Digoxin

DIGOXIN- digoxin solution
VistaPharm, Inc.

1 INDICATIONS AND USAGE

1.1 Heart Failure in Adults

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

1.2 Heart Failure in Pediatric Patients

Digoxin is indicated to increase myocardial contractility in pediatric patients with heart failure.

1.3 Atrial Fibrillation in Adults

Digoxin Oral Solution USP is indicated for the control of resting ventricular response rate in patients with chronic atrial fibrillation. Digoxin should not be used for the treatment of multifocal atrial tachycardia.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Considerations

The dose of digoxin should be based on clinical assessment but individual patient factors should be taken into consideration. Those factors are:

Because the pharmacokinetics of digoxin are complex, and because toxic levels of digoxin are only slightly higher than therapeutic levels, digoxin dosing can be difficult. The recommended approach is to:

  • estimate the patient’s daily maintenance dose
  • adjust the estimate to account for patient-specific factors
  • choose a dosing regimen
  • decide whether to initiate therapy with a loading dose
  • monitor the patient for toxicity and for therapeutic effect
  • adjust the dose

Dose titration may be accomplished by either of two general approaches that differ in dosage and frequency of administration, but reach the same total amount of digoxin accumulated in the body.

  • If rapid titration is considered medically appropriate, administer a loading dose based upon projected peak digoxin body stores. Maintenance dose can be calculated as a percentage of the loading dose.
  • More gradual titration may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives of the drug for the individual patient. Depending upon the patient’s renal function, this will take between 1 and 3 weeks.

2.2 Serum Digoxin Concentrations

In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication.

Studies have shown diminished efficacy at serum levels < 0.5 ng/mL, while levels above 2 ng/mL are associated with increased toxicity without increased benefit. The inotropic effects of digoxin tend to appear at lower concentrations than the electrophysiological effects. Based on retrospective analysis, adverse events may be higher in the upper therapeutic range.

Perform sampling of serum concentrations just before the next scheduled dose of the drug. If this is not possible, sample at least 6 hours or later 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. 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.

When decision-making is to be guided by serum digoxin levels, the clinician must consider the possibility of reported concentrations that have been falsely elevated by endogenous digoxin-like immunoreactive substances [see Drug Interactions (7.4)]. If the assay being used is sensitive to these substances, it may be prudent to obtain a baseline measurement before digoxin therapy is started, and correct later values by the reported baseline level.

2.3 Loading Dose

Loading doses for each age group are given in Table 1 below.

In pediatric patients, if a loading dose is needed, it can be administered with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 4- to 8-hour intervals, with careful assessment of clinical response before each additional dose. If the patient’s clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given as the loading dose [ see Table 1 and 2].

Table 1: Estimate the Loading Dose

Age

Oral Loading Dose, mcg/kg

Premature

20 to 30

Full-Term

25 to 35

1 to 24 months

35 to 60

2 to 5 years

30 to 45

5 to 10 years

20 to 35

Over 10 years

10 to 15

More gradual attainment of digoxin levels can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided in Table 2 (2.4 Estimate of Daily Maintenance Dose) can be used in calculating this dose for patients with normal renal function. Steady state will be attained after approximately 5 days in subjects with normal renal function.

2.4 Estimate of Daily Maintenance Dose

The recommended daily maintenance doses for each age group are given in Table 2 below. These recommendations assume the presence of normal renal function.

Table 2: Estimate of the Daily Maintenance Dose

Age

Daily Oral Maintenance Dose, mcg/kg/day

Dose Regimen, mcg/kg/dose

Premature

4.7 to 7.8

2.3 to 3.9 Twice Daily

Full-Term

7.5 to 11.3

3.8 to 5.6 Twice Daily

1 to 24 months

11.3 to 18.8

5.6 to 9.4 Twice Daily

2 to 5 years

9.4 to 13.1

4.7 to 6.6 Twice Daily

5 to 10 years

5.6 to 11.3

2.8 to 5.6 Twice Daily

Over 10 years

3.0 to 4.5

3.0 to 4.5 Once Daily

Dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, dosage selection must be based upon clinical assessment and ultimately therapeutic drug level monitoring of the patient.

Divided daily dosing is recommended for pediatric patients under age 10. In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be made as shown in Tables 1 and 2. Renal clearance is further reduced in the premature infant. Beyond the immediate newborn period, pediatric patients generally require proportionally larger doses than adults on the basis of body weight or body surface area. Pediatric patients over 10 years of age require adult dosages in proportion to their body weight. Some researchers have suggested that infants and young pediatric patients tolerate slightly higher serum concentrations than do adults. For pediatric patients with known or suspected renal dysfunction, lower starting doses should be considered combined with frequent monitoring of digoxin levels.

NOTE: The calibrated oral syringe supplied with the 60 mL bottle of digoxin oral solution is not appropriate to measure doses below 0.1 mL. Doses less than 0.1 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient.

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