"The U.S. Food and Drug Administration today approved Entresto (sacubitril/valsartan) tablets for the treatment of heart failure. The drug has been shown to reduce the rate of cardiovascular death and hospitalization related to heart failure."...
Heart Failure: DIGITEK (digoxin tablets) is indicated for the treatment of mild to moderate heart failure. Digoxin increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by exercise capacity and heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, digoxin should be used with a diuretic and an angiotensin-conver ting enzyme inhibitor, but an optimal order for star ting these three drugs cannot be specified.
DOSAGE AND ADMINISTRATION
General: Recommended dosages of digoxin may require considerable modification because of individual sensitivity of the patient to the drug, the presence of associated conditions, or the use of concurrent medications. In selecting a dose of digoxin, the following factors must be considered:
- The body weight of the patient. Doses should be calculated based upon lean (i.e., ideal) body weight.
- The patient's renal function, preferably evaluated on the basis of estimated creatinine clearance.
- 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)
- Concomitant disease states, concurrent medications, or other factors likely to alter the pharmacokinetic or pharmacodynamic profile of digoxin (see PRECAUTIONS).
Serum Digoxin Concentrations: In general, the dose of digoxin used should be determined on clinical grounds. However, measurement of serum digoxin concentrations can be helpful to the clinician in determining the adequacy of digoxin therapy and in assigning certain probabilities to the likelihood of digoxin intoxication. About two-thirds of adults considered adequately digitalized (without evidence of toxicit y) have serum digoxin concentrations ranging from 0.8 to 2 ng/mL. However, digoxin may produce clinical benefits even at serum concentrations below this range. About two-thirds of adult patients with clinical toxicit y have serum digoxin concentrations greater than 2 ng/mL. However, since one third of patients with clinical toxicit y have concentrations less than 2 ng/mL, values below 2 ng/mL do not rule out the possibility that a cer tain 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 verses 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 hour after a dose.
If a discrepancy exists between the repor ted serum concentration and the observed clinical response, the clinician should consider the following possibilities:
- Analytical problems in the assay procedure.
- Inappropriate serum sampling time.
- Administration of a digitalis glycoside other than digoxin.
- Conditions (described in WARNINGS and PRECAUTIONS) causing an alteration in the sensitivity of the patient to digoxin.
- Serum digoxin concentration may decrease acutely during periods of exercise without any associate change in clinical efficacy due to increased binding of digoxin to skeletal muscle.
Heart Failure: Adults: Digitalization may be accomplished by either of two general approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount of digoxin accumulated in the body.
- If rapid digitalization is considered medically appropriate, it may be achieved by administering a loading dose based upon projected peak digoxin body stores. Maintenance dose can be calculated as a percentage of the loading dose.
- More gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly. Steady-state serum digoxin concentrations will be achieved in approximately five half-lives of the drug for the individual patient. Depending upon the patient's renal function, this will take between 1 and 3 weeks.
Rapid Digitalization with a Loading Dose: Peak digoxin body stores of 8 to 12 mcg /kg should provide therapeutic effect with minimum risk of toxicit y in most patients with heart failure and normal sinus rhythm. Because of altered digoxin distribution and elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e., 6 to 10 mcg/kg) [see PRECAUTIONS].
The loading dose should be administered in several por tions, with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 6- to 8-hour intervals, with careful assessment of clinical response before each additional dose.
If the patient's clinical response necessitates a change from the calculated loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given.
A single initial dose of 500 to 750 mcg (0.5 to 0.75 mg) of digoxin tablets usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2 to 6 hours. Additional doses of 125 to 375 mcg (0.125 to 0.375 mg) may be given cautiously at 6- to 8- hour intervals until clinical evidence of an adequate effect is noted. The usual amount of digoxin tablets that a 70-kg patient requires to achieve 8 to 12 mcg/kg peak body stores is 750 to 1,250 mcg (0.75 to 1.25 mg).
Digoxin Injection is frequently used to achieve rapid digitalization, with conversion to digoxin tablets or Digoxin Solution in Capsules for maintenance therapy. If patients are switched from intravenous to oral digoxin formulations, allowances must be made for differences in bioavailabilit y when calculating maintenance dosages (see table, CLINICAL PHARMACOLOGY).
Maintenance Dosing: The doses of digoxin used in controlled trials in patients with heart failure have ranged from 125 to 500 mcg (0.125 to 0.5 mg) once daily. In these studies, the digoxin dose has been generally titrated according to the patient's age, lean body weight, and renal function. Therapy is generally initiated at a dose of 250 mcg (0.25 mg) once daily in patients under age 70 with good renal function, at a dose of 125 mcg (0.125 mg) once daily in patients over age 70 or with impaired renal function, and at a dose of 62.5 mcg (0.0625 mg) in patients with marked renal impairment. Doses may be increased every 2 weeks according to clinical response.
In a subset of approximately 1,800 patients enrolled in the DIG trial (wherein dosing was based on an algorithm similar to that in Table 5) the mean (±SD) serum digoxin concentrations at 1 month and 12 months were 1.01 ± 0.47 ng/mL and 0.97 ± 0.43 ng/mL, respectively.
The maintenance dose should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use:
Maintenance Dose = Peak Body Stores (i.e., Loading Dose) x % Daily Loss/100
Where: % Daily Loss = 14 + Ccr/5 (Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body sur face area.)
Table 5 provides average daily maintenance dose requirements of digoxin tablets for patients with heart failure based upon lean body weight and renal function:
Table 5: Usual Daily Maintenance Dose Requirements (mcg)
of Digoxin for Estimated Peak Body Stores of 10 mcg/kg
|Corrected Ccr (mL/min per 70 kg)*||Lean Body Weight||Number of Days Before Steady-State Achieved†|
|*Ccr is creatinine clearance, corrected to 70 kg body weight
or 1.73 m2 body sur face 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.
†If no loading dose administered.
‡62.5 mcg = 0.0625 mg
Example: Based on the above table, a patient in heart failure with an estimated lean body weight of 70 kg and a Ccr of 60 mL/min, should be given a dose of 250 mcg (0.25 mg) daily of digoxin tablets, usually taken after the morning meal. If no loading dose is administered, steady-state serum concentrations in this patient should be anticipated at approximately 11 days.
Infants and Children: In general, divided daily dosing is recommended for infants and young children (under age 10). In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body sur face area. Children over 10 years of age require adult dosages in propor tion to their body weight. Some researchers have suggested that infants and young children tolerate slightly higher serum concentrations than do adults.
Daily maintenance doses for each age group are given in Table 6 and should provide therapeutic effects with minimum risk of toxicit y in most patients with heart failure and normal sinus rhythm. These recommendations assume the presence of normal renal function:
Table 6: Daily Maintenance Doses in Children with Normal
|Age||Daily Maintenance Dose (mcg/kg)|
| 2 to 5 years
5 to 10 years
Over 10 years
| 10 to 15
7 to 10
3 to 5
In children with renal disease, digoxin must be carefully titrated based upon clinical response.
It cannot be overemphasized that both the adult and pediatric dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, ultimate dosage selection must be based upon clinical assessment of the patient.
Atrial Fibrillation: Peak digoxin body stores larger than the 8 to 12 mcg/kg required for most patients with heart failure and normal sinus rhythm have been used for control of ventricular rate in patients with atrial fibrillation. Doses of digoxin used for the treatment of chronic atrial fibrillation should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects. Data are not available to establish the appropriate resting or exercise target rates that should be achieved.
Dosage Adjustment When Changing Preparations: The difference in bioavailability between Digoxin injection or Digoxin Solution in Capsules and Digoxin Pediatric Elixir or digoxin tablets must be considered when changing patients from one dosage form to another.
Doses of 100 mcg (0.1 mg) and 200 mcg (0.2 mg) of Digoxin Solution in Capsules are approximately equivalent to 125-mcg (0.125-mg) and 250-mcg (0.25-mg) doses of digoxin tablets and Pediatric Elixir, respectively. (see table in CLINICAL PHARMACOLOGY: Pharmacokinetics).
DIGITEK® (digoxin tablets, USP) 125 mcg (0.125 mg) are yellow, round tablets, and imprinted with B 145 on the scored side of the tablet. They are available as follows:
NDC 62794-145-01......................................bottles of 100 tablets
NDC 62794-145-10......................................bottles of 1000 tablets
NDC 62794-145-56......................................bottles of 5000 tablets
DIGITEK™ (digoxin tablets, USP) 250 mcg (0.25 mg) are white, round tablets, and imprinted with B 146 on the scored side of the tablet. They are avail- able as follows:
NDC 62794-146-01......................................bottles of 100 tablets
NDC 62794-146-10......................................bottles of 1000 tablets
NDC 62794-146-56......................................bottles of 5000 tablets
Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP.
Distributed by: BERTEK PHARMACEUTICALS INC. Sugar Land, TX 77478, USA. Manufactured by: AMIDE PHARMACEUTICAL, INC. 101 East Main Street, Little Falls, NJ 07424., USA. FDA Rev date: n/a
Last reviewed on RxList: 4/14/2008
This monograph has been modified to include the generic and brand name in many instances.
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