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Lanoxin (Digoxin) - Indications and Dosage

 
 



INDICATIONS AND USAGE

Heart Failure

LANOXIN is indicated for the treatment of mild to moderate heart failure. LANOXIN 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, LANOXIN should be used with a diuretic and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these 3 drugs cannot be specified.

Atrial Fibrillation

LANOXIN is indicated for the control of ventricular response rate in patients with chronic atrial fibrillation.

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:

  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 1.5mg/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 2.0ng/mL (lower serum trough concentrations of 0.5 to 1 ng/mL may be appropriate in some adult patients, see Maintenance Dosing). 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 2.0ng/mL. However, since one-third of patients with clinical toxicity have concentrations less than 2.0ng/mL, values below 2.0ng/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 0.8ng/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 8hours 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 24versus 8hours, 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 12hours 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 2 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 5 half-lives of the drug for the individual patient. Depending upon the patient's renal function, this will take between 1 and 3weeks.

Rapid Digitalization With a Loading Dose

Peak digoxin body stores of 8 to 12mcg/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 10mcg/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 dose of 500 to 750mcg (0.5 to 0.75mg) of LANOXIN Tablets usually produces a detectable effect in 0.5 to 2hours that becomes maximal in 2 to 6hours. Additional doses of 125 to 375mcg (0.125 to 0.375mg) may be given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate effect is noted. The usual amount of LANOXIN Tablets that a 70-kg patient requires to achieve 8 to 12mcg/kg peak body stores is 750 to 1,250mcg (0.75 to 1.25mg).

LANOXIN Injection is frequently used to achieve rapid digitalization, with conversion to LANOXIN Tablets 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).

Maintenance Dosing

The doses of digoxin used in controlled trials in patients with heart failure have ranged from 125 to 500mcg (0.125 to 0.5mg) 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 250mcg (0.25mg) once daily in patients under age 70 with good renal function, at a dose of 125mcg (0.125mg) once daily in patients over age 70 or with impaired renal function, and at a dose of 62.5mcg (0.0625mg) in patients with marked renal impairment. Doses may be increased every 2weeks 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 Table5) the mean ( SD) serum digoxin concentrations at 1month and 12months were 1.010.47ng/mL and 0.970.43ng/mL, respectively. There are no rigid guidelines as to the range of serum concentrations that are most efficacious. Several post hoc analyses of heart failure patients in the DIG trial suggest that the optimal trough digoxin serum level may be 0.5ng/mL to 1ng/mL.

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 1.73m2 body surface area.)

Table5 provides average daily maintenance dose requirements of LANOXIN Tablets for patients with heart failure based upon lean body weight and renal function:

Table 5. Usual Daily Maintenance Dose Requirements (mcg) of LANOXIN for Estimated Peak Body Stores of 10 mcg/kg

Corrected Ccr

(mL/min per 70 kg)a

Lean Body Weight

Number of Days

kg

50

60

70

80

90

100

Before Steady

lb

110

132

154

176

198

220

State Achievedb

0

62.5c

125

125

125

187.5

187.5

22

10

125

125

125

187.5

187.5

187.5

19

20

125

125

187.5

187.5

187.5

250

16

30

125

187.5

187.5

187.5

250

250

14

40

125

187.5

187.5

250

250

250

13

50

187.5

187.5

250

250

250

250

12

60

187.5

187.5

250

250

250

375

11

70

187.5

250

250

250

250

375

10

80

187.5

250

250

250

375

375

9

90

187.5

250

250

250

375

500

8

100

250

250

250

375

375

500

7

aCcr 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 70kg 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.

bIf no loading dose administered.

c62.5mcg = 0.0625mg.

Example: Based on Table 5, a patient in heart failure with an estimated lean body weight of 70kg and a Ccr of 60mL/min should be given a dose of 250mcg (0.25mg) daily of LANOXIN 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 11days.

Infants and Children

In general, divided daily dosing is recommended for infants and young children (under age10). 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 surface area. Children over 10years of age require adult dosages in proportion 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 Table6 and should provide therapeutic effects with minimum risk of toxicity 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 Renal Function

Age

Daily Maintenance Dose (mcg/kg)

2 to 5 Years

10 to 15

5 to 10 Years

7 to 10

Over 10 Years

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 12mcg/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 LANOXIN Injection or LANOXIN Tablets must be considered when changing patients from one dosage form to the other.

HOW SUPPLIED

LANOXIN (digoxin) Tablets, Scored 125mcg (0.125mg): Bottles of 100 with child-resistant cap (NDC 0173-0242-55) and 1,000 (NDC 0173-0242-75); unit dose pack of 100 (NDC 0173-0242-56). Imprinted with LANOXIN and Y3B (yellow).

Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature] in a dry place and protect from light.

LANOXIN (digoxin) Tablets, Scored 250mcg (0.25mg): Bottles of 100 with child-resistant cap (NDC 0173-0249-55), 1,000 (NDC 0173-0249-75), and 5,000 (NDC 0173-0249-80); unit dose pack of 100 (NDC 0173-0249-56). Imprinted with LANOXIN and X3A (white).

Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature] in a dry place.

LANOXIN and DIGIBIND are registered trademarks of GlaxoSmithKline

DIGIFAB is a registered trademark of Prostherics Inc.

Manufactured for

GlaxoSmithKline

Research Triangle Park, NC 27709

by DSM Pharmaceuticals, Inc.

Greenville, NC 27834 or

GlaxoSmithKline

Research Triangle Park, NC 27709

2009, GlaxoSmithKline. All rights reserved.

August 2009

LNT:1PI

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