ATC categoryCardiology, angiology
ATC subcategoryCardiac glycosides
Each tablet contains:
active ingredient: digoxin – 0.25 mg;
excipients: lactose monohydrate, corn starch, povidone, talc, magnesium stearate.
Mode of Action:
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 hyperkalaemia 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 sympathetic tone and diminished impulse conduction rate through the atria and atrioventricular 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 favourably influence survival. Whether this is achieved via direct sympathoinhibitory effects or by resensitising baroreflex mechanisms remains unclear.
Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5 to 30 minutes; this reaches a maximum in 1 to 5 hours. 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 fibre, however, the amount absorbed from an oral dose may be reduced. Using the oral route the onset of effect occurs in 0.5 to 2 hours and reaches its maximum at 2 to 6 hours. The bioavailability of orally administered Digoxin is approximately 63% in tablet form and 75% as paediatric elixir.
The initial distribution of digoxin from the central to the peripheral compartment generally lasts from 6 to 8 hours. 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 litres 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.
The major route of elimination is renal excretion of the unchanged drug.
Digoxin is a substrate for P-glycoprotein.
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 4.5 Interaction with other medicinal products and other forms of interaction).
Following intravenous 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 mil/min in a healthy control population.
In a small percentage of individuals, orally administered digoxin is converted to cardioinactivate reduction products (digoxin reduction products or DRPs) by colonic bacteria in the gastrointestinal tract. In these subjects over 40% of the dose may be excreted as DRPs in the urine. Renal clearances of the two main metabolites, dihydrodigoxin and digoxygenin, 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 half life of digoxin in patients with normal renal function is 30 to 40 hours. It is prolonged in patients with impaired renal function, and in anuric patients may be of the order of 100 hours.
In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed.
This is specially 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/1.73m2 at 3 months, compared to only 32 ± 7 ml/min/1.73m2 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.
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 five hours of haemodialysis.
Posology and method of administration
Digoxin has a narrow therapeutic index. Effect appear within about 2 hours and the maximum effect may be reached in about 6 hours. Initially a loading dose may be given to digitalise the patient, although this may not be necessary in, for example, mild heart failure.
Dosage depends on individual patient. Factors which may be considered include the patient’s age, lean body-mass, renal status, thyroid status, electrolyte balance, degree of tissue oxygenation, and the nature of the underlying cardiac or pulmonary disease. A total loading dose of 500 to 1000 micrograms of digoxin may be given by mouth during the initial 24-hour period, either as a single dose, or in divided doses at 6-12 hourly intervals. In some patients, for example those with mild heart failure, a loading dose may not be necessary, and digitalisation may be achieved more slowly with doses of 250 micrograms once or twice daily; steady-state plasma concentrations are achieved in about 7 days in patients with normal renal function. The usual maintenance dose of digoxin is 250 to 500 micrograms by mouth daily, but may range from 62.5 to 500 micrograms daily. In elderly patients therapy should generally be initiated gradually and with smaller doses.
Children’s doses are complex. They are based on body-weight and the developmental stage of the child as well as on response. Children up to about 10 years of age, require doses 25 to 45 micrograms/kg (UK ) over 24 hours. or 20 to 60 micrograms/kg.(USA).For children older than 12 months the adult guidelines can probably be followed.
Administration in renal impairment
Dose 10 micrograms/kg for loading is suggested.Because of the reduction in renal clearance of digoxin, maintenance doses must be reduced in line with renal function. Serum-digoxin concentration should be monitored although the presence of digoxin-like immunoreactive substances may make interpretation difficult.The interpretation of digoxin assays is further confounded by the presence of digoxin-like immunoreactive substances in patients with renal or hepatic impairment in pregnant woman and in neonatans
The symptoms and signs of toxicity are generally similar to those described in the Undesirable Effects section but maybe more frequent and can be more severe.Signs and symptoms of digoxin toxicity become more frequent with levels above 2.0 nanograms/mL (2.56 nanomol/L) although there is considerable interindividual variation. 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.
In adults without heart disease, clinical observation suggests that an overdose of digoxin of 10 to 15 mg was the dose resulting in death of half of the patients.
Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3 to 6 hours following overdosage and may persist for the ensuing 24 hours 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 atrioventricular (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, second, third degree heart blocks and AV disocciation 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.
Hypokalaemia may contribute to toxicity.
Acute massive digoxin overdosage can result in mild to pronounced hyperkalaemia due to inhibition of the sodium-potassium (Na+- K+) pump.
Gastrointestinal symptoms are very common in both acute and chronic toxicity. The symptoms precede cardiac manifestations in approximately half of the patients in most literature reports. Anorexia, nausea and vomiting have been reported with an incidence up to 80%. These symptoms usually present early 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 colour 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, such as malaise and weakness, may predominate.
In children aged 1 to 3 years without heart disease, clinical observation suggests that an overdose of digoxin of 6 to 10 mg was the dose resulting in death in half of the patients.
Most manifestations of toxicity in children occur during or shortly after the loading phase with digoxin.
The same arrhythmias or combination of arrhythmias that occur in adults can occur in children. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in the paediatric population.
Paediatric 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 verntricular fibrillation have been reported.
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.
The frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, 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 ischaemia, drowsiness and behavioural disturbances including psychotic manifestations have been reported in overdose.
After recent ingestion, such as accidental or deliberate selfpoisoning, 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 more than 25 mg of digoxin was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin binding Fab antibody fragments (Digibind®) resulted. If more than 10 mg of digoxin was ingested by a child aged 1 to 3 years without heart disease, the outcome was uniformly fatal when Fab fragment treatment was not given.
Hypokalaemia should be corrected. In cases where a large amount of Digoxin has been ingested, hyperkalaemia 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 lignocaine or phenytoin.
Dialysis is not particularly effective in removing digoxin from the body in potentially lifethreatening toxicity.
Rapid reversal of the complications that are associated with serious poisoning by digoxin, digitoxin and related glycosides has followed intravenous administration of digoxinspecific (ovine) antibody fragments (Fab) when other therapies have failed. Digibind® is the only specific treatment for digoxin toxicity.
Digoxin is contraindicated in arrhythmias caused by cardiac glycoside intoxication.
Digoxin is contraindicated in supraventricuar arrhythmias associated with an accessory atrioventricular pathway, as in the Wolff-Parkinson-White
Syndrome, unless the electrophysiological characteristics of the accessory pathway and any possible deleterious effect of digoxin on these characteristics have been evaluated. If an accessory pathway is known or suspected to be present and there is no history of previous supraventricular arrhythmias, digoxin is similarly contraindicated.
Digoxin is contraindicated in ventricular tachycardia or ventricular fibrillation.
Digoxin is contraindicated in hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure but even then caution should be exercised if Digoxin is to be used.
Digoxin is contraindicated in patients known to be hypersensitive to digoxin, other digitalis glycosides, or to any component of the preparation.
Metabolism and nutrition disorders
Very Rare: Anorexia
Very rare: Psychosis, apathy, confusion
Nervous system disorders
Common: CNS disturbances, dizziness
Very rare: Headache
Common: Visual disturbances (blurred or yellow vision)
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
Common: Nausea, vomiting, diarrhoea
Very rare: Intestinal ischaemia, intestinal necrosis
Common: Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia
Reproductive system and breast disorders
Very rare: Gynaecomastia can occur with long term administration
General disorders and administration site conditions
Very rare: Fatigue, malaise, weakness
Arrhythmias may be precipitated by digoxin toxicity, some of which can resemble arrhythmias for which the drug could be advised. For example, atrial tachycardia with varying atrioventricular block requires particular care as clinically the rhythm resembles atrial fibrillation.
In some cases of sinoatrial disorder (i.e. Sick Sinus Syndrome) digoxin may cause or exacerbate sinus bradycardia or cause sinoatrial block.
Determination of the serum digoxin concentration may be very helpful in making a decision to treat with further digoxin, but toxic doses of other glycosides may crossreact in the assay and wrongly suggest apparently satisfactory measurements. Observations during the temporary withholding of digoxin might be more appropriate.
In cases where cardiac glycosides have been taken in the preceding two 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.
Hypokalaemia sensitises the myocardium to the actions of cardiac glycosides.
Hypoxia, hypomagnesaemia and marked hypercalcaemia 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 gastrointestinal reconstructions may require larger doses of digoxin.
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 hours before cardioversion is performed. In emergencies, such as cardiac arrest, when attempting cardioversion the lowest
effective energy should be applied. Direct current cardioversion is inappropriate in the treatment of arrhythmia thought to be caused by cardiac glycosides.
Many beneficial effects of digoxin on arrhythmias result from a degree of atrioventricular conduction blockade. However, when incomplete atrioventricular 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.
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 ischaemia, and some retrospective followup studies have suggested digoxin to be associated with an
increased risk of death. However, the possibility of arrhythmias arising in patients who may be hypokalaemic after myocardial infarction and are likely to be cardiologically 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 with caution 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. There is also some published information indicating that digoxin may inhibit the uptake of
thiamine in myocytes in beri beri heart disease.
Digoxin should not be used in constrictive 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 haemodynamic profile. However, the benefit of 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 STT changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.
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.
Although many patients with chronic congestive cardiac failure benefit from acute administration of digoxin, there are some in whom it does not lead to constant, marked or lasting haemodynamic improvement. It is therefore important to evaluate the response of each patient individually when digoxin is continued longterm.
Patients with severe respiratory disease may have an increased myocardial sensitivity to digitalis glycosides.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines
– Since central nervous system and visual disturbances have been reported in patients receiving Digoxin, patients should exercise caution before driving, using machinery or participating in dangerous activities.
No data are available on whether or not digoxin has teratogenic effects.
There is no information available on the effect of digoxin on human fertility.
The use of digoxin in pregnancy is not contraindicated, although the dosage and control 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 foetus.
Despite extensive antenatal exposure to digitalis preparations, no significant adverse effects have been observed in the foetus 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 foetal tachycardia and congestive heart failure.
Adverse foetal effects have been reported in mothers with digitalis toxicity.
Although digoxin is excreted in breast milk, the quantities are minute and breast feeding is not contraindicated.
Interactions may arise from effects on the renal excretion, tissue binding, plasma protein binding, distribution within the body, gut absorptive capacity and sensitivity to Digoxin. 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 beta-adrenoceptor blocking drugs, may increase atrioventricular conduction time.
Agents causing hypokalaemia or intracellular potassium deficiency may cause increased sensitivity to Digoxin; they include diuretics, lithium salts, corticosteroids and carbenoxolone.
Patients receiving Digoxin are more susceptible to the effects of suxamethonium exacerbated hyperkalaemia.
Calcium, particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients.
Serum levels of digoxin may be increased by concomitant administration of the following:
– Alprazolam, amiodarone, flecainide, gentamicin, indometacin, itraconazole, prazosin, propafenone, quinidine, quinine, spironolactone, macrolide antibiotics (e.g. erythromycin and clarithromycin), tetracycline (and possibly other antibiotics), trimethoprim, propantheline, atorvastatin, ciclosporin, epoprostenol (transient) and carvedilol.
Serum levels of digoxin may be reduced by concomitant administration of the following:
– Adrenaline (epinephrine), antacids, kaolinpectin, some bulk laxatives, colestyramine, acarbose, salbutamol, sulfasalazine, neomycin, rifampicin, some cytostatics, phenytoin, metoclopramide, penicillamine and the herbal remedy 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. Isradipine causes no change in serum digoxin levels. Angiotensin converting enzyme (ACE) inhibitors may also increase or cause no change in serum digoxin concentrations.
Milrinone does not alter steadystate serum digoxin levels.
Digoxin is a substrate of P-glycoprotein.
Thus, inhibitors of P-glycoprotein may increase blood concentrations of digoxin by enhancing its absorption and/or by reducing its renal clearance
Antithyroid drugs: Reduced peak serum-digoxin concentration. Caution is also needed since changes in thyroid function may independently affect sensitivity to digoxin.
Sucralfate may also reduce the absorption of digoxin.
Neuromuscular blockers:Pancuronium or suxamethonium may interact with digitalis glycosides resulting in an increased incidence of arrhythmias; the interaction is more likely with pancuronium.
NSAIDs.An increase in serum-digoxin concentration has been reported with aspirin, ibuprofen, indometacin, fenbufen, and diclofenac.
White flat scored tablets
1 blister packet with 40 tablets and leaflet inserted in the cardboard box.
3 years. Do not use after the expiration date.
Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from light.