Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord-UK Ltd (Trading style: Accord), Whiddon Valley, Barnstaple, Devon, EX32 8NS
The following schedules are intended as an initial guide but each patient has to be tailored individually according to age, lean body weight and renal function for his/her needs:
Suggested doses are intended only as an initial guide.
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 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%.
Rapid oral loading: 750-1500micrograms (0.75mg-1.5mg) as a single dose. If a greater risk or less urgency eg the elderly, the oral loading dose should be given in divided doses 6 hours apart, assessing clinical response, before giving each additional dose.
Slow oral loading: 250-750micrograms (0.25mg-0.75mg) should be given daily for 1 week, followed by appropriate maintenance dose. A clinical response should be seen within one week.
The clinical state of the patient and the urgency of the condition will depend on the choice between slow or rapid oral loading.
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 = loading dose; % daily loss = 14 + creatinine clearance (Ccr)/5.
Ccr is creatinine clearance corrected to 70kg body weight or 1.73m² body surface area. If only serum creatinine (Scr) concentrations are available, a Ccr (corrected to 70kg body weight) may be estimated in men as:
Ccr = 140-age / (Scr (in mg/100ml))
NB:
Serum creatinine values are in micromol/l, these can be converted to mg/100ml (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: Multiply the result by 0.85.
This formulae cannot be used for creatinine clearance in children.
In practice, this will mean that most patients will be maintained on 0.125 to 0.25mg digoxin daily, however, in those who show increased sensitivity to the adverse effects of digoxin, a dosage of 62.5microgram (0.0625mg) daily or less may suffice. Conversely, some patients may require a higher dose.
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 ten years of age require adult dosages in proportion to their body weight.
Oral loading dose: This should be administered in accordance with the following schedule: pre-term neonates less than 1.5kg (25 micrograms/kg body weight over 24 hours); pre-term neonates 1.5-2.5kg (30 micrograms/kg body weight over 24 hours); term neonates to 2 years (45 micrograms/kg body weight over 24 hours); 2-5 years (35 micrograms/kg body weight over 24 hours); 5-10 years (25 micrograms/kg body weight 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 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 is 20% of 24 hour loading dose); term neonates and children up to 10 years (daily dose is 25% of 24 hour loading dose).
These dosage schedules are meant as guidelines and careful clinical observation and monitoring of serum digoxin levels should be used as a basis for adjustment of dosage in these paediatric patient groups. 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 above.
Measurements of plasma levels of digoxin are useful in individualising therapy during the early stages of treatment, for detecting poor patient compliance and for diagnosing toxicity. Serum concentrations of digoxin 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 hours or more after the last dose of digoxin. There are no rigid guidelines as to the range of serum concentrations that are most efficacious but most patients will benefit, with little risk of toxic symptoms and signs developing, with digoxin concentrations from 0.8 nanogram/ml, ng/ml (1.02 nanomol/litre, nm/L) to 2.0ng/ml (2.56nm/L). Above this range toxic symptoms and signs become more frequent and levels above 3ng/ml (3.84nm/L) are quite likely to be toxic. However, in deciding whether a patient’s symptoms are due to digoxin, the patent’s clinical state together with the serum potassium level and thyroid function are important factors. 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.
The tendency to impaired renal function and low lean body mass in the elderly influences the pharmacokinetics of digoxin, such that high serum digoxin levels and associated toxicity can occur quite readily, unless dosages of digoxin lower than those in non-elderly patients are used. Serum digoxin levels should be checked regularly and hypokalaemia avoided.
Loading and maintenance doses of digoxin should be reduced as outlined above in patients with impaired renal function because the major route of elimination is renal excretion of unchanged drug.
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 reconstruction may require larger doses of digoxin.
For oral administration.
The symptoms and signs of toxicity are generally similar to those described in 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 pre-dialysis 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 overdose 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 are 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 pre-treatment 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 I.V. administration of digoxin-specific (ovine) antibody fragments (Fab). For details, consult the literature supplied with antibody fragments.
PVC Blister packs: Four years from the date of manufacture.
Polypropylene or polyethylene tablet containers with polyethylene lids: Three years from the date of manufacture.
Amber glass bottles with screw caps: Three years from the date of manufacture.
Store below 25°C in a dry place.
The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool.
The product may also be supplied in blister packs in cartons:
Pack sizes: 28s, 30s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250’s, 500’s, 1000’s
Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.
Maximum size of bulk packs: 50,000.
Not applicable.
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