Digoxin Oral Solution

Dosage Form: oral solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Digoxin Oral Solution

Heart Failure

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.

Heart Failure in Pediatric Patients

Digoxin increases myocardial contractility in pediatric patients with heart failure.

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.

Digoxin Oral Solution Dosage and Administration

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:

• Lean body weight


• Renal function


• Patient age


• Concurrent disease [see Warnings and Precautions (5)]


• Concomitant medication [see Drug Interactions (7)]

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.

1. 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.


2. 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.

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.

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 - 30
Full-Term	25 - 35
1 to 24 months	35 - 60
2 to 5 years	30 - 45
5 to 10 years	20 - 35
Over 10 years	10 - 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.

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 – 7.8	2.3 – 3.9 Twice daily
Full-Term	7.5 – 11.3	3.8 – 5.6 Twice daily
1 to 24 months	11.3 – 18.8	5.6 – 9.4 Twice daily
2 to 5 years	9.4 – 13.1	4.7 – 6.6 Twice daily
5 to 10 years	5.6 – 11.3	2.8 – 5.6 Twice daily
Over 10 years	3.0 – 4.5	3.0 – 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 dropper supplied with the 60 mL bottle of Digoxin Oral Solution is not appropriate to measure doses below 0.2 mL. Doses less than 0.2 mL require appropriate methods or measuring devices designed to administer an accurate amount to the patient, such as a graduated syringe.

Adjustment of Dose

The body’s handling of digoxin can be affected by many different patient-specific factors. Some of the possible effects are small, so anticipatory dose adjustment might not be required, but others should be considered before initial dosing [see Clinical Pharmacology (12.2) and Drug Interactions (7)].

Both adults and pediatric patients with abnormal renal function need to have the dose of digoxin proportionally reduced. Recommended maintenance doses based upon lean body weight and renal function are listed in Table 3. Developmental changes in pediatric renal function were factored into Table 3. However, age-related and other changes in adult renal function were not.

The volume of distribution of digoxin is proportional to lean body weight and doses listed in Table 3 assume average body composition. The dose of digoxin must be reduced in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema. 

Table 3: Usual Maintenance Dose Requirements (mcg) of Digoxin Based upon Age, Lean Body Weight and Renal Function

* Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body surface area. Foradults, 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. † The doses are rounded to whole numbers. ‡ Twice daily dosing is recommended for pediatric patients under 10 years of age. Once daily dosing is recommended for pediatric patients above 10 years of age and adults.
Corrected Ccr (mL/min per 70 kg)*		Dose† to be given Twice Daily‡							Dose to be given Once Daily							Number of Days Before Steady State Achieve
		< 10 years of age							> 10 years of age and adults
		Lean Body Weight							Lean Body Weight
	kg	5	10	20	30	40	50	60	40	50	60	70	80	90	100
	lb	11	22	44	66	88	110	132	88	110	132	154	176	198	220
10		10	20	40	60	80	100	120	80	100	120	140	160	180	200	19
20		11	23	45	68	90	113	135	90	113	135	158	180	203	225	16
30		13	25	50	75	100	125	150	100	125	150	175	200	225	250	14
40		14	28	55	83	110	138	165	110	138	165	193	220	248	275	13
50		15	30	60	90	120	150	180	120	150	180	210	240	270	300	12
60		16	33	65	98	130	163	195	130	163	195	228	260	293	325	11
70		18	35	70	105	140	175	210	140	175	210	245	280	315	350	10
80		19	38	75	113	150	188	225	150	188	225	263	300	338	375	9
90		20	40	80	120	160	200	240	160	200	240	280	320	360	400	8
100		21	43	85	128	170	213	255	170	213	255	298	340	383	425	7

Determination of the target dose in milliliters of Digoxin Oral Solution based on body weight is shown in Table 4. Provided is the volume required per dose, NOT per day. 

Table 4: Dose in Milliliters

		Volume to be given in mL
		2	3	4	5	6	8	10	12	14	16	18	20	30
	2	0.08b	0.12b	0.16b	0.2	0.2	0.3	0.4	0.5	0.6	0.6	0.7	0.8	1.2
	3	0.12b	0.18b	0.2	0.3	0.4	0.5	0.6	0.7	0.8	1.0	1.1	1.2	1.8
	4	0.16b	0.2	0.3	0.4	0.5	0.6	0.8	1.0	1.1	1.3	1.4	1.6	2.4
	5	0.2	0.3	0.4	0.5	0.6	0.8	1.0	1.2	1.4	1.6	1.8	2.0	3.0
	6	0.2	0.4	0.5	0.6	0.7	1.0	1.2	1.4	1.7	1.9	2.2	2.4	3.6
	7	0.3	0.4	0.6	0.7	0.8	1.1	1.4	1.7	2.0	2.2	2.5	2.8	4.2
	8	0.3	0.5	0.6	0.8	1.0	1.3	1.6	1.9	2.2	2.6	2.9	3.2	4.8
	9	0.4	0.5	0.7	0.9	1.1	1.4	1.8	2.2	2.5	2.9	3.2	3.6	5.4
	10	0.4	0.6	0.8	1.0	1.2	1.6	2.0	2.4	2.8	3.2	3.6	4.0	6.0
	11	0.4	0.7	0.9	1.1	1.3	1.8	2.2	2.6	3.1	3.5	4.0	4.4	6.6
	12	0.5	0.7	1.0	1.2	1.4	1.9	2.4	2.9	3.4	3.8	4.3	4.8	7.2
	13	0.5	0.8	1.0	1.3	1.6	2.1	2.6	3.1	3.6	4.2	4.7	5.2	7.8
	14	0.6	0.8	1.1	1.4	1.7	2.2	2.8	3.4	3.9	4.5	5.0	5.6	8.4
	15	0.6	0.9	1.2	1.5	1.8	2.4	3.0	3.6	4.2	4.8	5.4	6.0	9.0
	20	0.8	1.2	1.6	2.0	2.4	3.2	4.0	4.8	5.6	6.4	7.2	8.0	12.0
	30	1.2	1.8	2.4	3.0	3.6	4.8	6.0	7.2	8.4	9.6	10.8	12.0	18.0
	40	1.6	2.4	3.2	4.0	4.8	6.4	8.0	9.6	11.2	12.8	14.4	16.0	24.0
	50	2.0	3.0	4.0	5.0	6.0	8.0	10.0	12.0	14.0	16.0	18	20.0	30.0
	60	2.4	3.6	4.8	6.0	7.2	9.6	12.0	14.4	16.8	19.2	21.6	24.0	36.0
	70	2.8	4.2	5.6	7.0	8.4	11.2	14.0	16.8	19.6	22.4	25.2	28.0	42.0
	80	3.2	4.8	6.4	8.0	9.6	12.8