Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Mercury Pharma International Ltd, 4045, Kingswood Road, City West Business Park, Co Dublin, Ireland
Digoxin is indicated in the management of chronic cardiac failure where the dominant problem is systolic dysfunction. The therapeutic benefit of digoxin is greater in patients with ventricular dilatation.
Digoxin is specifically indicated where cardiac failure is accompanied by atrial fibrillation.
Digoxin is indicated in the management of certain supraventricular arrhythmias, particularly chronic atrial fibrillation and flutter, where its major beneficial effect is to reduce the ventricular rate.
Digoxin injection is indicated when emergency parenteral digitilisation is required in patients who have not been given cardiac glycosides within the preceding two weeks.
Digoxin Injection is for administration by slow intravenous infusion (see Method of administration below).
The dose of digoxin 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.
If 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 difference in bioavailability between injectable digoxin and oral formulations must be considered when changing from one dosage form to another. For example if patients are switched from oral to the I.V. formulation the dosage should be reduced by approximately 33%.
Emergency parenteral digitalisation (in patients who have not been given cardiac glycosides within the preceding two weeks):
Parenteral loading should only be used in patients who have not been given cardiac glycosides within the preceding two weeks.
The total loading dose of parenteral digoxin is 500 to 1000 micrograms (0.5 to 1.0 mg) depending on age, lean body weight and renal function. The total loading dose should be administered in divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of 4-8 hours. An assessment of clinical response should be performed before giving each additional dose.
Each dose should be given by intravenous infusion (see Method of administration) over a period of 10-20 minutes.
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:
Maintenance Dose = Peak body stores X % daily loss / 100
Where:
Peak body stores = Personalised Loading Dose
% Daily Loss = 14 + Creatinine Clearance (Ccr)/5
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
Ccr = (140-age) / Scr (in mg/100ml)
NOTE: Where serum creatinine values are obtained in micromol/L these may be converted to mg/100 ml (mg %) as follows:
Scr (mg/100ml) = Scr (micromol/L) X 113.12 / 10,000 = Scr (micromol/L) / 88.4
Where 113.12 is the molecular weight of creatinine.
For women, this result should be multiplied by 0.85.
NOTE: These formulae cannot be used for creatinine clearance in children.
In practice, this will mean that most patients with heart failure will be maintained on 125 to 250 micrograms (0.125 to 0.25 mg) digoxin daily; however in those who show increased sensitivity to the adverse effects of digoxin, a dosage of 62.5 microgram (0.0625 mg) daily or less may suffice. Conversely, some patients may require a higher dose.
If cardiac glycosides have been given in the two weeks preceding commencement of digoxin therapy, it should be anticipated that optimum loading doses of digoxin will be less than those recommended below.
In the newborn, particularly in the premature infant, renal clearance of digoxin is diminished and suitable dose reductions must be observed, over and above general dosage 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 over 10 years of age require adult dosages in proportion to their body weight.
The I.V. loading dose in the above groups should be administered in accordance with the following schedule:
Pre-term neonates:
Less than 1.5kg: 20 micrograms/kg over 24 hours
Pre-term neonates:
1.5-2.5kg: 30 micrograms/kg over 24 hours
Full-term neonates:
To age 2 years: 35 micrograms/kg over 24 hours
Age 2-5 years: 35 micrograms/kg over 24 hours
Age 5-10 years: 25 micrograms/kg over 24 hours
The loading dose should be administered in divided doses with approximately half the total dose given as the first dose and further fractions of the total dose given at intervals of 4-8 hours, assessing the clinical response before giving each additional dose. Each dose should be given by intravenous infusion (see Method of Administration) over a period of 10-20 minutes.
The maintenance dose should be administered in accordance with the following schedule:
Preterm neonates:
daily dose = 20% of 24-hour loading dose (intravenous or oral)
Term neonates and children up to 10 years:
daily dose = 25% of 24-hour loading dose (intravenous or oral)
These dosage schedules are meant as guidelines and careful clinical observation and monitoring of serum digoxin levels (see Section 4.4) should be used as a basis for adjustment of dosage in these paediatric patient groups.
The possibility of reduced renal function and lower lean body mass should be taken into account when dealing with elderly patients. If necessary, the dosage should be reduced and adjusted to the changed pharmacokinetics to prevent elevated serum digoxin levels and the risk of toxicity. The serum digoxin levels should be checked regularly and hypokalaemia should be avoided.
The dosage recommendations should be reconsidered if patients are elderly or if there are other reasons for the renal clearance of digoxin being reduced. A reduction in both initial and maintenance doses should be considered (See section 4.4).
Digoxin injection can be administered undiluted or diluted with a 4-fold or greater volume of 0.9% Sodium Chloride Injection, 0.18% Sodium Chloride/4% Glucose Injection or 5% Glucose Injection. A 4-fold volume of diluent equates to adding one 2 ml ampoule of digoxin to 6 ml of injection solution. The use of less than a 4-fold volume of diluent could lead to precipitation of digoxin.
Digoxin Injection may be diluted with the following solutions:
Sodium Chloride Intravenous Infusion BP 0.9% w/v
Glucose Intravenous Infusion BP 5.0% w/v
Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion BP
When diluted in the ratio of 1 to 250 (i.e. one 2ml ampoule containing 500 micrograms digoxin added to 500ml of infusion solution), Digoxin Injection B.P. is known to be compatible with the above mentioned infusion solutions and stable for up to 48 hours at room temperature (20-25°C).
Dilution should be carried out either under full aseptic conditions or immediately prior to use. Any unused solution should be discarded (see Section 6.6).
Each dose should be given by intravenous infusion over of 10-20 minutes.
The total loading dose should be administered in divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of 4 – 8 hours. An assessment of clinical response should be performed before giving each additional dose.
The intramuscular route is painful and is associated with muscle necrosis. This route cannot be recommended.
Rapid intravenous 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.
The symptoms and signs of toxicity are generally similar to those described Section 4.8 but may be 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 inter-individual 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 (see section 4.2). In patients undergoing haemodialysis, digoxin use is associated with increased mortality; patients with low predialysis potassium concentrations are most at risk.
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. 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 resulted.
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 over dosage 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 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 overdose can result in mild to pronounced hyperkalaemia due to inhibition of the sodium-potassium (Na-K) pump. Hypokalaemia may contribute to toxicity (See section 4.4).
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, non-specific non-cardiac 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.
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.
Most manifestations of chronic toxicity in children occur during or shortly after digoxin overdose.
The same arrhythmias or combination of arrhythmias that occur in adults can occur in paediatrics. 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 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 digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.
The frequent non-cardiac 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 self-poisoning, the load available for absorption may be reduced by gastric lavage.
Gastric lavage increases vagal tone and may precipitate or worsen arrhythmias. Consider pretreatment with atropine if gastric lavage is performed. Treatment with digitalis Fab antibody usually renders gastric lavage unnecessary. In the rare instances in which gastric lavage is indicated, it should only be performed by individuals with proper training and expertise.
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 hypokalaemia is present, it should be corrected with potassium supplements either orally or intravenously, depending on the urgency of the situation. 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 life-threatening toxicity.
Digoxin-specific antibody Fab 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 intravenous administration of digoxin-specific (ovine) antibody fragments (Fab) when other therapies have failed.
For details, consult the literature supplied with antibody fragments.
Unopened: 4 years.
After reconstitution: not applicable.
After first opening: 4 years*.
* If only part of an ampoule is used, discard the remaining solution.
Do not store above 25°C.
Keep the ampoule in the outer carton in order to protect from light.
2ml, clear One point cut (OPC) glass ampoules, glass type 1 Ph.Eur. borosilicate glass, packed in cardboard cartons to contain 10 × 2ml ampoules.
If only part used, discard the remaining solution.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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