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Indications/Uses
Cardiac Failure: Management of chronic cardiac failure where the dominant problem is systolic dysfunction. The therapeutic benefit of Lanoxin is greatest in those patients with ventricular dilatation.
It is specifically indicated where cardiac failure is accompanied by atrial fibrillation.
Supraventricular Arrhythmias: Management of certain supraventricular arrhythmias, particularly chronic atrial flutter and fibrillation.
It is specifically indicated where cardiac failure is accompanied by atrial fibrillation.
Supraventricular Arrhythmias: Management of certain supraventricular arrhythmias, particularly chronic atrial flutter and fibrillation.
Dosage/Direction for Use
The dose of Lanoxin for each patient has to be tailored individually according to age, lean body weight and renal function. Suggested doses are intended only as an initial guide.
The difference in bioavailability between injectable Lanoxin and oral formulations must be considered when changing from one dosage form to another. For example, if patients are switched from oral to the IV formulation, the dosage should be reduced by approximately 33%.
Lanoxin oral solution, 50 mcg/mL is supplied with a graduated pipette and this should be used in measurement of all doses.
Monitoring: Serum concentrations of Lanoxin may be expressed in conventional units of ng/mL or SI units of nmol/L. To convert ng/mL to nmol/L, multiply ng/mL by 1.28. The serum concentration of digoxin can be determined by radioimmunoassay. Blood should be taken ≥6 hrs after the last dose of Lanoxin.
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 Digitalis Investigation Group trial suggest that the optimal trough digoxin serum level may be 0.5 ng/mL (0.64 nanomol/L) to 1 ng/mL (1.28 nanomol/L).
Lanoxin toxicity is more commonly associated with serum digoxin concentration >2 ng/mL. However, toxicity may occur with lower digoxin serum concentrations. In deciding whether a patient's symptoms are due to digoxin, the clinical state together with the serum potassium level and thyroid function are important factors (see Overdosage).
Other glycosides, including metabolites of digoxin, can interfere with the assays that are available and one should always be wary of values which do not seem commensurate with the clinical state of the patient.
Adults and Children >10 years: Parenteral Loading Dose: For use in patients who have not been given cardiac glycosides within the preceding 2 weeks.
The total loading dose of parenteral Lanoxin is 500-1000 mcg (0.5-1 mg) depending on age, lean body weight and renal function.
The total loading dose should be administered in divided doses with approximately ½ of the total dose given as the 1st dose and further fractions of the total dose given at intervals of 4-8 hrs. An assessment of clinical response should be performed before giving each additional dose. Each dose should be given by IV infusion (see Dilution of Lanoxin Injection under Cautions for Usage) over 10-20 min.
Rapid Oral Loading Dose: If medically appropriate, rapid digitalisation may be achieved in a number of ways eg, the following: 750-1500 mcg as a single dose.
Where there is less urgency or greater risk of toxicity eg, in the elderly, the oral loading dose should be given in divided doses 6 hrs apart, with approximately ½ the total dose given as the 1st dose.
Clinical response should be assessed before giving each additional dose (see Precautions).
Slow Oral Loading Dose: In some patients eg, those with mild heart failure, digitalisation may be achieved more slowly with doses of 250-750 mcg (0.25-0.75 mg) daily for 1 week followed by an appropriate maintenance dose. A clinical response should be seen within 1 week.
Note: The choice between slow and rapid oral loading dose depends on the clinical state of the patient and the urgency of the condition.
Maintenance Dose: The maintenance dosage should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use:
The difference in bioavailability between injectable Lanoxin and oral formulations must be considered when changing from one dosage form to another. For example, if patients are switched from oral to the IV formulation, the dosage should be reduced by approximately 33%.
Lanoxin oral solution, 50 mcg/mL is supplied with a graduated pipette and this should be used in measurement of all doses.
Monitoring: Serum concentrations of Lanoxin may be expressed in conventional units of ng/mL or SI units of nmol/L. To convert ng/mL to nmol/L, multiply ng/mL by 1.28. The serum concentration of digoxin can be determined by radioimmunoassay. Blood should be taken ≥6 hrs after the last dose of Lanoxin.
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 Digitalis Investigation Group trial suggest that the optimal trough digoxin serum level may be 0.5 ng/mL (0.64 nanomol/L) to 1 ng/mL (1.28 nanomol/L).
Lanoxin toxicity is more commonly associated with serum digoxin concentration >2 ng/mL. However, toxicity may occur with lower digoxin serum concentrations. In deciding whether a patient's symptoms are due to digoxin, the clinical state together with the serum potassium level and thyroid function are important factors (see Overdosage).
Other glycosides, including metabolites of digoxin, can interfere with the assays that are available and one should always be wary of values which do not seem commensurate with the clinical state of the patient.
Adults and Children >10 years: Parenteral Loading Dose: For use in patients who have not been given cardiac glycosides within the preceding 2 weeks.
The total loading dose of parenteral Lanoxin is 500-1000 mcg (0.5-1 mg) depending on age, lean body weight and renal function.
The total loading dose should be administered in divided doses with approximately ½ of the total dose given as the 1st dose and further fractions of the total dose given at intervals of 4-8 hrs. An assessment of clinical response should be performed before giving each additional dose. Each dose should be given by IV infusion (see Dilution of Lanoxin Injection under Cautions for Usage) over 10-20 min.
Rapid Oral Loading Dose: If medically appropriate, rapid digitalisation may be achieved in a number of ways eg, the following: 750-1500 mcg as a single dose.
Where there is less urgency or greater risk of toxicity eg, in the elderly, the oral loading dose should be given in divided doses 6 hrs apart, with approximately ½ the total dose given as the 1st dose.
Clinical response should be assessed before giving each additional dose (see Precautions).
Slow Oral Loading Dose: In some patients eg, those with mild heart failure, digitalisation may be achieved more slowly with doses of 250-750 mcg (0.25-0.75 mg) daily for 1 week followed by an appropriate maintenance dose. A clinical response should be seen within 1 week.
Note: The choice between slow and rapid oral loading dose depends on the clinical state of the patient and the urgency of the condition.
Maintenance Dose: The maintenance dosage should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use:
Ccr is creatinine clearance corrected to 70-kg body weight or 1.73 m2 body surface area. If only serum creatinine (Scr) concentrations are available, a Ccr (corrected to 70-kg body weight) may be estimated in men as:
For women, this result should be multiplied by 0.85.
Note: These formulas cannot be used for creatinine clearance in children.
In practice, this will mean that most patients with heart failure will be maintained on digoxin 125-250 mcg (0.125-0.25 mg) daily; however, in those who show increased sensitivity to the adverse effects of digoxin, a dose of ≤62.5 mcg daily may suffice. Conversely, some patients may require a higher dose.
Neonates, Infants and Children up to 10 years: (If cardiac glycosides have not been given in the preceding 2 weeks).
If cardiac glycosides have been given in the 2 weeks preceding commencement of digoxin therapy, it should be anticipated that optimum loading doses of digoxin will be less than those recommended as follows. In the newborn, particularly in the premature infant, renal clearance of Lanoxin is diminished and suitable dose reductions must be observed over and above general instructions.
Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area as indicated in the schedule below. Children >10 years require adult dosages in proportion to their body weight.
Parenteral Loading Dose: The IV loading dose in the previously mentioned groups should be administered in accordance with the following schedule: Children 5-10 years: 25 mcg/kg; 2-5 years: 35 mcg/kg. Term Neonates to 2 years: 35 mcg/kg. Pre-Term Neonates: 1.5-2.5 kg: 30 mcg/kg; <1.5 kg: 20 mcg/kg. All doses to be given over 24 hrs.
The loading dose should be administered in divided doses with approximately ½ the total dose given as the 1st dose and further fractions of the total dose given at intervals of 4-8 hrs, assessing clinical response before giving each additional dose. Each dose should be given by IV infusion (see Dilution of Lanoxin Injection under Cautions for Usage) over 10-20 min.
Oral Loading Dose: This should be administered in accordance with the following schedule: Children 5-10 years: 25 mcg/kg; 2-5 years: 35 mcg/kg. Term Neonates to 2 years: 45 mcg/kg. Pre-Term Neonates 1.5-2.5 kg: 30 mcg/kg; <1.5 kg: 25 mcg/kg. All doses to be given over 24 hrs.
The loading dose should be administered in divided doses with approximately ½ the total dose given as the 1st dose and further fractions of the total dose given at intervals of 4-8 hrs, assessing clinical response before giving each additional dose.
Maintenance: The maintenance dose should be administered in accordance with the following schedule:
Pre-Term Neonates: Daily dose=20% of 24-hr loading dose (IV or oral). Term Neonates and Children up to 10 years: Daily dose=25% of 24-hr loading dose (IV or oral).
These dosage schedules are meant as guidelines and careful clinical observation and monitoring of serum Lanoxin levels (see previous text on Monitoring) should be used as a basis for adjustment of dosage in these pediatric patient groups.
Elderly: The tendency to impaired renal function and low lean body mass in the elderly influences the pharmacokinetics of Lanoxin such that high serum digoxin levels and associated toxicity can occur quite readily, unless doses of Lanoxin lower than those in non-elderly patients are used. Serum digoxin levels should be checked regularly and hypokalemia avoided.
Dose Recommendations in Specific Patient Groups: See Precautions.
Overdosage
Symptoms: The symptoms of toxicity are generally similar to those described in the Adverse Reactions section but may be more frequent and can be more severe.
Signs and symptoms of digoxin toxicity become more frequent with levels >2 ng/mL (2.56 nanomol/L). However, in deciding whether a patient's symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors (see Dosage & Administration).
Adults: In adults without heart disease, clinical observation suggests that an overdose of Lanoxin 10-15 mg was the dose resulting in death of ½ of the patients. If Lanoxin >25 mg was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments (Digibind) resulted.
Cardiac Manifestations: Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3-6 hr following overdosage and may persist for the ensuing 24 hr or longer. Digoxin toxicity may result in almost any type of arrhythmia. Multiple rhythm disturbances in the same patient are common. These include paroxysmal atrial tachycardia with variable AV block, accelerated junctional rhythm, slow atrial fibrillation (with very little variation in the ventricular rate) and bi-directional ventricular tachycardia.
Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmia. Bigeminy or trigeminy also occur frequently.
Sinus bradycardia and other bradyarrhythmias are very common.
First-, 2nd-, 3rd- degree heart blocks and AV dissociation are also common.
Early toxicity may only be manifested by prolongation of the PR interval.
Ventricular tachycardia may also be a manifestation of toxicity.
Cardiac arrest from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal.
Acute massive digoxin overdosage can result in mild to pronounced hyperkalemia due to inhibition of the Na+K+ pump. Hypokalemia may contribute to toxicity (see Precautions).
Non-Cardiac Manifestations: Gastrointestinal symptoms are very common in both acute and chronic toxicity. The symptoms precede cardiac manifestations in approximately ½ of the patients in most literature reports. Anorexia, nausea and vomiting have been reported with an incidence up to 80%. These symptoms are usually present in the course of an overdose.
Neurologic and visual manifestations occur in both acute and chronic toxicity. Dizziness, various CNS disturbances, fatigue and malaise are very common. The most frequent visual disturbance is an aberration of color vision (predominance of yellow green). These neurological and visual symptoms may persist even after other signs of toxicity have resolved.
In chronic toxicity, nonspecific extracardiac symptoms eg, malaise and weakness, may predominate.
Children: In children 1-3 years without heart disease, clinical observation suggests that an overdose of digoxin 6-10 mg was the dose resulting in death in ½ of the patients. If >10 mg of digoxin was ingested by a child 1-3 years without heart disease, the outcome was uniformly fatal when Digibind Fab fragment treatment was not given.
Most manifestations of toxicity in children occur during or shortly after the loading phase with Lanoxin.
Cardiac Manifestations: The same arrhythmias or combination of arrhythmias that occur in adults can occur in pediatrics. Sinus tachycardia, supraventricular tachycardia and rapid atrial fibrillation are seen less frequently in the pediatric population.
Pediatric patients are more likely to present with an AV conduction disturbance or a sinus bradycardia.
Ventricular ectopy is less common, however in massive overdose, ventricular ectopy, ventricular tachycardia and ventricular fibrillation have been reported.
In neonates, sinus bradycardia or sinus arrest and/or prolonged PR intervals are frequent signs of toxicity. Sinus bradycardia is common in young infants and children. In older children, AV blocks are the most common conduction disorders.
Any arrhythmia or alteration in cardiac conduction that develops in a child taking Lanoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.
Extracardiac Manifestations: The frequent extracardiac manifestations similar to those seen in adults are GI, CNS and visual. However, nausea and vomiting are not frequent in infants and small children.
In addition to the undesirable effects seen with recommended doses, weight loss in older age groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischemia, drowsiness and behavioral disturbances including psychotic manifestations have been reported in overdose.
Treatment: After recent ingestion eg, accidental or deliberate self-poisoning, the load available for absorption may be reduced by gastric lavage.
Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation.
If hypokalemia is present, it should be corrected with potassium supplements either orally or IV, depending on the urgency of the situation. In cases where a large amount of Lanoxin has been ingested, hyperkalemia may be present due to release of potassium from skeletal muscle. Before administering potassium in digoxin overdose, the serum potassium level must be known.
Bradyarrhythmias may respond to atropine but temporary cardiac pacing may be required. Ventricular arrhythmias may respond to lidocaine or phenytoin.
Dialysis is not particularly effective in removing Lanoxin from the body in potentially life-threatening toxicity.
Digibind is a specific treatment for digoxin toxicity and is very effective. Rapid reversal of the complications that are associated with serious poisoning by digoxin, digitoxin and related glycosides has followed IV administration of digoxin-specific (ovine) antibody fragments (Fab).
Signs and symptoms of digoxin toxicity become more frequent with levels >2 ng/mL (2.56 nanomol/L). However, in deciding whether a patient's symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors (see Dosage & Administration).
Adults: In adults without heart disease, clinical observation suggests that an overdose of Lanoxin 10-15 mg was the dose resulting in death of ½ of the patients. If Lanoxin >25 mg was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments (Digibind) resulted.
Cardiac Manifestations: Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3-6 hr following overdosage and may persist for the ensuing 24 hr or longer. Digoxin toxicity may result in almost any type of arrhythmia. Multiple rhythm disturbances in the same patient are common. These include paroxysmal atrial tachycardia with variable AV block, accelerated junctional rhythm, slow atrial fibrillation (with very little variation in the ventricular rate) and bi-directional ventricular tachycardia.
Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmia. Bigeminy or trigeminy also occur frequently.
Sinus bradycardia and other bradyarrhythmias are very common.
First-, 2nd-, 3rd- degree heart blocks and AV dissociation are also common.
Early toxicity may only be manifested by prolongation of the PR interval.
Ventricular tachycardia may also be a manifestation of toxicity.
Cardiac arrest from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal.
Acute massive digoxin overdosage can result in mild to pronounced hyperkalemia due to inhibition of the Na+K+ pump. Hypokalemia may contribute to toxicity (see Precautions).
Non-Cardiac Manifestations: Gastrointestinal symptoms are very common in both acute and chronic toxicity. The symptoms precede cardiac manifestations in approximately ½ of the patients in most literature reports. Anorexia, nausea and vomiting have been reported with an incidence up to 80%. These symptoms are usually present in the course of an overdose.
Neurologic and visual manifestations occur in both acute and chronic toxicity. Dizziness, various CNS disturbances, fatigue and malaise are very common. The most frequent visual disturbance is an aberration of color vision (predominance of yellow green). These neurological and visual symptoms may persist even after other signs of toxicity have resolved.
In chronic toxicity, nonspecific extracardiac symptoms eg, malaise and weakness, may predominate.
Children: In children 1-3 years without heart disease, clinical observation suggests that an overdose of digoxin 6-10 mg was the dose resulting in death in ½ of the patients. If >10 mg of digoxin was ingested by a child 1-3 years without heart disease, the outcome was uniformly fatal when Digibind Fab fragment treatment was not given.
Most manifestations of toxicity in children occur during or shortly after the loading phase with Lanoxin.
Cardiac Manifestations: The same arrhythmias or combination of arrhythmias that occur in adults can occur in pediatrics. Sinus tachycardia, supraventricular tachycardia and rapid atrial fibrillation are seen less frequently in the pediatric population.
Pediatric patients are more likely to present with an AV conduction disturbance or a sinus bradycardia.
Ventricular ectopy is less common, however in massive overdose, ventricular ectopy, ventricular tachycardia and ventricular fibrillation have been reported.
In neonates, sinus bradycardia or sinus arrest and/or prolonged PR intervals are frequent signs of toxicity. Sinus bradycardia is common in young infants and children. In older children, AV blocks are the most common conduction disorders.
Any arrhythmia or alteration in cardiac conduction that develops in a child taking Lanoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.
Extracardiac Manifestations: The frequent extracardiac manifestations similar to those seen in adults are GI, CNS and visual. However, nausea and vomiting are not frequent in infants and small children.
In addition to the undesirable effects seen with recommended doses, weight loss in older age groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischemia, drowsiness and behavioral disturbances including psychotic manifestations have been reported in overdose.
Treatment: After recent ingestion eg, accidental or deliberate self-poisoning, the load available for absorption may be reduced by gastric lavage.
Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation.
If hypokalemia is present, it should be corrected with potassium supplements either orally or IV, depending on the urgency of the situation. In cases where a large amount of Lanoxin has been ingested, hyperkalemia may be present due to release of potassium from skeletal muscle. Before administering potassium in digoxin overdose, the serum potassium level must be known.
Bradyarrhythmias may respond to atropine but temporary cardiac pacing may be required. Ventricular arrhythmias may respond to lidocaine or phenytoin.
Dialysis is not particularly effective in removing Lanoxin from the body in potentially life-threatening toxicity.
Digibind is a specific treatment for digoxin toxicity and is very effective. Rapid reversal of the complications that are associated with serious poisoning by digoxin, digitoxin and related glycosides has followed IV administration of digoxin-specific (ovine) antibody fragments (Fab).
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to digoxin or other digitalis glycosides, or to any of the excipients of Lanoxin. Intermittent complete heart block or 2nd-degree AV block, especially if there is a history of Stokes-Adams attack; arrhythmias caused by cardiac glycoside intoxication; supraventricular arrhythmias associated with an accessory AV pathway, as in the Wolff-Parkinson-White syndrome, unless the electrophysiological characteristics of the accessory pathway and any possible deleterious effect of Lanoxin on these characteristics has been evaluated. If an accessory pathway is known or suspected to be present and there is no history of previous supraventricular arrhythmias, Lanoxin is similarly contraindicated; ventricular tachycardia or fibrillation; hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure, but even then, caution should be exercised if Lanoxin is to be used.
Special Precautions
Arrhythmias may be precipitated by digoxin toxicity, some of which can resemble arrhythmias for which the drug could be advised eg, atrial tachycardia with varying AV block requires particular care as clinically, the rhythm resembles atrial fibrillation.
Many beneficial effects of digoxin on arrhythmias result from a degree of AV conduction blockade. However, when incomplete AV block already exists, the effects of a rapid progression in the block should be anticipated. In complete heart block, the idioventricular escape rhythm may be suppressed.
In some cases of sinoatrial disorder (ie, sick sinus syndrome), digoxin may cause or exacerbate sinus bradycardia or cause sinoatrial block.
The administration of digoxin in the period immediately following myocardial infarction is not contraindicated. However, the use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand and ischemia and some retrospective follow-up studies have suggested digoxin to be associated with an increased risk of death. The possibility of arrhythmias arising in patients who may be hypokalemic after myocardial infarction and are likely to be hemodynamically unstable must be borne in mind. The limitations imposed thereafter on direct current cardioversion must also be remembered.
Treatment with digoxin should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if alternative treatments are not appropriate, digoxin can be used to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation.
Digoxin can rarely precipitate vasoconstriction and therefore should be avoided in patients with myocarditis.
Patients with beri-beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly.
Digoxin should not be used in constructive pericarditis unless it is used to control the ventricular rate in atrial fibrillation or to improve systolic dysfunction.
Digoxin improves exercise tolerance in patients with impaired left ventricular systolic dysfunction and normal sinus rhythm. This may or may not be associated with an improved hemodynamic profile. However, the benefit of digoxin in patients with supraventricular arrhythmias is most evident at rest, less evident with exercise.
In patients receiving diuretics and an ACE inhibitor or diuretics alone, the withdrawal of digoxin has been shown to result in clinical deterioration.
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.
In cases where cardiac glycosides have been taken in the preceding 2 weeks, the recommendations for initial dosing of a patient should be reconsidered and a reduced dose is advised.
The dosing recommendations should be reconsidered if patients are elderly or there are other reasons for the renal clearance of digoxin being reduced. A reduction in both initial and maintenance doses should be considered.
Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine concentration) assessed periodically; the frequency of assessments will depend on the clinical setting.
Determination of the serum digoxin concentration may be very helpful in making a decision to treat with further digoxin, but other glycosides and endogenous digoxin-like substances may cross-react in the assay giving false-positive results. Observations while temporarily withholding digoxin might be more appropriate.
The IM route is painful and is associated with muscle necrosis. This route cannot be recommended.
Rapid IV injection can cause vasoconstriction producing hypertension and/or reduced coronary flow. A slow injection rate is therefore important in hypertensive heart failure and acute myocardial infarction.
Patients with severe respiratory disease may have an increased myocardial sensitivity to digitalis glycosides.
Hypokalemia sensitizes the myocardium to the actions of cardiac glycosides.
Hypoxia, hypomagnesemia and marked hypercalcemia increase myocardial sensitivity to cardiac glycosides.
Administering digoxin to a patient with thyroid disease requires care. Initial and maintenance doses of digoxin should be reduced when thyroid function is subnormal. In hyperthyroidism, there is relative digoxin resistance and the dose may have to be increased. During the course of treatment of thyrotoxicosis, dosage should be reduced as the thyrotoxicosis comes under control.
Patients with malabsorption syndrome or GI reconstructions may require larger doses of digoxin.
Direct Current Cardioversion: The risk of provoking dangerous arrhythmias with direct current cardioversion is greatly increased in the presence of digitalis toxicity and is in proportion to the cardioversion energy used.
For elective direct current cardioversion of a patient who is taking digoxin, the drug should be withheld for 24 hrs before cardioversion is performed. In emergencies eg, cardiac arrest, when attempting cardioversion, the lowest effective energy should be applied.
Direct current cardioversion is inappropriate in the treatment of arrhythmias thought to be caused by cardiac glycosides.
Effects on the Ability to Drive or Operate Machinery: Since CNS and visual disturbances have been reported in patients receiving digoxin, patients should exercise caution before driving, using machinery or participating in dangerous activities.
Impairment of Fertility: There is no information available on the effect of digoxin on human fertility.
No data are available on whether or not digoxin has teratogenic effects.
Use in pregnancy: The use of digoxin in pregnancy is not contraindicated, although the dosage may be less predictable in pregnant than in nonpregnant women, with some requiring an increased dosage of digoxin during pregnancy. As with all drugs, use should be considered only when the expected clinical benefit of treatment to the mother outweighs any possible risk to the developing fetus.
Despite extensive antenatal exposure to digitalis preparations, no significant adverse effects have been observed in the fetus or neonate when maternal serum digoxin concentrations are maintained within the normal range. Although it has been speculated that a direct effect of digoxin on the myometrium may result in relative prematurity and low birthweight, a contributing role of the underlying cardiac disease cannot be excluded. Maternally administered digoxin has been successfully used to treat fetal tachycardia and congestive heart failure.
Adverse fetal effects have been reported in mothers with digitalis toxicity.
Use in lactation: Although digoxin is excreted in breast milk, the quantities are minute and breastfeeding is not contraindicated.
Many beneficial effects of digoxin on arrhythmias result from a degree of AV conduction blockade. However, when incomplete AV block already exists, the effects of a rapid progression in the block should be anticipated. In complete heart block, the idioventricular escape rhythm may be suppressed.
In some cases of sinoatrial disorder (ie, sick sinus syndrome), digoxin may cause or exacerbate sinus bradycardia or cause sinoatrial block.
The administration of digoxin in the period immediately following myocardial infarction is not contraindicated. However, the use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand and ischemia and some retrospective follow-up studies have suggested digoxin to be associated with an increased risk of death. The possibility of arrhythmias arising in patients who may be hypokalemic after myocardial infarction and are likely to be hemodynamically unstable must be borne in mind. The limitations imposed thereafter on direct current cardioversion must also be remembered.
Treatment with digoxin should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if alternative treatments are not appropriate, digoxin can be used to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation.
Digoxin can rarely precipitate vasoconstriction and therefore should be avoided in patients with myocarditis.
Patients with beri-beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly.
Digoxin should not be used in constructive pericarditis unless it is used to control the ventricular rate in atrial fibrillation or to improve systolic dysfunction.
Digoxin improves exercise tolerance in patients with impaired left ventricular systolic dysfunction and normal sinus rhythm. This may or may not be associated with an improved hemodynamic profile. However, the benefit of digoxin in patients with supraventricular arrhythmias is most evident at rest, less evident with exercise.
In patients receiving diuretics and an ACE inhibitor or diuretics alone, the withdrawal of digoxin has been shown to result in clinical deterioration.
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.
In cases where cardiac glycosides have been taken in the preceding 2 weeks, the recommendations for initial dosing of a patient should be reconsidered and a reduced dose is advised.
The dosing recommendations should be reconsidered if patients are elderly or there are other reasons for the renal clearance of digoxin being reduced. A reduction in both initial and maintenance doses should be considered.
Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine concentration) assessed periodically; the frequency of assessments will depend on the clinical setting.
Determination of the serum digoxin concentration may be very helpful in making a decision to treat with further digoxin, but other glycosides and endogenous digoxin-like substances may cross-react in the assay giving false-positive results. Observations while temporarily withholding digoxin might be more appropriate.
The IM route is painful and is associated with muscle necrosis. This route cannot be recommended.
Rapid IV injection can cause vasoconstriction producing hypertension and/or reduced coronary flow. A slow injection rate is therefore important in hypertensive heart failure and acute myocardial infarction.
Patients with severe respiratory disease may have an increased myocardial sensitivity to digitalis glycosides.
Hypokalemia sensitizes the myocardium to the actions of cardiac glycosides.
Hypoxia, hypomagnesemia and marked hypercalcemia increase myocardial sensitivity to cardiac glycosides.
Administering digoxin to a patient with thyroid disease requires care. Initial and maintenance doses of digoxin should be reduced when thyroid function is subnormal. In hyperthyroidism, there is relative digoxin resistance and the dose may have to be increased. During the course of treatment of thyrotoxicosis, dosage should be reduced as the thyrotoxicosis comes under control.
Patients with malabsorption syndrome or GI reconstructions may require larger doses of digoxin.
Direct Current Cardioversion: The risk of provoking dangerous arrhythmias with direct current cardioversion is greatly increased in the presence of digitalis toxicity and is in proportion to the cardioversion energy used.
For elective direct current cardioversion of a patient who is taking digoxin, the drug should be withheld for 24 hrs before cardioversion is performed. In emergencies eg, cardiac arrest, when attempting cardioversion, the lowest effective energy should be applied.
Direct current cardioversion is inappropriate in the treatment of arrhythmias thought to be caused by cardiac glycosides.
Effects on the Ability to Drive or Operate Machinery: Since CNS and visual disturbances have been reported in patients receiving digoxin, patients should exercise caution before driving, using machinery or participating in dangerous activities.
Impairment of Fertility: There is no information available on the effect of digoxin on human fertility.
No data are available on whether or not digoxin has teratogenic effects.
Use in pregnancy: The use of digoxin in pregnancy is not contraindicated, although the dosage may be less predictable in pregnant than in nonpregnant women, with some requiring an increased dosage of digoxin during pregnancy. As with all drugs, use should be considered only when the expected clinical benefit of treatment to the mother outweighs any possible risk to the developing fetus.
Despite extensive antenatal exposure to digitalis preparations, no significant adverse effects have been observed in the fetus or neonate when maternal serum digoxin concentrations are maintained within the normal range. Although it has been speculated that a direct effect of digoxin on the myometrium may result in relative prematurity and low birthweight, a contributing role of the underlying cardiac disease cannot be excluded. Maternally administered digoxin has been successfully used to treat fetal tachycardia and congestive heart failure.
Adverse fetal effects have been reported in mothers with digitalis toxicity.
Use in lactation: Although digoxin is excreted in breast milk, the quantities are minute and breastfeeding is not contraindicated.
Use In Pregnancy & Lactation
Use in pregnancy: The use of digoxin in pregnancy is not contraindicated, although the dosage may be less predictable in pregnant than in nonpregnant women, with some requiring an increased dosage of digoxin during pregnancy. As with all drugs, use should be considered only when the expected clinical benefit of treatment to the mother outweighs any possible risk to the developing fetus.
Despite extensive antenatal exposure to digitalis preparations, no significant adverse effects have been observed in the fetus or neonate when maternal serum digoxin concentrations are maintained within the normal range. Although it has been speculated that a direct effect of digoxin on the myometrium may result in relative prematurity and low birthweight, a contributing role of the underlying cardiac disease cannot be excluded. Maternally administered digoxin has been successfully used to treat fetal tachycardia and congestive heart failure.
Adverse fetal effects have been reported in mothers with digitalis toxicity.
Use in lactation: Although digoxin is excreted in breast milk, the quantities are minute and breastfeeding is not contraindicated.
Despite extensive antenatal exposure to digitalis preparations, no significant adverse effects have been observed in the fetus or neonate when maternal serum digoxin concentrations are maintained within the normal range. Although it has been speculated that a direct effect of digoxin on the myometrium may result in relative prematurity and low birthweight, a contributing role of the underlying cardiac disease cannot be excluded. Maternally administered digoxin has been successfully used to treat fetal tachycardia and congestive heart failure.
Adverse fetal effects have been reported in mothers with digitalis toxicity.
Use in lactation: Although digoxin is excreted in breast milk, the quantities are minute and breastfeeding is not contraindicated.
Adverse Reactions
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.
Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/100), very rare (<1/10,000), including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare (including isolated reports).
Blood and Lymphatic System Disorders: Very Rare: Thrombocytopenia.
Metabolism and Nutrition Disorders: Very Rare: Anorexia.
Psychiatric Disorders: Uncommon: Depression. Very Rare: Psychosis, apathy, confusion.
Nervous System Disorders: Common: CNS disturbances, dizziness. Very Rare: Headache.
Eye Disorders: Common: Visual disturbances (blurred or yellow vision).
Cardiac Disorders: Common: Arrhythmia, conduction disturbances, bigeminy, trigeminy, PR prolongation, sinus bradycardia. Very Rare: Supraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, ventricular premature contraction, ST segment depression.
Gastrointestinal Disorders: Common: Nausea, vomiting, diarrhea. Very Rare: Intestinal ischemia and necrosis.
Skin Disorders: Common: Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia.
Reproductive System and Breast Disorders: Very Rare: Gynecomastia can occur with long-term administration.
General Disorders and Administration Site Conditions: Very Rare: Fatigue, malaise, weakness.
Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/100), very rare (<1/10,000), including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare (including isolated reports).
Blood and Lymphatic System Disorders: Very Rare: Thrombocytopenia.
Metabolism and Nutrition Disorders: Very Rare: Anorexia.
Psychiatric Disorders: Uncommon: Depression. Very Rare: Psychosis, apathy, confusion.
Nervous System Disorders: Common: CNS disturbances, dizziness. Very Rare: Headache.
Eye Disorders: Common: Visual disturbances (blurred or yellow vision).
Cardiac Disorders: Common: Arrhythmia, conduction disturbances, bigeminy, trigeminy, PR prolongation, sinus bradycardia. Very Rare: Supraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, ventricular premature contraction, ST segment depression.
Gastrointestinal Disorders: Common: Nausea, vomiting, diarrhea. Very Rare: Intestinal ischemia and necrosis.
Skin Disorders: Common: Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia.
Reproductive System and Breast Disorders: Very Rare: Gynecomastia can occur with long-term administration.
General Disorders and Administration Site Conditions: Very Rare: Fatigue, malaise, weakness.
Drug Interactions
These may arise from effects on the renal excretion, tissue-binding, plasma protein-binding, distribution within the body, gut absorptive capacity and sensitivity to Lanoxin. Consideration of the possibility of an interaction whenever concomitant therapy is contemplated is the best precaution and a check on serum digoxin concentration is recommended when any doubt exists.
Digoxin, in association with β-adrenergic blocking drugs, may increase AV conduction time.
Agents causing hypokalemia or intracellular potassium deficiency may cause increased sensitivity to Lanoxin; they include some diuretics, lithium salts, corticosteroids and carbenoxolone.
Patients receiving digoxin are more susceptible to the effects of suxamethonium-exacerbated hyperkalemia.
Calcium, particularly if administered rapidly by the IV route, may produce severe arrhythmias in digitalized patients.
Serum levels of digoxin may be increased by concomitant administration of amiodarone, flecainide, prazosin, propafenone, quinidine, spironolactone, macrolide antibiotics eg, erythromycin and clarithromycin, tetracycline (and possibly other antibiotics), gentamicin, itraconazole, quinine, trimethoprim, alprazolam, indomethacin, propantheline, nefazodone, atorvastatin, cyclosporine, epoprostenol (transient) and carvedilol.
Serum levels of digoxin may be reduced by concomitant administration of antacids, some bulk laxatives, kaolin-pectin, acarbose, neomycin, penicillamine, rifampicin, some cytostatics, metoclopramide, sulfasalazine, adrenaline, salbutamol, cholestyramine, phenytoin, St. John's wort (Hypericum perforatum).
Calcium channel blocking agents may either increase or cause no change in serum digoxin levels. Verapamil, felodipine and tiapamil increase serum digoxin levels. Nifedipine and diltiazem may increase or have no effect on serum digoxin levels while isradipine causes no change. Angiotensin-converting enzyme inhibitors may also increase or cause no change in serum digoxin levels.
Milrinone does not alter steady-state serum digoxin levels.
Digoxin is a substrate of P-gp. Thus, inhibitors of P-gp may increase blood concentrations of digoxin by enhancing its absorption and/or by reducing its renal clearance (see Pharmacology: Pharmacokinetics under Actions).
Digoxin, in association with β-adrenergic blocking drugs, may increase AV conduction time.
Agents causing hypokalemia or intracellular potassium deficiency may cause increased sensitivity to Lanoxin; they include some diuretics, lithium salts, corticosteroids and carbenoxolone.
Patients receiving digoxin are more susceptible to the effects of suxamethonium-exacerbated hyperkalemia.
Calcium, particularly if administered rapidly by the IV route, may produce severe arrhythmias in digitalized patients.
Serum levels of digoxin may be increased by concomitant administration of amiodarone, flecainide, prazosin, propafenone, quinidine, spironolactone, macrolide antibiotics eg, erythromycin and clarithromycin, tetracycline (and possibly other antibiotics), gentamicin, itraconazole, quinine, trimethoprim, alprazolam, indomethacin, propantheline, nefazodone, atorvastatin, cyclosporine, epoprostenol (transient) and carvedilol.
Serum levels of digoxin may be reduced by concomitant administration of antacids, some bulk laxatives, kaolin-pectin, acarbose, neomycin, penicillamine, rifampicin, some cytostatics, metoclopramide, sulfasalazine, adrenaline, salbutamol, cholestyramine, phenytoin, St. John's wort (Hypericum perforatum).
Calcium channel blocking agents may either increase or cause no change in serum digoxin levels. Verapamil, felodipine and tiapamil increase serum digoxin levels. Nifedipine and diltiazem may increase or have no effect on serum digoxin levels while isradipine causes no change. Angiotensin-converting enzyme inhibitors may also increase or cause no change in serum digoxin levels.
Milrinone does not alter steady-state serum digoxin levels.
Digoxin is a substrate of P-gp. Thus, inhibitors of P-gp may increase blood concentrations of digoxin by enhancing its absorption and/or by reducing its renal clearance (see Pharmacology: Pharmacokinetics under Actions).
Caution For Usage
Instructions for Use and Handling: Dilution of Lanoxin Injection: Lanoxin injection can be administered undiluted with a 4-fold or greater volume of diluent. The use of <4-fold volume diluent could lead to precipitation of Lanoxin.
Lanoxin injection 250 mcg/mL when diluted in the ratio of 1-250 (ie, one 2 mL ampule containing 500 mcg added to 500 mL of infusion solution) is known to be compatible with the following infusion solutions and stable for up to 48 hrs at room temperature (20-25°C): Sodium chloride IV infusion, BP (0.9% w/v); sodium chloride (0.18% w/v) and glucose IV infusion, BP (4% w/v); glucose IV infusion, BP (5% w/v).
Dilution should be carried out either under full aseptic conditions or immediately before use. Any unused solution should be discarded.
Lanoxin Elixir (oral solution) should not be diluted.
Lanoxin injection 250 mcg/mL when diluted in the ratio of 1-250 (ie, one 2 mL ampule containing 500 mcg added to 500 mL of infusion solution) is known to be compatible with the following infusion solutions and stable for up to 48 hrs at room temperature (20-25°C): Sodium chloride IV infusion, BP (0.9% w/v); sodium chloride (0.18% w/v) and glucose IV infusion, BP (4% w/v); glucose IV infusion, BP (5% w/v).
Dilution should be carried out either under full aseptic conditions or immediately before use. Any unused solution should be discarded.
Lanoxin Elixir (oral solution) should not be diluted.
Storage
Store below 25°C. Protect from light.
Action
Pharmacology: Pharmacodynamics: Digoxin increases contractility of the myocardium by direct activity. This effect is proportional to dose in the lower range and some effect is achieved with quite low dosing; it occurs even in normal myocardium although it is then entirely without physiological benefit. The primary action of digoxin is specifically to inhibit adenosine triphosphatase and thus sodium-potassium (Na+-K+) exchange activity, the altered ionic distribution across the membrane resulting in an augmented calcium ion influx and thus an increase in the availability of calcium at the time of excitation-contraction coupling. The potency of digoxin may therefore appear considerably enhanced when the extracellular potassium concentration is low, with hyperkalemia having the opposite effect.
Digoxin exerts the same fundamental effect of inhibition of the Na+-K+ exchange mechanism on cells of the autonomic nervous system, stimulating them to exert indirect cardiac activity. Increases in efferent vagal impulses result in reduced symphathetic tone and diminished impulse conduction rate through the atria and atrioventricular (AV) node. Thus, the major beneficial effect of digoxin is reduction of ventricular rate.
Indirect cardiac contractility changes also result from changes in venous compliance brought about by the altered autonomic activity and by direct venous stimulation. The interplay between direct and indirect activity governs the total circulatory response, which is not identical for all subjects. In the presence of certain supraventricular arrhythmias, the neurogenically mediated slowing of AV conduction is paramount.
The degree of neurohormonal activation occurring in patients with heart failure is associated with clinical deterioration and an increased risk of death. Digoxin reduces activation of both the sympathetic nervous system and the (renin-angiotensin) system independently of its inotropic actions and may thus favorably influence survival. Whether this is achieved via direct sympatho-inhibitory effects or by resensitizing baroreflex mechanisms remain unclear.
Pharmacokinetics: Absorption: Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5-30 min; this reaches a maximum in 1-5 hrs. Upon oral administration, digoxin is absorbed from the stomach and upper part of the small intestine. When digoxin is taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in fiber, however, the amount absorbed from an oral dose may be reduced.
Using the oral route, the onset of effect occurs in 0.5-2 hrs and reaches its maximum at 2-6 hrs. The bioavailability of orally administered lanoxin is approximately 63% in tablet form and 75% as pediatric elixir (oral suspension).
Distribution: The initial distribution of digoxin from the central to the peripheral compartment generally lasts from 6-8 hrs. This is followed by a more gradual decline in serum digoxin concentration, which is dependent upon digoxin elimination from the body. The volume of distribution is large (Vdss = 510 L in healthy volunteers), indicating digoxin to be extensively bound to body tissues. The highest digoxin concentrations are seen in the heart, liver and kidney that in the heart averaging 30-fold that in the systemic circulation. Although the concentration in skeletal muscle is far lower, this store cannot be overlooked since skeletal muscle represents 40% of total body weight. Of the small proportion of digoxin circulating in plasma, approximately 25% is bound to protein.
Metabolism: The major metabolites of digoxin are dihydrodigoxin and digoxygenin.
Elimination: The major route of elimination is renal excretion of the unchanged drug.
Digoxin is a substrate for P-glycoprotein (P-gp). As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin. P-glycoprotein in renal proximal tubules appears to be an important factor in the renal elimination of digoxin (see Interactions).
Following IV administration to healthy volunteers, between 60 and 75% of a digoxin dose is recovered unchanged in the urine over a 6-day follow-up period. Total body clearance of digoxin has been shown to be directly related to renal function and percent daily loss is thus a function of creatinine clearance, which in turn may be estimated from a stable serum creatinine. The total and renal clearances of digoxin have been found to be 193±25 mL/min and 152±24 mL/min in a healthy control population.
In a small percentage of individuals, orally administered digoxin is converted to cardio-inactive reduction products (digoxin reduction products or DRPs) by colonic bacteria in the GIT. In these subjects, >40% of the dose may be excreted as DRPs in the urine. Renal clearances of the 2 main metabolites, dihydrodigoxin and digoxigenin, have been found to be 79±13 mL/min and 100±26 mL/min, respectively. In the majority of cases however, the major route of digoxin elimination is renal excretion of the unchanged drug.
The terminal elimination t½ of digoxin in patients with normal renal function is 30-40 hrs.
Since most of the drug is bound to the tissues rather than circulating in the blood, digoxin is not effectively removed from the body during cardiopulmonary bypass. Furthermore, only about 3% of a digoxin dose is removed from the body during 5 hrs of hemodialysis.
Special Patient Populations: Neonates, Infants and Children ≤10 years: 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 since renal clearance reflects maturation of renal function. Digoxin clearance has been found to be 65.6±30 mL/min/1.73 m2 at 3 months, compared to only 32±7mL/min/1.73 m2 at 1 week. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight and body surface area.
Renal Impairment: The terminal elimination t½ is prolonged in patients with impaired renal function and in anuric patients may be of the order of 100 hrs.
Toxicology: Carcinogenicity and Mutagenicity: Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin.
Digoxin exerts the same fundamental effect of inhibition of the Na+-K+ exchange mechanism on cells of the autonomic nervous system, stimulating them to exert indirect cardiac activity. Increases in efferent vagal impulses result in reduced symphathetic tone and diminished impulse conduction rate through the atria and atrioventricular (AV) node. Thus, the major beneficial effect of digoxin is reduction of ventricular rate.
Indirect cardiac contractility changes also result from changes in venous compliance brought about by the altered autonomic activity and by direct venous stimulation. The interplay between direct and indirect activity governs the total circulatory response, which is not identical for all subjects. In the presence of certain supraventricular arrhythmias, the neurogenically mediated slowing of AV conduction is paramount.
The degree of neurohormonal activation occurring in patients with heart failure is associated with clinical deterioration and an increased risk of death. Digoxin reduces activation of both the sympathetic nervous system and the (renin-angiotensin) system independently of its inotropic actions and may thus favorably influence survival. Whether this is achieved via direct sympatho-inhibitory effects or by resensitizing baroreflex mechanisms remain unclear.
Pharmacokinetics: Absorption: Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5-30 min; this reaches a maximum in 1-5 hrs. Upon oral administration, digoxin is absorbed from the stomach and upper part of the small intestine. When digoxin is taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in fiber, however, the amount absorbed from an oral dose may be reduced.
Using the oral route, the onset of effect occurs in 0.5-2 hrs and reaches its maximum at 2-6 hrs. The bioavailability of orally administered lanoxin is approximately 63% in tablet form and 75% as pediatric elixir (oral suspension).
Distribution: The initial distribution of digoxin from the central to the peripheral compartment generally lasts from 6-8 hrs. This is followed by a more gradual decline in serum digoxin concentration, which is dependent upon digoxin elimination from the body. The volume of distribution is large (Vdss = 510 L in healthy volunteers), indicating digoxin to be extensively bound to body tissues. The highest digoxin concentrations are seen in the heart, liver and kidney that in the heart averaging 30-fold that in the systemic circulation. Although the concentration in skeletal muscle is far lower, this store cannot be overlooked since skeletal muscle represents 40% of total body weight. Of the small proportion of digoxin circulating in plasma, approximately 25% is bound to protein.
Metabolism: The major metabolites of digoxin are dihydrodigoxin and digoxygenin.
Elimination: The major route of elimination is renal excretion of the unchanged drug.
Digoxin is a substrate for P-glycoprotein (P-gp). As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin. P-glycoprotein in renal proximal tubules appears to be an important factor in the renal elimination of digoxin (see Interactions).
Following IV administration to healthy volunteers, between 60 and 75% of a digoxin dose is recovered unchanged in the urine over a 6-day follow-up period. Total body clearance of digoxin has been shown to be directly related to renal function and percent daily loss is thus a function of creatinine clearance, which in turn may be estimated from a stable serum creatinine. The total and renal clearances of digoxin have been found to be 193±25 mL/min and 152±24 mL/min in a healthy control population.
In a small percentage of individuals, orally administered digoxin is converted to cardio-inactive reduction products (digoxin reduction products or DRPs) by colonic bacteria in the GIT. In these subjects, >40% of the dose may be excreted as DRPs in the urine. Renal clearances of the 2 main metabolites, dihydrodigoxin and digoxigenin, have been found to be 79±13 mL/min and 100±26 mL/min, respectively. In the majority of cases however, the major route of digoxin elimination is renal excretion of the unchanged drug.
The terminal elimination t½ of digoxin in patients with normal renal function is 30-40 hrs.
Since most of the drug is bound to the tissues rather than circulating in the blood, digoxin is not effectively removed from the body during cardiopulmonary bypass. Furthermore, only about 3% of a digoxin dose is removed from the body during 5 hrs of hemodialysis.
Special Patient Populations: Neonates, Infants and Children ≤10 years: 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 since renal clearance reflects maturation of renal function. Digoxin clearance has been found to be 65.6±30 mL/min/1.73 m2 at 3 months, compared to only 32±7mL/min/1.73 m2 at 1 week. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight and body surface area.
Renal Impairment: The terminal elimination t½ is prolonged in patients with impaired renal function and in anuric patients may be of the order of 100 hrs.
Toxicology: Carcinogenicity and Mutagenicity: Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin.
MedsGo Class
Cardiac Drugs
Features
Brand
Lanoxin
Full Details
Dosage Strength
250 mcg / mL
Drug Ingredients
- Digoxin
Drug Packaging
Solution for Injection (I.M./I.V.) 2ml x 1's
Generic Name
Digoxin
Dosage Form
Solution For Injection (I.M./I.V.)
Registration Number
DR-261
Drug Classification
Prescription Drug (RX)