reported with the use of digoxin.

Digoxin may worsen the outflow obstruction in patients with idiopathic hypertrophic subaortic stenosis (IHSS). Unless cardiac failure is severe, it is doubtful whether digoxin should be employed. Patients with chronic constrictive pericarditis may fail to respond to digoxin. In addition, slowing of the heart rate by digoxin in some patients may further decrease cardiac output. Patients with heart failure from amyloid heart disease or constrictive cardiomyopathies respond poorly to treatment with digoxin. Patients with severe carditis, such as carditis associated with rheumatic fever or viral myocarditis, are especially sensitive to digoxin-induced disturbances of rhythm.

Incomplete AV block, especially in patients with Stokes-Adams attacks, may progress to advanced or complete heart block if digoxin is given. Heart failure in these patients can usually be controlled by other measures and by increasing the heart rate. If digitalization is essential, electrical pacing of the ventricles may be indicated. In some patients with sinus node disease (i.e., Sick Sinus Syndrome), digoxin may worsen sinus bradycardia or sinoatrial block. Digoxin is not indicated for the treatment of sinus tachycardia unless it is associated with heart failure.

Reduction of digoxin dosage may be desirable prior to electrical cardioversion to avoid induction of ventricular arrhythmias, but the physician must consider the consequences of rapid increase in ventricular response to atrial fibrillation if digoxin is withheld 1 to 2 days prior to cardioversion. If there is a suspicion that digitalis toxicity exists, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the energy level selected should be minimal at first and carefully increased in an attempt to avoid precipitating ventricular arrhythmias.

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.

Patients with renal insufficiency require smaller than usual maintenance doses of digoxin (see Dosage and Administration).

If the patient has been given digoxin during the previous week or any other less rapidly excreted drug of the digitalis group during the previous 2 weeks, the dose of digoxin must be reduced accordingly. Digoxin toxicity develops more frequently and lasts longer in patients with renal impairment because of the decreased excretion of digoxin. Therefore, it should be anticipated that dosage requirements will be decreased in patients with moderate to severe renal disease (see Dosage and Administration). Because of impaired renal function and excretion in elderly patients, they frequently require lower than recommended doses. Because of the prolonged half-life, a longer period of time is required to achieve an initial or new steady-state concentration in patients with renal impairment than in patients with normal renal function.

Digitalis alone or with other drugs has been used in the treatment of obesity. This use of digoxin or other digitalis glycosides is unwarranted. Moreover, since they may cause potentially fatal arrhythmias or other adverse effects, the use of these drugs solely for the treatment of obesity is dangerous.

Anorexia, nausea, vomiting and arrhythmias may accompany heart failure or may be indications of digitalis intoxication. Clinical evaluation of the cause of the symptoms should be attempted before further digitalis administration. In such circumstances determination of the serum digoxin concentration may be an aid in deciding whether or not digitalis toxicity is likely to be present. If the possibility of digitalis intoxication cannot be excluded, cardiac glycosides should be temporarily withheld, if permitted by the clinical situation.

Patients with renal insufficiency require smaller than usual maintenance doses of LANOXIN (Digoxin Tablets, C.S.D. and Digoxin Oral Solution, C.S.D.) (see Dosage and Administration).

Heart failure accompanying acute glomerulonephritis requires extreme care in digitalization. Relatively low loading and maintenance doses and concomitant use of antihypertensive drugs may be necessary and careful monitoring is essential. LANOXIN (Digoxin Tablets, C.S.D. and Digoxin Oral Solution, C.S.D.) should be discontinued as soon as possible, especially if a therapeutic trial does not result in improvement. Patients with severe carditis, such as carditis associated with rheumatic fever or viral myocarditis, are especially sensitive to digoxin-induced disturbances of rhythm.

Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive and dosage must not only be reduced but must be individualized according to their degree of maturity. Impaired renal function must also be carefully taken into consideration.

Dosage of digoxin must be carefully titrated and differences in the bioavailability of parenteral preparations, oral solution and tablets taken into account when changing patients from one preparation to another.

Patients receiving LANOXIN (Digoxin Tablets, C.S.D. and Digoxin Oral Solution, C.S.D.) should have their serum electrolytes and renal function (BUN and/or serum creatinine) assessed periodically; the frequency of assessments will depend on the clinical setting. For discussion of serum digoxin concentrations, see Dosage and Administration.

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.

Digitalis glycosides are a major cause of poisoning in children. The tolerance of newborn infants to digitalis glycosides is variable, since their renal clearance of the medication is reduced. Premature and immature infants are especially sensitive. Dosage of digoxin should be reduced and individualized according to the infant’s degree of maturity, since renal clearance increases as the infant matures. Children older than 1 month of age generally require proportionally larger doses than adults on the basis of body weight or body surface area.

In patients with Wolff-Parkinson-White Syndrome and atrial fibrillation, digoxin can enhance transmission of impulses through the accessory pathway. This effect may result in extremely rapid ventricular rates and even ventricular fibrillation.

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.

Although appropriate studies on the relationship of age to the effects of digitalis glycosides have not been performed in the geriatric population, the majority of experience with digoxin is in this population. Elderly patients may be more likely to have age-related renal function impairment, which may significantly increase the elimination half-life of digoxin. Additionally, elderly patients may have a decreased volume of distribution of digitalis due to decreased muscle mass. These factors may contribute to digitalis toxicity in elderly patients.

Teratogenic Effects: 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, although there have been no reports of teratogenic effects following the use of digoxin in pregnancy since its availability in 1929. Digoxin should be given to pregnant women only if clearly needed.

Studies have shown that digoxin concentrations in the mother’s serum and milk are similar. However, the estimated daily dose to a nursing infant 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.

Following drug administration, a 6- to 8-hour distribution phase is observed. This is followed by a much more gradual serum concentration decline, which is dependent on digoxin elimination 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 postdistribution serum levels are in equilibrium with tissue levels and correlate with pharmacologic effects. In individual patients, these postdistribution serum concentrations are linearly related to maintenance dosage and may be useful in evaluating therapeutic and toxic effects.

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, serum digoxin concentration in the newborn is similar to the serum level in the mother. Approximately 20 to 25% of plasma digoxin 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 (ideal) body weight, not total body weight.

Gastrointestinal absorption of digoxin is a passive process. Absorption of digoxin from tablets is 60 to 80%. Absorption of Digoxin Oral Solution formulation has been demonstrated to be 70% to 85% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When digoxin oral solution/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 fibre; however, the amount absorbed from an oral dose may be reduced.

In some patients, orally administered digoxin is converted to cardioinactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggest that 1 in 10 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 constant with the extent of bacterial interaction and may be as much as two-fold in some cases.

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 i.v. administration to normal subjects, 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 subjects with normal renal function, digoxin has a half-life of 1.5 to 2 days.

Digoxin is primarily removed from the body by renal elimination. Although the digoxin clearance in women is about 10-15% lower than in men, the effect of gender on the pharmacokinetics of digoxin is not expected to be clinically significant when initiating and monitoring digoxin therapy in patients.

Metabolism occurs partially in the stomach, but also may occur in the liver and, although only about 16% of a dose of digoxin is metabolized, several metabolites of digoxin and their metabolic pathways have been identified. The bis-digitoxoside and mono-digitoxoside metabolites are considered to be cardioactive. Other metabolites, such as digoxigenin, are considered to be less cardioactive than digoxin. In some patients (estimated to be approximately 10% of patients taking digoxin), other cardioinactive metabolites, such as dihydrodigoxin and dihydrodigoxigenin, may result from the metabolism of digoxin by intestinal bacteria. In these individuals, as much as 40% or more of the oral dose of digoxin may be converted to these inactive reduction products. The metabolism of digoxin is not dependent upon the cytochrome P-450 system.

The effect of genetic polymorphism on the pharmacokinetics of LANOXIN was not studied.

The tolerance of newborn infants to digitalis glycosides is variable, since their renal clearance of the medication is reduced. Premature and immature infants are especially sensitive. Dosage should be reduced and individualized according to the infant's degree of maturity, since renal clearance increases as the infant matures. Children older than l month of age generally require proportionally larger doses than adults on the basis of body weight or body surface area (see Dosage and Administration).

Elderly patients may be more likely to have age-related renal function impairment, which may significantly increase the elimination half-life of digoxin. Additionally, elderly patients may have a decreased volume of distribution of digitalis due to decreased muscle mass. These factors may contribute to digitalis toxicity in elderly patients.

Plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects.

The influence of digitalis glycosides on the myocardium is dose related, and involves both direct action on cardiac muscle and the specialized conduction system, and indirect actions on cardiovascular system mediated by the autonomic nervous system. The indirect actions mediated by the autonomic nervous system involve a vagomimetic action, which is responsible for the effects of digitalis on the sinoatrial (SA) and atrioventricular (AV) nodes; and also a baroreceptor sensitization which results in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increment in mean arterial pressure. The pharmacologic consequences of these direct and indirect effects are: an increase in the force and velocity of myocardial systolic contraction (positive inotropic action); a slowing of heart rate (negative chronotropic effect); and decreased conduction velocity through the AV node. In higher doses, digitalis increases sympathetic outflow from the CNS to both cardiac and peripheral sympathetic nerves. This increase in sympathetic activity may be an important factor in digitalis cardiac toxicity. Most of the extracardiac manifestations of digitalis toxicity are also mediated by the CNS.

Race differences in digoxin pharmacokinetics have not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected.

The clearance of digoxin can be primarily correlated with renal function as indicated by creatinine clearance. In children with renal disease, digoxin must be carefully titrated based on clinical response.

The half-life of digoxin in anuric patients is prolonged to 4 to 6 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion or during cardiopulmonary bypass because most of the drug is in the tissue rather than circulating in the blood.

Subgroup Analyses of Mortality and Hospitalization During the First Two Years Following Randomization in the DIG Trial with LANOXIN

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.