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LANNETT CO. INC
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00527132401

brand digox 125 mcg tablet

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Uses

Dosage and Administration

Administration

Digoxin usually is administered orally as a single daily dose. The manufacturers recommend divided daily dosing in infants and young children (younger than 10 years of age). Because the importance of the higher peak serum concentrations associated with once daily dosing of the liquid-filled capsules has not been established, divided daily dosing with this dosage form currently is recommended for infants and children younger than 10 years of age, patients requiring a daily dosage of 300 mcg (0.3 mg) or more, patients with a history of cardiac glycoside toxicity or those considered likely to become toxic, and patients in whom compliance is not a problem; when compliance is considered a problem, once daily dosing may be appropriate.

When oral therapy is not feasible or when rapid therapeutic effect is necessary, the drug may be administered by IV injection. However, oral therapy should replace IV administration as soon as possible. For IV administration, digoxin injection is given either undiluted over a period of at least 5 minutes or diluted with a 4-fold or greater volume of sterile water for injection, 5% dextrose injection, or 0.9% sodium chloride injection and given over a period of at least 5 minutes; the use of less than a 4-fold volume of diluent may result in precipitation of digoxin. Diluted IV solutions of digoxin should be used immediately. Slow IV infusion of digoxin is preferred to rapid IV (i.e., bolus) administration. Rapid IV infusion of digoxin may cause systemic and coronary arteriolar constriction, which may be clinically undesirable; caution should be exercised. If a tuberculin syringe is used to measure very small doses, the possibility of inadvertent overdosage should be considered. Following IV administration, the syringe should not be flushed with the parenteral solution. Mixing of digoxin injection with other drugs in the same container or simultaneous administration in the same IV line is not recommended.

Although digoxin injection also has been given IM, this route of administration of the drug is rarely justified because it frequently causes severe local irritation and pain, and IV administration produces more rapid, predictable effects. IV injection of digoxin is preferred to IM injection. IM injection of digoxin offers no advantages unless other routes of administration are contraindicated. If the drug is given IM, the injection should be made deep into the muscle and should be followed by massage of the injection site; no more than 2 mL of digoxin injection should be given at one site. Therapy with oral digoxin should replace IM administration as soon as possible.

Dosage

General Considerations

Dosage guidelines provided are based upon average patient response and substantial patient variation can be expected.Ultimate dosage selection must be based upon clinical assessment of the patient. Although some clinicians recommend using serum digoxin concentrations for selecting the appropriate dosage of the drug, there is little evidence to support such action; the radioimmunoassay for digoxin was intended to assist in evaluating toxicity not efficacy of the drug.

Digoxin has a low therapeutic index; therefore, cautious dosage determination is essential. Usual dosages are averages that may require considerable modification as determined by individual requirements and response; the general condition, cardiovascular status, and renal function of the patient; lean (i.e., ideal body) weight and age of the patient; concomitant disease states, drugs, or other factors likely to alter the pharmacokinetics or pharmacodynamics of digoxin; and digoxin plasma concentrations.Differences in the bioavailability of IV and oral or IM preparations should be considered when patients are switched from one route of administration to another. One study showed that there is no substantial difference in bioavailability of digoxin tablets or elixir, and most clinicians believe that these dosage forms usually can be used interchangeably. When switching from oral (tablets or elixir) or IM to IV therapy, digoxin dosage must be reduced by about 20-25%. When switching from tablets, elixir, or IM therapy to liquid-filled capsules, digoxin dosage must be reduced by about 20%. Since the liquid-filled capsules are 90-100% absorbed, dosage with the capsules is equivalent to IV dosage.

Considerations for ECG Monitoring and Dosage Reduction

ECG monitoring of cardiac function should be performed during digoxin therapy, especially when the drug is given IV, when it is given orally for prolonged periods, or when it is given to patients with increased risk of adverse reactions to digoxin, such as those with severe heart or renal disease. Dosage of cardiac glycosides should be reduced in patients with hypokalemia, hypothyroidism, extensive myocardial damage, or conduction disorders, and in geriatric patients, especially those with coronary artery disease. Dosage of digoxin must be carefully individualized in patients receiving quinidine concurrently, since clearance and volume of distribution of digoxin may be decreased.

Heart Failure in Adults

Digitalization may be accomplished by one of two approaches (i.e., slow digitalization or rapid digitalization) that vary in dosage and frequency of administration but achieve the same total amount of digoxin accumulated in the body. The American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) do not recommend the use of rapid digitalization (i.e., loading doses) to initiate therapy in adults with heart failure but suggest instead that therapy be initiated via slow digitalization.

For slow digitalization, therapy should be initiated with an appropriate daily maintenance dose, which allows digoxin body stores to accumulate slowly. Steady-state serum digoxin concentrations will be achieved in about 5 half-lives of the drug for the individual patient; depending on the patient's renal function, this may take 1-3 weeks.

For rapid digitalization (if considered medically appropriate), a loading dose should be administered based upon projected peak digoxin body stores. A daily maintenance dose (calculated as a percentage of the loading dose) should then follow the loading dose. Peak digoxin body stores of 8-12 mcg/kg generally provide therapeutic effect with minimum risk of toxicity in most patients with heart failure, normal sinus rhythm, and normal renal function.

Loading Dose (for Rapid Digitalization)

Loading doses are administered in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose; additional fractions of the loading dose (generally 25% fractions) are administered at 6- to 8-hour intervals orally, IM, or IV, with careful assessment of the patient's clinical response before each additional dose is administered. If the patient's clinical response requires a change from the calculated loading dose, then calculation of the maintenance dose is based upon the amount (i.e., total loading dose) actually administered.

Usually, a single initial oral dose of 500-750 mcg (0.5-0.75 mg) of digoxin tablets or 400-600 mcg (0.4-0.6 mg) of digoxin liquid-filled capsules produces a detectable effect in 0.5-2 hours that becomes maximal in 2-6 hours in adults. Additional doses of 125-375 mcg (0.125-0.375 mg) of digoxin tablets or 100-300 mcg (0.1-0.3 mg) of digoxin liquid-filled capsules may be cautiously administered at 6- to 8-hour intervals until clinical evidence of an adequate response is achieved. The usual amount (i.e., total loading dose) of digoxin tablets or liquid-filled capsules that a 70-kg patient requires to achieve 8-12 mcg/kg peak body stores is 750-1250 mcg (0.75-1.25 mg) or 600-1000 mcg (0.6-1 mg), respectively.

Usually, a single initial IV dose of 400-600 mcg (0.4-0.6 mg) of digoxin produces a detectable effect in 5-30 minutes that becomes maximal in 1-4 hours in adults. Additional doses of 100-300 mcg (0.1-0.3 mg) of digoxin IV may be cautiously administered at 6- to 8-hour intervals until clinical evidence of an adequate response is achieved. The usual amount (i.e., total loading dose) of digoxin IV that a 70-kg patient requires to achieve 8-12 mcg/kg peak body stores is 600-1000 mcg (0.6-1 mg).

Maintenance Dosage

Since daily maintenance digoxin dosage is a replacement of daily digoxin loss from the body, the daily maintenance dosage for a particular patient can be estimated by multiplying the daily percentage loss (see Pharmacokinetics: Elimination) by the peak body stores (i.e., loading dose) that produced a satisfactory response. About 30% of the total amount of digoxin in the body is eliminated daily in patients with normal renal function; anuric patients eliminate approximately 14% of the total daily. The percentage of digoxin eliminated from the body daily can be estimated by the following equation. This method should be used with caution, since creatinine clearance does not accurately measure renal or total body clearance of digoxin.

daily % loss = 14 + (creatinine clearance [in mL/minute] / 5)

The usual oral adult maintenance dosage of digoxin administered as tablets is 125-500 mcg (0.125-0.5 mg) once daily; the dosage should be titrated according to the patient's age, lean body weight, and renal function. ACCF and AHA state that digoxin is commonly initiated and maintained at a dosage of 125-250 mcg (0.125-0.25 mg daily) for the treatment of heart failure. The manufacturer states that the maintenance dosage should generally be initiated at 250 mcg (0.25 mg) once daily in adults younger than 70 years of age with normal renal function; the dosage may be increased every 2 weeks according to clinical response. The usual oral adult maintenance dosage of digoxin administered as liquid-filled capsules is 150-350 mcg (0.15-0.35 mg) daily in patients with creatinine clearance of 50 mL/minute or greater. The usual IV adult maintenance dosage of digoxin is 125-350 mcg (0.125-0.35 mg) IV once daily in patients with creatinine clearance of 50 mL/minute or greater.

Atrial Fibrillation in Adults

Peak digoxin body stores exceeding the 8-12 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.

In the treatment of chronic atrial fibrillation, the dosage of digoxin should be titrated to the minimum dosage that achieves the desired ventricular rate control without causing undesirable adverse effects. Appropriate target resting or exercising rates have not been established.

Pediatric Dosage

Dosage should be carefully titrated in neonates, especially in premature infants, because renal clearance of digoxin is reduced. Infants and young children (up to 10 years of age) generally require proportionally larger doses than children older than 10 years of age and adults when calculated on the basis of lean or ideal body weight or body surface area. Children older than 10 years of age require adult dosages in proportion to the child's body weight. Liquid-filled capsules may not be the formulation of choice in infants and young children (younger than 10 years of age) where dosage adjustment is frequent and outside of the fixed dosages provided by the capsules.

Digitalizing (i.e., Loading) and Maintenance Dosages

Total digitalizing (i.e., loading) doses and maintenance dosages in pediatric patients (depending on the dosage form administered) are given in the tables that follow, and should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure, normal sinus rhythm, and normal renal function.

Loading doses are administered in divided doses, with about 50% of the total dose given as the first (i.e., initial) dose; additional fractions (generally 25%) are administered at 4- to 8-hour intervals IV or 6- to 8-hour intervals orally or IM, with careful assessment of the patient's clinical response before each additional dose is administered. If the patient's clinical response requires a change from the calculated loading dose, then calculation of the maintenance dose is based upon the amount (i.e., total loading dose) actually administered.

Table 1. Usual Pediatric Maintenance Dosages for Digoxin Tablets (normal renal function, based on lean body weight)398403
Age Oral Maintenance Dosage (mcg/kg daily)
2-5 years of age 10-15
5-10 years of age 7-10
>10 years of age 3-5

Divided daily dosing is generally recommended in infants and young children (younger than 10 years of age).398403

Table 2. Usual Pediatric Digitalizing and Maintenance Dosages for Digoxin Elixir (normal renal function, based on lean body weight)402
Age Oral Digitalizing (Loading) Dose (mcg/kg) Oral Maintenance Dosage (mcg/kg daily)
Premature neonates 20-30 20-30% of oral loading dose
Full-term neonates 25-35 25-35% of oral loading dose
1-24 months 35-60 25-35% of oral loading dose
2-5 years of age 30-40 25-35% of oral loading dose
5-10 years of age 20-35 25-35% of oral loading dose
>10 years of age 10-15 25-35% of oral loading dose

IV digitalizing doses are 80% of oral digitalizing doses of digoxin tablets or elixir.401402

Divided daily dosing is generally recommended in infants and young children (younger than 10 years of age).402

Estimated or actual digitalizing dose that provides desired clinical response.402

Table 3. Usual Pediatric Digitalizing and Maintenance Dosages for Digoxin Liquid-Filled Capsules (normal renal function, based on lean body weight)399
Age Oral Digitalizing (Loading) Dose (mcg/kg) Oral Maintenance Dosage (mcg/kg daily)
2-5 years of age 25-35 25-35% of oral or IV loading dose
5-10 years of age 15-30 25-35% of oral or IV loading dose
>10 years of age 8-12 25-35% of oral or IV loading dose

IV digitalizing doses are the same as oral digitalizing doses of liquid-filled capsules.399

Divided daily dosing is generally recommended in infants and young children (younger than 10 years of age).399

Estimated or actual digitalizing dose that provides desired clinical response.399

Table 4. Usual Pediatric Digitalizing and Maintenance Dosages for IV Digoxin (normal renal function, based on lean body weight)401
Age IV Digitalizing (Loading) Dose (mcg/kg) IV Maintenance Dosage (mcg/kg daily)
Premature neonates 15-25 20-30% of IV loading dose
Full-term neonates 20-30 25-35% of IV loading dose
1-24 months 30-50 25-35% of IV loading dose
2-5 years of age 25-35 25-35% of IV loading dose
5-10 years of age 15-30 25-35% of IV loading dose
>10 years of age 8-12 25-35% of IV loading dose

IV digitalizing doses are 80% of oral digitalizing doses of digoxin tablets or elixir.401402

Divided daily dosing is generally recommended in infants and young children (younger than 10 years of age).401

Estimated or actual digitalizing dose that provides desired clinical response.401

Geriatric Dosage

Dosage of digoxin should be reduced in geriatric patients, especially in those with coronary artery disease. Advanced age may be an indicator of decreased renal function even in patients with a normal serum creatinine concentration (i.e., less than 1.5 mg/dL).(See Dosage in Renal Impairment under Dosage and Administration: Dosage.) In geriatric patients 70 years of age or older, the maintenance dosage generally should be initiated at 125 mcg (0.125 mg) once daily orally (as digoxin tablets).

Dosage in Hepatic Impairment

Apparently, no dosage adjustment is necessary in patients with liver disease if renal function is normal.

Dosage in Renal Impairment

Loading doses (based upon projected peak digoxin body stores) in patients with renal insufficiency (particularly those with creatinine clearances less than 10 mL/minute) should be conservative (i.e., based upon peak digoxin body stores of 6-10 mcg/kg) because of altered digoxin distribution and elimination.

Adults

The maintenance dosage generally should be initiated at 125 mcg (0.125 mg) once daily orally (as digoxin tablets) in patients with impaired renal function or at 62.5 mcg (0.0625 mg) once daily orally (as digoxin tablets) in patients with marked renal impairment; the dosage may be increased every 2 weeks according to clinical response.

Pediatric Patients

Dosage should be cautiously adjusted based on clinical response.

Pharmacokinetics

Absorption

Following oral administration of digoxin in a tablet or elixir, approximately 60-85% of the dose is usually absorbed. Liquid-filled digoxin capsules (Lanoxicaps) are approximately 90-100% absorbed. Absorption of digoxin is mainly from the small intestine, presumably by a passive, nonsaturable process. Delayed gastric emptying or the presence of food in the GI tract may slow the rate but not the extent of absorption of orally administered digoxin. In one single-dose study, however, decreased absorption of digoxin occurred when the drug was given orally simultaneously with a high fiber meal. Gastric pH apparently does not affect the degree of digoxin absorption. Intestinal absorption of the drug may be impaired in patients with certain malabsorption states, but absorption is not substantially changed by partial gastrectomy or jejunoileal bypass. Peak serum digoxin concentrations are higher following administration of liquid-filled digoxin capsules than with tablets. In addition, because of the enhanced absorption of the liquid-filled capsules compared to digoxin tablets or elixir, the capsules are associated with reduced interindividual and intraindividual variability in steady-state serum digoxin concentrations. About 80% of an IM dose of digoxin is absorbed.

There are interindividual variations in plasma concentrations of digoxin with a specific dose and in plasma concentrations of the drug that produce therapeutic and toxic effects. A specific plasma concentration may be therapeutic or toxic in an individual patient. The myocardial to plasma concentration ratio of digoxin generally is constant in individual patients. Myocardial uptake of digoxin at any given plasma concentration is nearly twice as great in infants as in adults. If plasma concentrations of the drug are to be determined, blood samples should be obtained at least 6-8 hours after the daily dose and preferably just prior to the next scheduled daily dose. Therapeutic plasma concentrations of digoxin in adults generally are 0.5-2 ng/mL. Some experts suggest that plasma concentrations of 0.5-0.9 ng/mL are sufficient for the treatment of heart failure in adults; however, limited data are available. In some patients with atrial fibrillation, slowing of ventricular rate may require steady-state plasma concentrations of 2-4 ng/mL. In adults, toxicity is usually, but not always, associated with steady-state plasma digoxin concentrations exceeding 2 ng/mL. Toxicity may also occur with lower digoxin levels, especially if hypokalemia, hypomagnesemia, or hypothyroidism coexists. Although neonates and infants appear to tolerate slightly higher plasma concentrations of digoxin than do adults, evidence suggests that plasma concentrations exceeding 2 ng/mL are associated with little, if any, additional therapeutic benefit in these patients. Some clinicians suggest that steady-state plasma concentrations of 1.1-1.7 ng/mL generally are associated with adequate therapeutic effects in neonates and infants. Serum concentrations of digoxin should be interpreted in the overall clinical context; thus, an isolated serum concentration measurement should not be used alone as the basis for adjusting dosage.

In undigitalized patients after oral administration of a single 500- to 750-mcg (0.5-0.75 mg) dose of digoxin in a tablet, elixir, or liquid-filled capsule, the onset of action occurs in 0.5-2 hours and maximal effects occur in 2-6 hours. After IM administration of a single 1000-mcg (1 mg) dose of digoxin, the onset of action occurs in 30 minutes and maximal effects occur in 4-6 hours. After IV administration of a single 400- to 600-mcg (0.4-0.6 mg) dose of digoxin in previously undigitalized patients, the onset of action occurs in 5-30 minutes and maximal effects occur in 1-4 hours. Pharmacologic effects may persist 3-4 days after withdrawal of digoxin in digitalized patients.

Distribution

With therapeutic plasma concentrations, about 20-30% of digoxin in blood is bound to plasma proteins. Digoxin protein binding is not appreciably changed in uremic patients. Patients with severe renal impairment have smaller apparent volumes of distribution of digoxin than do normal subjects. For further information on the distribution of digoxin,

Elimination

The initial (distribution) half-life (t½) of digoxin is about 30 minutes after IV administration in both anephric patients and patients with normal renal function. In patients with normal renal function, digoxin has an elimination t½ of 34-44 hours. The elimination t½ of digoxin is prolonged in patients with renal failure; in anephric patients the elimination t½ is about 4.5 days or longer. The elimination t½ is decreased in patients with acute digoxin overdosage. Elimination t½ of digoxin is prolonged in hypothyroid patients and decreased in hyperthyroid patients. In patients with biliary fistulas, plasma t½ is unchanged. In undigitalized patients, institution of fixed daily digoxin maintenance therapy without an initial loading dose results in steady-state plasma concentrations after 4-5 elimination t½s (about 7 days in patients with normal renal function).

In most patients, only small amounts of digoxin are metabolized, but the extent of metabolism is variable and may be substantial in some patients. Some metabolism presumably occurs in the liver, but digoxin is also apparently metabolized by bacteria within the lumen of the large intestine following oral administration and possibly after biliary elimination following parenteral administration. The extent of metabolism by bacteria in the large intestine following oral administration appears to vary inversely with the bioavailability of the preparation. Digoxin undergoes stepwise cleavage of the sugar moieties to form digoxigenin-bisdigitoxoside, digoxigenin-monodigitoxoside, and digoxigenin; these metabolites have progressively decreasing cardioactivity. Digoxigenin is subsequently epimerized and/or conjugated to form cardioinactive compounds. Digoxin also undergoes reduction of the lactone ring to form dihydrodigoxin, which also undergoes stepwise cleavage of the sugar moieties to form dihydrodigoxigenin-bisdigitoxoside, dihydrodigoxigenin-monodigitoxoside, and dihydrodigoxigenin; the reduced metabolites are essentially cardioinactive. Some patients may form substantial amounts of the reduced metabolites; data suggest that, in about 10% of patients receiving digoxin, about 40% or more of the drug excreted in urine will consist of reduced metabolites. Because of the rapid and enhanced absorption, use of liquid-filled capsules may minimize the formation of reduced metabolites in such patients. In patients who form substantial amounts of reduced metabolites, alteration of enteric bacterial flora by some anti-infective agents (e.g., erythromycin) may result in a substantial change in digitalization.

Digoxin is excreted mainly in urine, principally as unchanged drug, by glomerular filtration and active tubular secretion; tubular reabsorption may also occur. In most patients, small amounts of reduced metabolites are also excreted in urine, but in some patients, about 40% or more of the drug excreted in urine consists of reduced metabolites. In healthy individuals, about 50-70% of an IV dose of digoxin is excreted unchanged in urine. Small amounts of cardioactive metabolites and unchanged digoxin are also excreted in the bile and feces. In patients with renal failure, fecal excretion of digoxin and its metabolites may be increased.

The amount of digoxin eliminated daily is a function of the amount of drug in the body. About 30% of the total amount of digoxin in the body is eliminated daily in patients with normal renal function; anuric patients eliminate approximately 14% of the total daily. The percentage of digoxin eliminated from the body daily can be estimated by the following equation:

daily % loss = 14 + (creatinine clearance [in mL/minute] / 5)

This method should be used cautiously, since creatinine clearance does not accurately measure renal or total body clearance of digoxin. Increased urinary output apparently does not increase digoxin excretion. Digoxin metabolism and excretion are apparently not altered in patients with liver disease and normal renal function.

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