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LANOXIN
Glaxo Wellcome
Digoxin
Cardiotonic Glycoside
 
Action And Clinical Pharmacology: 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.

Pharmacokinetics: Gastrointestinal absorption of digoxin is a passive process. Absorption of Lanoxin digoxin from tablets is 60 to 80%. 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 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.

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 (see Dosage, 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, 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.

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. The half-life 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.

Indications And Clinical Uses: Congestive Heart Failure: The increased cardiac output resulting from the inotropic action of digoxin ameliorates the disturbances characteristic of heart failure (venous congestion, edema, dyspnea, orthopnea and cardiac asthma).

Digoxin is more effective in low output (pump) failure than in "high output" heart failure secondary to arteriovenous fistula, anemia, infection hyperthyroidism, or bronchopulmonary insufficiency.

Digoxin is usually continued after failure is controlled unless some known precipitating factor is corrected. Studies have shown, however, that even though hemodynamic effects can be demonstrated in almost all patients, corresponding improvement in the signs and symptoms of heart failure is not necessarily apparent. Therefore, 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.

Atrial Fibrillation: Digoxin reduces ventricular rate through increased AV nodal block and thereby improves hemodynamics. Palpitation, precordial distress or weakness are relieved and concomitant congestive heart failure ameliorated. Digoxin should be continued in doses necessary to maintain the desired ventricular rate.

Atrial Flutter: Digoxin slows the heart and regular sinus rhythm may appear. Frequently the flutter is converted to atrial fibrillation with a controlled ventricular response. Stopping digitalis at this point may be followed by restoration of sinus rhythm, especially if the flutter is of the paroxysmal type. It is preferable, however to continue digitalis if failure ensues or if atrial flutter is a frequent occurrence. (Electrical cardioversion is often the treatment of choice for atrial flutter. See discussion of cardioversion in Precautions).

Paroxysmal Atrial Tachycardia (PAT): Digoxin may convert PAT to sinus rhythm by slowing conduction through the AV node. If heart failure has ensued or paroxysms occur frequently, digoxin should be continued. In infants, digoxin is usually continued for 3 to 6 months after a single episode of PAT to prevent recurrence.

Contra-Indications: Digitalis glycosides are contraindicated in ventricular fibrillation.

In a given patient, an untoward effect requiring permanent discontinuation of other digitalis preparations usually constitutes a contraindication to digoxin. Hypersensitivity to digoxin itself is a contraindication to its use. Allergy to digoxin, though rare, does occur. It may not extend to all such preparations, and another digitalis glycoside may be tried with caution.

Manufacturers' Warnings In Clinical States: 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 digoxin (see Dosage).

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. Digoxin 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.

Note: Digitalis glycosides are an important cause of accidental poisoning in children.

Precautions: General: 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). 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.

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 Overdose: Symptoms and Treatment).

Calcium, particularly when administered rapidly by the i.v. 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.

Quinidine and verapamil cause a rise in serum digoxin concentration, with the implication that digitalis intoxication may result. This rise appears to be proportional to the dose. The effect is mediated by a reduction in digoxin clearance and, in the case of quinidine, decreased volume of distribution as well. Due to the considerable variability of these interactions, digoxin dosage should be carefully individualized when patients receive coadministered medications.

Certain antibiotics may increase digoxin absorption in patients who convert digoxin to inactive metabolites in the gut (see Pharmacology, Pharmacokinetics). 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.

Patients with acute myocardial infarction or severe pulmonary disease may be unusually sensitive to digoxin-induced disturbances of rhythm. Atrial arrhythmias associated with hypermetabolic states (e.g., hyperthyroidism) are particularly resistant to digoxin treatment. Large doses of digoxin are not recommended as the only treatment of these arrhythmias and care must be taken to avoid toxicity if large doses of digoxin are required. In hypothyroidism the digoxin requirements are reduced. Digoxin responses in patients with compensated thyroid disease are normal.

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.

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.

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 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.

Digoxin is not indicated for the treatment of sinus tachycardia unless it is associated with heart failure.

Digoxin may produce false positive ST-T changes in the electrocardiogram during exercise testing.

Dosage of digoxin must be carefully titrated and differences in the bioavailability of parenteral preparations, elixirs and tablets taken into account when changing patients from one preparation to another. I.M. injection of digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.

Laboratory Tests: Patients receiving digoxin 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.

Drug Interactions: Potassium-depleting corticosteroids and diuretics may be major contributing factors to digitalis toxicity. Calcium, particularly if administered rapidly by the i.v. route, may produce serious arrhythmias in digitalized patients. Quinidine and verapamil cause a rise in serum digoxin concentration, with the implication that digitalis intoxication may result. Certain antibiotics 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, cholestryramine, phenytoin 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 b-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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: There have been no long-term studies performed in animals to evaluate carcinogenic potential.

Pregnancy: 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.

Lactation: 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.

Adverse Reactions: The frequency and severity of adverse reactions to digoxin depend on the dose and route of administration, as well as on the patient's underlying disease or concomitant therapies (see Precautions). The overall incidence of adverse reactions have been reported as 5 to 20% with 15 to 20% of them being considered serious (1 to 4% of patients receiving digoxin). Evidence suggests that the incidence of toxicity has decreased since the introduction of the serum digoxin assay and improved standardization of digoxin tablets. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions.

Adults: Cardiac: 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. This suggests approaching toxicity and a lower dose of digoxin plus a small dose of a beta-blocker may give better control.

Ventricular tachycardia 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.

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.

Gastrointestinal: Anorexia, nausea, vomiting, and less commonly, diarrhea are common early symptoms of overdosage. However, uncontrolled heart failure may also produce such symptoms.

It is inadvisable to rely on nausea as an early warning of excessive digoxin as arrhythmias may occur first.

CNS: Visual disturbances (blurred or yellow vision), headache, weakness, apathy and psychosis can occur.

Other: Gynecomastia is occasionally observed.

Infants and Children: 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.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Arrhythmias: Adults: Digoxin should be discontinued until all signs of toxicity are gone. Discontinuation may be all that is necessary if toxic manifestations are not severe and appear only near the expected time for maximum effect of the drug.

Correction of factors that may contribute to toxicity such as electrolyte disturbances, hypoxia, acid-base disturbances and removal of aggravating agents such as catecholamines, should also be considered. Potassium salts may be indicated particularly if hypokalemia is present. Potassium administration may be dangerous in the setting of massive digitalis overdosage (see Massive Overdose subsection below). Potassium chloride in divided oral doses totaling 3 to 6 g of the salt (40 to 80 mEq K for adults may be given provided renal function is adequate (see Infants and Children subsection below for potassium recommendation).

When correction of the arrhythmia is urgent and the serum potassium concentration is low or normal, potassium should be administered i.v. in 5% dextrose injection. For adults, a total of 40 to 80 mEq (diluted to a concentration of 40 mEq/500 mL) may be given at a rate not exceeding 20 mEq/hour, or slower if limited by pain due to local irritation. Additional amounts may be given if the arrhythmia is uncontrolled and potassium well-tolerated. ECG monitoring should be performed to watch for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. The infusion may be stopped when the desired effect is achieved.

Note: Potassium should not be used and may be dangerous in heart block due to digoxin, unless primarily related to supraventricular tachycardia.

Other agents that have been used for the treatment of digoxin intoxication include lidocaine, procainamide, propranolol and phenytoin, although use of the latter must be considered experimental. Quinidine, procainamide, and beta-adrenergic blocking agents should be used with caution when AV block is a component of digitalis intoxication as they may exaggerate this arrhythmic property.

In advanced heart block, atropine and/or temporary ventricular pacing may be beneficial. Digibind (digoxin immune Fab [ovine]) can be used to reverse potentially life-threatening digoxin (or digitoxin) intoxication. Improvement in signs and symptoms of digitalis toxicity usually begins within 0.5 hour of Digibind administration. Each 38 mg vial of Digibind will neutralize 0.5 mg digoxin (which is a usual body store of an adequately digitalized 70 kg patient). For further information consult the Digibind package insert or product monograph.

Infants and Children: See Adults section for general recommendations for the treatment of arrhythmias produced by overdosage and for cautions regarding the use of potassium.

If a potassium preparation is used to treat toxicity, it may be given orally in divided doses totaling 1 to 1.5 mEq Kkg body weight (1 g of potassium chloride contains 13.4 mEq K. When correction of the arrhythmia with potassium is urgent, approximately 0.5 mEq/kg of potassium/hour may be given i.v., with careful ECG monitoring. The i.v. solution of potassium should be dilute enough to avoid local irritation; however, especially in infants, care must be taken to avoid i.v. fluid overload.

Massive Digitalis

Severe digitalis intoxication can cause life-threatening elevation in serum potassium concentration by shifting potassium from inside to outside the cell resulting in hyperkalemia. Administration of potassium supplements in the setting of massive intoxication may be hazardous.

Digibind, (digoxin immune Fab [Ovine]), may be used at a dose equimolar to digoxin in the body to reverse the effects of ingestion of a massive overdose. The decision to administer Digibind before the onset of toxic manifestations will depend on the likelihood that life-threatening toxicity will occur (see above). For further information consult the Digibind package insert or product monograph.

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 maneuvres may induce an acute vagal episode that can worsen digitalis-toxic arrhythmias.

Dosage And Administration: Recommended dosages are average values that may require considerable modification because of individual sensitivity or associated conditions. Diminished renal function is the most important factor requiring modification of recommended doses.

In deciding the dose of digoxin, several factors must be considered:

1. The disease being treated. Atrial arrhythmias may require larger doses than heart failure.

2. The body weight of the patient. Doses should be calculated based upon lean or ideal body weight.

3. The patient's renal function, preferably evaluated on the basis of creatinine clearance.

4. Age is an important factor in infants and children.

5. Concomitant disease states, drugs or other factors likely to alter the expected clinical response to digoxin (see Precautions and Drug Interactions).

Digitalization may be accomplished by either of 2 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.

Adults: Rapid Digitalization with a Loading Dose: Peak body digoxin stores of 8 to 12 g/kg should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Larger stores (10 to 15 g/kg) are often required for adequate control of ventricular rate in patients with atrial flutter or fibrillation. Because of altered digoxin distribution and elimination, projected peak body stores for patients with renal insufficiency should be conservative [(i.e., 6 to 10 g/kg) (see Precautions)].

The loading dose should be based on the projected peak body stores and 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 dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given.

In previously undigitalized patients, a single initial Lanoxin Tablet dose of 0.5 to 0.75 mg (500 to 750 g) usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2 to 6 hours. Additional doses of 0.125 to 0.375 mg (125 to 375 g) may be given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate effect is noted. The usual amount of Lanoxin Tablets that a 70 kg patient requires to achieve 8 to 15 g/kg peak body stores is 0.75 to 1.25 mg (750 to 1 250 g).

Although peak body stores are mathematically related to loading doses and are utilized to calculate maintenance doses, they do not correlate with measured serum concentrations. This discrepancy is caused by digoxin distribution within the body during the first 6 to 8 hours following a dose. Serum concentrations drawn during this time are usually not interpretable.

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 x % Daily Loss (i.e., Loading Dose) 100

Where % Daily Loss = 14+Ccr/5

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.

A common practice involves the use of Lanoxin Injection to achieve rapid digitalization, with conversion to Lanoxin Tablets for maintenance therapy. If patients are switched from i.v. to oral digoxin formulations, allowances must be made for the differences in bioavailability when calculating maintenance dosages.

Gradual Digitalization with a Maintenance Dose: Table II provides average Lanoxin Tablet daily maintenance dose requirements for patients with heart failure based upon lean body weight and renal function.

Example: Based on Table II, 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 0.25 mg (250 g) Lanoxin Tablet each day, usually taken after the morning meal. Steady-state serum concentration should not be anticipated before 11 days.

Infants and Children: Digitalization must be individualized. Divided daily dosing is recommended for infants and young children. Children over 10 years of age require adult dosages in proportion to their body weight.

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.

Lanoxin Injection Pediatric can be used to achieve rapid digitalization, with conversion to an oral Lanoxin formulation for maintenance therapy. If patients are switched from i.v. to oral digoxin tablets or elixir, allowances must be made for differences in bioavailability when calculating maintenance dosages.

I.M. injection of digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.

Digitalizing and daily maintenance doses for each age group are given in Table III and should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Larger doses are often required for adequate control of ventricular rate in patients with atrial flutter or fibrillation.

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 dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given.

More gradual digitalization can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided in Table III can be used in calculating this dose for patients with normal renal function. In children with renal disease, digoxin dosing must be carefully titrated based upon clinical response.

Long-term use of digoxin is indicated in many children who have been digitalized for acute heart failure, unless the cause is transient. Children with severe congenital heart disease, even after surgery, may require digoxin for prolonged periods.

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.

Serum Digoxin Concentrations: Measurement of serum digoxin concentrations can be helpful to the clinician in determining the state of digitalization and in assigning certain probabilities to the likelihood of digoxin intoxication. Studies in adults considered adequately digitalized (without evidence of toxicity) show that about two-thirds of such patients have serum digoxin levels ranging from 0.8 to 2.0 ng/mL. Patients with atrial fibrillation or atrial flutter require and appear to tolerate higher levels than do patients with other indications. On the other hand, in adult patients with clinical evidence of digoxin toxicity, about two-thirds will have serum digoxin levels greater than 2.0 ng/mL. Thus, whereas levels less than 0.8 ng/mL are infrequently associated with toxicity, levels greater than 2.0 ng/mL are often associated with toxicity. Values in between are not very helpful in deciding whether a certain sign or symptom is more likely to be caused by digoxin toxicity or by something else. There are rare patients who are unable to tolerate digoxin even at serum concentrations below 0.8 ng/mL. Some researchers suggest that infants and young children tolerate slightly higher serum concentrations than do adults.

To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations for clinical use should be at least 6 to 8 hours after the last dose, regardless of the route of administration or formulation used. On a twice daily dosing schedule, there will be only minor differences in the serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. After a single daily dose, the concentration will be 10 to 25% lower when sampled at 24 hours versus 8 hours, depending upon the patient's renal function. Ideally, sampling for assessment of steady state concentration should be done just before the next 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. The patient falls outside the norm in his response to or handling of digoxin. This decision should be reached only after exclusion of the other possibilities and generally should be confirmed by additional correlations of clinical observations with serum digoxin concentrations.

The serum concentration data should always be interpreted in the overall clinical context and an isolated serum concentration value should not be used alone as a basis for increasing or decreasing digoxin dosage.

Adjustment of Maintenance Dose in Previously Digitalized Patients: Digoxin maintenance doses in individual patients on steady-state digoxin can be adjusted upward or downward in proportion to the ratio of the desired versus the measured serum concentration. For example, a patient at steady-state on 0.125 mg (125 g) of digoxin/day with the measured serum concentration of 0.7 ng/mL, should have the dose increased to 0.25 mg/day (250 g) to achieve a steady-state serum concentration of 1.4 ng/mL, assuming the serum digoxin concentration measurement is correct, renal function remains stable during this time and the needed adjustment is not the result of a problem with compliance.

Dosage Adjustment When Changing Preparations: The difference in bioavailability between injectable Lanoxin and Lanoxin Elixir Pediatric or Lanoxin Tablets must be considered when changing patients from one dosage form to another.

I.M. injection of digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.

Availability And Storage: Injections: Each mL contains: digoxin CSD 0.05 mg (50 g) (pediatric) or 0.25 mg (250 g). Nonmedicinal ingredients: alcohol, anhydrous citric acid, propylene glycol and sodium phosphate. Lanoxin pediatric injection: ampuls of 1 mL. Lanoxin injection: ampuls of 2 mL. Store between 15 to 30C and protect from light.

Pediatric Elixir: Each mL of clear, light-green colored liquid with a lime odor and taste, contains: digoxin 0.05 mg (50 g). Nonmedicinal ingredients: alcohol 11.5 mL/100 mL of elixir, citric acid, D&C Green No. 5, D&C Yellow No. 10, lime oil concentrate, methylparaben, propylene glycol, sodium phosphate, sucrose and water. Tartrazine-free. Bottles of 115 mL with calibrated dropper. Store between 15 to 30C.

Tablets: 0.0625 mg: Each round, peach, flat-faced, bevelled-edge tablet with code LANOXIN U3A, contains: digoxin 0.0625 mg (62.5 g). Nonmedicinal ingredients, FD&C Yellow No. 6, lactose, magnesium stearate, pregelatinized starch and starch (corn and potato). Tartrazine-free. Bottles of 100.

0.125 mg: Each round, yellow, flat-faced tablet, with code LANOXIN Y3B on the same side as score mark, contains: digoxin 0.125 mg (125 g). Nonmedicinal ingredients: FD&C Yellow No. 6, D&C Yellow No. 10, lactose, magnesium stearate, pregelatinized starch and starch (corn and potato). Tartrazine-free. Bottles of 100 and 1 000.

0.25 mg: Each round, white, biconvex tablet, with code LANOXIN X3A on same side as score mark, contains: digoxin 0.25 mg (250 g). Nonmedicinal ingredients: lactose, magnesium stearate, pregelatinized starch and starch (corn and potato). Dye- and tartrazine-free. Bottles of 100 and 1 000.

Store between 15 to 30C in a dry place and protect from light. (Shown in Product Recognition Section)