When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Product ownership changed from GSK to Aspen
Addition of “However, the benefit of digoxin in patients with supraventricular arrhythmias is most evident at rest, less evident with exercise.”
Serum levels of digoxin may be INCREASED by concomitant administration of the following:
Addition of “epoprostenol (transient) and carvedilol.”
Symptoms and Signs
The symptoms and signs 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 above 2.0 nanograms/mL (2.56 nanomol/L) although there is considerable interindividual variation. However, in deciding whether a patient's symtoms are due to digoxin, the clinical state, together with serum electrolyte levels and thyroid function are important factors (see Dosage and Administration).
4.2:
......Monitoring
Serum concentrations of digoxin may be expressed in Conventional Units of nanograms/ml or SI Units of nanomol/l. To convert nanograms/ml to nanomol/l, multiply nanograms/ml by 1.28.
The serum concentration of digoxin can be determined by radioimmunoassay.
Blood should be taken six 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. 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 1.0 ng/mL (1.28 nanomol/L).
Digoxin toxicity is more commonly associated with serum digoxin concentration greater than 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 Overdose). .......
......
If medically appropriate, rapid digitalisation may be achieved in a number of ways, such as the following:
750 to 1500 micrograms (0.75 to 1.5 mg) as a single dose.
Where there is less urgency, or greater risk of toxicity e.g. in the elderly, the oral loading dose should be given in divided doses six hours apart, with approximately half the total dose given as the first dose.
Clinical response should be assessed before giving each additional dose (see Warnings and Precautions).
Slow oral loading:
In some patients, for example those with mild heart failure, digitalisation may be achieved more slowly with doses of
NOTE: The choice between slow and rapid oral loading depends on the clinical state of the patient and the urgency of the condition.
Parenteral Loading
NOTE: For use 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 four to eight hours. An assessment of clinical response should be performed before giving each additional dose. Each dose should be given by i.v. infusion (see Dilution of digoxin injection) over 10 to 20 mins.........
.....
4.3 Contraindications
.....Digoxin is contraindicated in patients known to be hypersensitive to digoxin, other digitalis glycosides or to any component of the preparation.
4.4 Warnings & precautions
...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 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 .......
4.8 Undesirable effects
......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 < 1/1000), 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:Thrombocytopaenia
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, diarrhoea
Very rare:Intestinal ischaemia, intestinal necrosis
Skin disorders
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
4.9 Overdose
Symptoms and
Signs and symptoms of digoxin toxicity become more frequent with levels above 3.0 nanograms/mL (3.84 nanomol/L) although there is considerable interindividual variation. However, in deciding whether a patient's symtoms are due to digoxin, the clinical state, together with serum electrolyte levels and thyroid function are important factors (see Dosage and Administration).
Adults
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
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.
Acute massive digoxin overdosage can result in mild to pronounced hyperkalaemia due to inhibition of the sodium-potassium (Na+-K+) pump. Hypokalaemia may contribute to toxicity (see Warnings and Precautions).
Non-cardiac manifestations
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 extracardiac symptoms, such as malaise and weakness, may predominate.
Children
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 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 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 verntricular 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.
Extracardiac manifestations
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.
Treatment
After recent ingestion, such as 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 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).
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 difoxin serum level may be 0.5 ng/mL (0.64 nanomol/L) to 1.0 ng/mL (1.28 nanomol/L).