General Injecatables & Vaccines, Inc
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General Injecatables & Vaccines, Inc Drugs
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Digoxin
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.
Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orally. Intramuscular injection can lead to severe pain at the injection site, thus intravenous administration is preferred. If the drug must be administered by the intramuscular route, it should be injected deep into the muscle followed by massage. No more than 500 mcg (2 mL) should be injected into a single site.
Digoxin Injection can be administered undiluted or diluted with a 4-fold or greater volume of Sterile Water for Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection. The use of less than a 4-fold volume of diluent could lead to precipitation of the digoxin. Immediate use of the diluted product is recommended.
If tuberculin syringes are used to measure very small doses, one must be aware of the problem of inadvertent overadministration of digoxin. The syringe should not be flushed with the parenteral solution after its contents are expelled into an indwelling vascular catheter.
Slow infusion of Digoxin Injection is preferable to bolus administration. Rapid infusion of digitalis glycosides has been shown to cause systemic and coronary arteriolar constriction, which may be clinically undesirable. Caution is thus advised and Digoxin Injection should probably be administered over a period of 5 minutes or longer. Mixing of Digoxin Injection with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended.
In selecting a dose of digoxin, the following 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 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 toxicity) 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 toxicity have serum digoxin concentrations greater than 2 ng/mL. However, since one-third of patients with clinical toxicity have concentrations less than 2 ng/mL, values below 2 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 than 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.
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.
1. 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.
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 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 DoseDigoxin Injection is frequently used to achieve rapid digitalization, with conversion to digoxin tablets or digoxin capsules for maintenance therapy. If patients are switched from intravenous to oral digoxin formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages (see Table 1, CLINICAL PHARMACOLOGY, Pharmacokinetics and dosing Table 5 below).
Intramuscular injection of digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.
Peak digoxin body stores of 8 to 12 mcg/kg should provide therapeutic effect with minimum risk of toxicity 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 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 loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given.
A single initial intravenous dose of 400 to 600 mcg (0.4 to 0.6 mg) of Digoxin Injection usually produces a detectable effect in 5 to 30 minutes that becomes maximal in 1 to 4 hours. Additional doses of 100 to 300 mcg (0.1 to 0.3 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 Injection that a 70-kg patient requires to achieve 8- to 12-mcg/kg peak body stores is 600 to 1000 mcg (0.6 to 1 mg).
Maintenance Dosing
The doses of oral 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 1800 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 surface area.)
Table 5 provides average daily maintenance dose requirements of Digoxin Injection for patients with heart failure based upon lean body weight and renal function:
Lean Body Weight
Corrected Ccr
kg
50
60
70
80
90
100
Number of Days Before Steady State Achieved‡
(mL/min per 70 kg)†
lb
110
132
154
176
198
220
0
75§
75
100
100
125
150
22
10
75
100
100
125
150
150
19
20
100
100
125
150
150
175
16
30
100
125
150
150
175
200
14
40
100
125
150
175
200
225
13
50
125
150
175
200
225
250
12
60
125
150
175
200
225
250
11
70
150
175
200
225
250
275
10
80
150
175
200
250
275
300
9
90
150
200
225
250
300
325
8
100
175
200
250
275
300
350
7
* Daily maintenance doses have been rounded to the nearest 25-mcg increment
† Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body 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.
‡ If no loading dose administered
§ 75 mcg = 0.075 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 175 mcg (0.175 mg) daily of Digoxin Injection. If no loading dose is administered, steady-state serum concentrations in this patient should be anticipated at approximately 11 days
Infants and Children
See the full prescribing information for pediatric digoxin injection (not available from West-Ward) for specific recommendations.
It cannot be overemphasized that 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 injectable digoxin and oral digoxin must be considered when changing patients from one dosage form to another (see Table 1 in CLINICAL PHARMACOLOGY, Pharmacokinetics). Intramuscular injection of digoxin is extremely painful and offers no advantage unless other routes of administration are contraindicated.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
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