Digitek (digoxin): Heart Failure Drug Side Effects & Warnings


Generic drug: digoxin

Brand name: Digitek

What is Digitek (digoxin), and how does it work?

Heart Failure: Digitek (digoxin) tablets are 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-converting enzyme inhibitor, but an optimal order for starting these three drugs cannot be specified.

Atrial Fibrillation: Digitek (digoxin tablets) is indicated for the control of ventricular response rate in patients with chronic atrial fibrillation.

What are the side effects of Digitek?

In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions.

Because some patients may be particularly susceptible to side effects with digoxin, the dosage of the drug should always be selected carefully and adjusted as the clinical condition of the patient warrants. In the past, when high doses of digoxin were used and little attention was paid to clinical status or concurrent medications, adverse reactions to digoxin were more frequent and severe.

Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. However, available evidence suggests that the incidence and severity of digoxin toxicity have decreased substantially in recent years.

In recent controlled clinical trials, in patients with predominantly mild to moderate heart failure, the incidence of adverse experiences was comparable in patients taking digoxin and in those taking a placebo. In a large mortality trial, the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking digoxin compared to 0.9% in patients taking placebo. In this trial, the most common manifestations of digoxin toxicity included gastrointestinal and cardiac disturbances; CNS manifestations were less common.

The following table summarizes the incidence of those adverse experiences listed above for patients treated with digoxin tablets or placebo from two randomized, double-blind, placebo-controlled withdrawal trials. Patients in these trials were also receiving diuretics with or without angiotensin-converting enzyme inhibitors. These patients have been stable on digoxin, and were randomized to digoxin or placebo.

The results shown in Table 4 reflect the experience in patients following dosage titration with the use of serum digoxin concentrations and careful follow-up. These adverse experiences are consistent with results from a large, placebo-controlled mortality trial (DIG trial) wherein over half the patients were not receiving digoxin prior to enrollment.

Table 4: Adverse Experiences In Two Parallel, Double-Blind, Placebo-Controlled Withdrawal Trials (Number of Patients Reporting)

Digoxin Patients
Placebo Patients

Adverse Experience
(n=123)
(n=125)

Cardiac

  Palpitation
1
4

  Ventricular extrasystole
1
1

  Tachycardia
2
1

  Heart arrest
1
1

Gastrointestinal

  Anorexia
1
4

  Nausea
4
2

  Vomiting
2
1

  Diarrhea
4
1

  Abdominal pain
0
6

CNS

  Headache
4
4

  Dizziness
6
5

  Mental disturbances
5
1

Other

  Rash
2
1

  Death
4
3

  • Infants and Children: The side effects of digoxin in infants and children differ from those seen in adults in several respects. Although digoxin may produce anorexia, nausea, vomiting, diarrhea, and CNS disturbances in young patients, these are rarely the initial symptoms of overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with digoxin in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia.
  • The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.

What is the dosage for Digitek?

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 1.5 mg /dL)
  4. Concomitant disease states, concurrent medications, or other factors likely to alter the pharmacokinetic or pharmacodynamic profile of digoxin.

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 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 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 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 the 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. The 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 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).

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 the 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 bioavailability when calculating maintenance dosages.

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†

kg
50
60
70
80
90
100

lb
110
132
154
176
198
220

0
62.5‡
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

*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.
‡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 surface area. Children over 10 years 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 Table 6 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
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.

What drugs interact with Digitek?

  • Potassium-depleting diuretics are a major contributing factor to digitalis toxicity.
  • Calcium, particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients.
  • Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone raise the serum digoxin concentration due to a reduction in clearance and/or in volume of distribution of the drug, with the implication that digitalis intoxication may result.
  • Erythromycin and clarithromycin (and possibly other macrolide antibiotics) and tetracycline may increase digoxin absorption in patients who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication may result.
  • Propantheline and diphenoxylate, by decreasing gut motility, may increase digoxin absorption.
  • Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs, and metoclopramide may interfere with intestinal digoxin absorption, resulting in unexpectedly low serum concentrations.
  • Rifampin may decrease serum digoxin concentration, especially in patients with renal dysfunction, by increasing the non-renal clearance of digoxin.
  • There have been inconsistent reports regarding the effects of other drugs [e.g., quinine, penicillamine] on serum digoxin concentration. Thyroid administration to a digitalized, hypothyroid patient may increase the dose requirement of digoxin.
  • Concomitant use of digoxin and sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in digitalized patients.
  • Although beta-adrenergic blockers or calcium channel blockers and digoxin may be useful in combination to control atrial fibrillation, their additive effects on AV node conduction can result in advanced or complete heart block.
  • Due to the considerable variability of these interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently. Furthermore, caution should be exercised when combining digoxin with any drug that may cause a significant deterioration in renal function, since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin.
  • Drug/Laboratory Test Interactions: The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram.
  • Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.

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Is Digitek safe to use while pregnant or breastfeeding?

Pregnancy: It is also
not known whether digoxin can cause fetal harm when administered to a pregnant
woman or can affect reproductive capacity. Digoxin should be given to a pregnant
woman only if clearly needed.

Nursing Mothers: Studies have shown that digoxin concentrations in the
mother’s serum and milk are similar. However, the estimated exposure of a nursing
infant to digoxin via breast feeding will be far below the usual infant maintenance
dose. Therefore, this amount should have no pharmacologic effect upon the infant.
Never theless, caution should be exercised when digoxin is administered to a
nursing woman.

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