Digoxin Tablets Bp 62.5 Micrograms
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
DIGOXIN TABLETS BP 62.5 micrograms
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 62.5 micrograms Digoxin PhEur.
3. PHARMACEUTICAL FORM
Blue uncoated tablets.
Blue, circular, flat bevelled edge, uncoated tablets impressed “C” on one face and the identifying letters “DD” on the reverse.
4. CLINICAL PARTICULARS
4.1 Therapeutic Indications
• Digoxin is indicated for the treatment of congestive cardiac failure.
• Digoxin may be used for certain supraventricular dysrhythmias, particularly atrial fibrillation.
4.2 Posology and method of administration
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:
Adults and children over 10 years:
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.
NB
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
is 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 1.73m 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.
NB
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.
Children up to 10 years: (No cardiac glycosides have been given in preceding two weeks.)
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.
Monitoring
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.
Elderly
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.
Renal impairment
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.
Thyroid disease
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.
Gastrointestinal disease
Patients with malabsorption syndrome or gastrointestinal reconstruction may require larger doses of digoxin.
Method of Administration For oral administration.
4.3 Contraindications
• Patients known to be hypersensitive to digoxin, other digitalis glycosides or any of the excipients.
• Patients with arrhythmias caused by cardiac glycoside intoxication.
• Patients with 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.
• Patients with supraventricular 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.
• Patients with intermittent complete heart block or second degree atrioventricular block, especially if there is a history of Stokes-Adams attacks.
• Patients with ventricular tachycardia or ventricular fibrillation.
4.4 Special Warnings and Precautions for Use
• Arrhythmias
Arrhythmias may be precipitated by digoxin toxicity, some of which can resemble arrhythmias for which the drug could be advised (e.g. atrial tachycardia with varying atrioventricular block requires 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.
• Hypokalaemia, hypomagnesaemia, hypercalcaemia
Hypokalaemia sensitises the myocardium to the actions of cardiac glycosides. Digoxin should be used with caution in patients taking drugs that may cause hypokalaemia (see section 4.5). Hypokalaemia may also accompany malnutrition, diarrhoea, vomiting and long standing wasting disease and the dose may be need to be reduced in such patients. Hypomagnesaemia and marked hypercalcaemia also increase myocardial sensitivity to cardiac glycosides.
• Direct current cardioversion
Direct current cardioversion is the preferred method of treatment for atrial flutter. 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 arrhythmias thought to be caused by cardiac glycosides.
• Myocardial infarction
The administration of digoxin in the period immediately following myocardial infarction is not contraindicated. 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.
• Chronic congestive heart failure
Although many patients with chronic congestive cardiac failure benefit from acute administration of digoxin, there are some in which 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 long-term.
• Severe respiratory disease
Patients with severe respiratory disease may have increased myocardial sensitivity to digitalis glycosides.
• Gastrointestinal disease
Patients with malabsorption syndrome or gastrointestinal reconstruction may require larger doses of digoxin.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take digoxin.
4.5 Interactions with other Medicaments and other forms of Interaction
These 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 level is recommended when any doubt exists.
• Antiarrhythmics
Amiodarone: plasma levels of digoxin are considerably increased by concurrent administration of amiodarone. This is due to a decrease in the renal and non-renal clearance of digoxin, a prolongation of its half life and a possible increase in absorption. Children are especially sensitive. The dose of digoxin should be reduced by a third to a half when it is given concurrently with amiodarone. Disopyramide may modify the cardiovascular effects of digoxin and reduce its volume of distribution. The loading dose of digoxin should be reduced in patients who are also receiving disopyramide.
Flecainide: plasma levels of digoxin are increased by concurrent administration of flecainide. This is likely to be clinically significant only in patients with high plasma levels of digoxin or those with atrioventricular nodal dysfunction. Moracizine: digoxin and moracizine have additive effects on cardiac conduction. Propafenone: plasma levels of digoxin are increased by concurrent administration of propafenone. There is considerable interindividual variation in the extent of this interaction but the dose of digoxin should be reduced and patients monitored for signs of digoxin toxicity. Quinidine: the renal and non-renal excretion of digoxin is reduced by co-administration of digoxin. Excretion in bile and tissue binding of digoxin may also be reduced Significant effects occur as soon as quinidine is given to a patient stabilised on digoxin and plasma levels of digoxin are usually doubled within 5 days. The dose of digoxin should be halved when quinidine is added to therapy and the possibility of an alternative anti-arrhythmic should be examined.
• Anti-infective drugs
Macrolides, tetracycline: presystemic metabolism of digoxin to inactive metabolites in the gastrointestinal tract occurs in about 10% of patients. Coadministration of macrolide antibiotics (azithromycin, clarithromycin, erythromycin, telithromycin) or tetracycline to this sub-group of patients can result in a clinically significant increase in plasma digoxin levels. Neomycin: absorption of digoxin from the gastrointestinal tract is inhibited by neomycin and plasma levels are reduced. Rifampicin: the metabolism of digoxin may be increased by co-administration with rifampicin. The interaction may be enhanced in patients with renal impairment. Trimethoprim: the renal excretion of digoxin is decreased by concurrent administration with trimethoprim. The interaction is more significant in elderly patients or those with renal impairment and digoxin plasma levels should be monitored. Amphotericin: hypokalaemia due to amphotericin administration may potentiate digoxin toxicity. Patients should be monitored and given potassium supplements when necessary. Itraconazole can cause a marked increase in plasma digoxin levels and toxicity may occur if the dose of digoxin is not reduced. Itraconazole may also oppose the positive inotropic effects of digoxin. Quinine, hydroxychloroquine and chloroquine can increase plasma levels of digoxin by decreasing non-renal clearance.
• Calcium channel blockers
Diltiazem and digoxin co-administration can result in increased digoxin plasma levels and toxicity and patients should be monitored. Nifedipine may increase digoxin plasma levels but there is considerable interindividual variation. Patients taking high doses of digoxin or those with renal impairment are most at risk. Nisoldipine may also increase plasma levels of digoxin but amlodipine, felodipine, isradipine, lercanidipine, nicardipine, nimodipine and nitrendipine do not appear to have significant effects on digoxin plasma levels but it is prudent to monitor the effects of co-administration. Verapamil increases plasma digoxin levels by inhibiting the active tubular secretion and non-renal clearance of digoxin. The dose of digoxin should be reduced and plasma levels monitored. Verapamil may also increase atrioventricular block and tachycardia in patients taking digoxin.
• Calcium salts and vitamin D analogues
Intravenous administration of calcium salts to patients taking digoxin can result in dangerous cardiac arrhythmias and should be avoided. Vitamin D analogues can also increase digoxin toxicity due to elevations in plasma calcium concentrations.
• Cardiovascular drugs
ACE inhibitors and angiotensin II antagonists may cause hyperkalaemia which can reduce tissue binding of digoxin resulting in higher serum levels. These drugs may also cause a deterioration in renal function resulting in elevated serum levels of digoxin because of impaired renal excretion. Concurrent administration of captopril has been associated with increases in plasma digoxin levels but this may only be clinically significant in patients with impaired renal function or severe congestive heart failure. Telmisartan administration has been associated with increases in plasma digoxin levels and patients receiving both drugs should be monitored. No clinically significant interactions have been noted with other ACE inhibitors or angiotensin II antagonists examined (cilazapril, enalapril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril; candesartan, eprosartan, irbesartan, losartan and valsartan)) but it is prudent to monitor the effects of co-administration. There is an increased risk of atrioventricular block and bradycardia when digoxin and beta blockers are taken concomitantly. Nitroprusside and hydralazine increase the renal clearance of digoxin by increasing renal blood flow and tubular secretion and lowering plasma digoxin levels.
• Central nervous system drugs
St John’s wort: co-administration of digoxin with St John’s wort should be avoided because plasma levels are significantly reduced. Nefazodone, trazodone: Plasma levels of digoxin are increased by concomitant administration of nefazodone or trazodone and it may be necessary to reduce the dose of digoxin. Phenytoin increases total clearance of digoxin and reduces its elimination half-life, resulting in a decrease in plasma levels. Intravenous phenytoin should not be used to treat digitalis induced arrhythmias or in patients with a high degree of heart block or marked bradycardia because of the risk of cardiac arrest. Topiramate: co-administration of digoxin and topiramate reduces the bioavailability of digoxin and patients should be monitored. Alprazolam and diazepam can decrease digoxin clearance, resulting in increased plasma concentrations. Patients should be monitored for digoxin toxicity, especially those aged over 65. Digoxin may have detrimental effects on the short term control of bipolar disorder in patients treated with lithium.
• Diuretics
Potassium depletion due to acetazolamide, loop diuretics and thiazide diuretics potentiates the effects of digoxin on the myocardium and may also have a small effect on reducing the renal tubular secretion of digoxin. Patients should be monitored for hypokalaemia and given potassium supplements when necessary. Spironolactone decreases renal excretion of digoxin, increasing plasma levels. The dose of digoxin should be decreased in susceptible patients.
• Gastrointestinal drugs
Antacids and adsorbents, such as kaolin, can inhibit the absorption of digoxin from the gastrointestinal tract, resulting in a fall in digoxin plasma levels. The interaction can be prevented by separating the doses by about 2 hours. Carbenoxolone may cause fluid retention and hypokalaemia which can increase susceptibility to digoxin toxicity. Metabolism of digoxin in the gastrointestinal tract is inhibited by omeprazole, resulting in increased plasma levels of digoxin. Smaller effects have been seen withpantoprazole and rabeprazole. Sucralfate decreases the absorption of digoxin from the gastrointestinal tract, lowering plasma levels. Plasma levels of digoxin may be reduced by co-administration with sulfasalazine because of decreased absorption. Patients receiving both drugs should be monitored. No interaction has been seen between digoxin and another mesalazine prodrug, balsalazide.
• Lipid regulating drugs
Increases in plasma levels of digoxin have been observed in patients taking atorvastatin and it may be necessary to reduce the dose of digoxin. Although fluvastatin, pravastatin and simvastatin do not appear to cause significant increases in plasma digoxin levels it is prudent to monitor the effects of coadministration. Colestipol and colestyramine bind to digoxin in the gastrointestinal tract, reducing its absorption and lowering plasma digoxin levels. The interaction can be prevented by separating the doses of digoxin and anion exchange resin by about 2 hours.
• Muscle relaxants
Edrophonium should not be given to patients with atrial flutter and tachycardia who are taking digoxin as the combination may cause excessive bradycardia and atrioventricular block. Serious cardiac arrhythmias can develop in patients taking digoxin if they are given suxamethonium and pancuronium due to rapid removal of potassium from myocardial cells. Concomitant use should be avoided. Tizanidine may potentiate hypotension and bradycardia when administered concurrently with digoxin.
• NSAIDs
NSAIDs have the potential to cause renal impairment, reducing the renal clearance of digoxin with a subsequent increase in plasma levels. Aspirin, azapropazone, diclofenac, fenbufen, ibuprofen, indometacin and tiaprofenic acid have all been shown to increase plasma concentrations of digoxin but this may only be clinically significant in patients with impaired renal function.
Etoricoxib, ketoprofen, meloxicam, piroxicam and rofecoxib do not appear to increase plasma digoxin levels. Patients being treated with digoxin often need to take NSAIDs and digoxin plasma concentrations should be monitored whenever an NSAID is initiated or discontinued. Phenylbutazone stimulates hepatic metabolism of digoxin so plasma levels should be monitored in these drugs are given concurrently.
• Other drugs
Acarbose inhibits the absorption of digoxin in the gastrointestinal tract, resulting in lower plasma levels. Plasma levels of digoxin are increased by concomitant administration of prazosin. Carbimazole or penicillamine may reduce plasma levels of digoxin. Changes in thyroid function may affect sensitivity to digoxin independently of plasma levels. Increased plasma digoxin levels have been reported when ciclosporin has been administered to patients taking digoxin due to reduced renal elimination. Patients should be monitored closely and the digoxin dose adjusted when required. Corticosteroids cause potassium loss and sodium and water retention which increase the risk of digoxin toxicity and heart failure. Patients taking prolonged courses of corticosteroids should be monitored closely. Many cytotoxic drugs damage the intestinal lining, impairing the absorption of digoxin and decreasing plasma levels. The effect is reversed shortly after discontinuing cytotoxic drug administration. Selective beta2 agonists may cause hypokalaemia which can increase susceptibility to digoxin induced arrhythmias. Concurrent administration of salbutamol has also been associated with increases in plasma digoxin levels.
4.6 Pregnancy and Lactation
• Pregnancy
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 non-pregnant 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 used successfully to treat foetal bradycardia and congestive heart failure.
• Breast feeding
Although digoxin is excreted in breast milk, the quantities are minute and breast feeding is not contraindicated.
4.7 Effects on Ability to Drive and Use Machines
Neurological adverse effects and visual disturbances have been reported in patients receiving digoxin. Patients should make sure they are not affected before they drive or operate machinery.
4.8 Undesirable Effects
The adverse effects produced by digoxin are frequently due to the narrow margin between therapeutic and toxic doses. Plasma levels in excess of 2nmol.L-1 indicate that the patient is at special risk, although there is considerable interindividual variation. Special care should be taken in patients at high risk of developing digoxin toxicity, such as the elderly and those with renal impairment or thyroid disease (see Special warnings, above). In addition, care should be taken when digoxin is taken with other medications as many have the potential to affect plasma digoxin concentrations or electrolytes and cause toxicity (see section 4.5).
• Blood and lymphatic system disorders Thrombocytopenia has been reported in patients taking digoxin. Agranulocytosis has been reported rarely.
• Immune system disorders
Hypersensitivity reactions have been reported rarely in patients taking digoxin. These include pruritus, erythematous rashes, papules, vesicles and angioedema.
• Endocrine disorders
Digoxin has oestrogenic activity and is associated with gynaecomastia in men following prolonged administration.
• Psychiatric disorders
Digoxin is associated with disorientation, mental confusion, amnesia and depression. Acute psychosis, delirium, visual and auditory hallucinations have been reported rarely, especially in elderly patients. Epilepsy has been reported rarely.
• Nervous system disorders
Neurological effects are also common symptoms of excessive digoxin dosage. They include headache, fatigue, weakness, dizziness, drowsiness, bad dreams, restlessness, nervousness, agitation and apathy.
• Eye disorders
Visual disturbances, including blurred vision and photophobia, may occur. Colour vision may be affected infrequently, with objects appearing yellow or, less frequently, green, red, blue, brown or white.
• Cardiac disorders
The most serious adverse effects of digoxin are on the heart. Usually an early stage of digoxin toxicity is the occurrence of ventricular premature contractions; they can proceed to bigeminy or even trigeminy. Toxic doses may cause or aggravate heart failure. Supraventricular or ventricular arrhythmias and defects of conduction are common and may be an early indication of excessive dosage. The underlying heart condition influences the occurrence and severity of arrhythmias. Supraventricular tachycardia, especially atrioventricular node junctional tachycardia and atrial tachycardia with block are particularly indicative of digoxin toxicity. Ventricular arrhythmias, including extrasystoles, sinoatrial block, sinus bradycardia and atrioventricular block, may also occur.
• Gastrointestinal disorders
Centrally mediated anorexia, nausea and vomiting may be early signs of an excessive dose of digoxin. Abdominal pain and diarrhoea may occur, particularly in elderly patients. Intestinal ischaemia which responds to verapamil has been reported rarely.
Undesirable effects in children
Children are especially sensitive to the effects of digoxin (see section 4.2). Anorexia, nausea, vomiting, diarrhoea and CNS disturbances may occur but they are rarely the initial symptoms of overdose. Cardiac arrhythmias are the most frequent sign of excessive dosing with digoxin. The most common are conduction disturbances or superventricular tachyarrhythmias, such as atrial tachycardia with or without block. Ventricular arrhythmias are less common. Sinus bradycardia may indicate digoxin toxicity, especially in infants.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
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 gastrointestinal tract during enterohepatic recirculation.
An overdosage of digoxin of 10 to 15 mg in adults without heart disease and of 6 to 10mg in children aged 1 to 3 years without heart disease appeared to be the dose resulting in death in half of the patients. If more than 25mg of digoxin was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments resulted. If more than 10mg 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.
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 lidocaine or phenytoin. Dialysis is not particularly effective in removing digoxin from the body in potentially life-threatening toxicity.
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) (Digibind®) when other therapies have failed.
5. Pharmacological Properties
5.1 Pharmacodynamic properties
ATC code: C01A A05 Cardiac glycosides
The pharmacological receptor of digoxin is the membrane bound cation dependent sodium- and potassium-linked adenosine triphosphatase (Na+,K+ATPase). Digoxin binds to this enzyme and inhibits it, resulting in an increase in the intracellular concentration of calcium which, in turn, alters the intracellular disposition of calcium.
The effect of digitalis on intracellular calcium concentrations results in an increase in the force and velocity of myocardial systolic contraction (i.e. a positive inotropic effect on myocardial cells). Digoxin has a negative chronotropic effect as it slows the overall heart rate. These actions result in a decrease in the rate of contractility, particularly through the atrioventricular node, with subsequent effects on atrial fibrillation. Digoxin also has complex direct effects on conduction velocities and refractory periods of the conducting fibres in cardiac muscle. In addition to its direct effects, digoxin acts indirectly by increasing vagal input through direct vagal stimulation and decreasing sympathetic drive. These effects contribute to the slowing of the ventricular rate by digoxin, both in sinus rhythm and in atrial fibrillation.
5.2 Pharmacokinetic properties
Absorption
Digoxin is incompletely (about 70%) absorbed from the gastrointestinal tract, most absorption taking place in the stomach and the upper intestine. Food decreases the rate but not the extent of absorption. The onset of effect occurs within about 2 hours and reaches its maximum after about 6 hours following an oral dose. The generally accepted therapeutic plasma level is 0.8 to 2 nmol.L-1 but there are wide interindividual variations.
• Distribution
Digoxin has a large volume of distribution and is widely distributed in tissues, including the heart, brain, erythrocytes and skeletal muscles, and it crosses the blood brain barrier. The concentration of digoxin in the myocardium is considerably higher than in plasma. From 20 to 30% of a dose is bound to plasma proteins. The volume of distribution is decreased in patients with renal impairment and hypothyroidism and it is increased in patients with hyperthyroidism.
• Metabolism and elimination
Most of a dose of digoxin is excreted unchanged by the kidneys, although some of the dose is metabolised to pharmacologically active and inactive metabolites. It is subject to glomerular filtration and to active secretion and passive resorption by the renal tubules. The balance between these two mechanisms results in a close relationship between renal clearance of digoxin and creatinine. Bacterial flora in the gastrointestinal tract metabolise digoxin to cardio-inactive metabolites in about 10% of patients. The elimination halflife of digoxin is about 40 hours in patients with normal renal function but it can be prolonged to 96 hours in severe renal impairment.
5.3. Preclinical Safety Data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Also contains: lactose, magnesium stearate, maize starch, pregelatinised maize starch, FD & C Blue 2 HT Lake (E132).
6.2. Incompatibilities
None known.
Shelf Life
6.3.
Shelf-life
Three years from the date of manufacture.
Shelf-life after dilution/reconstitution Not applicable.
Shelf-life after first opening Not applicable.
6.4. Special Precautions for Storage
Store below 25°C in a dry place.
6.5. Nature and Contents of Container
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:
a) Carton: Printed carton manufactured from white folding box board.
b) Blister pack: (i) 250pm white rigid PVC. (ii) Surface printed 20pm hard temper aluminium foil with 5-7g/M2 PVC and PVdC compatible heat seal lacquer on the reverse side.
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: 100,000.
6.6. Instructions for Use/Handling Not applicable.
7 MARKETING AUTHORISATION HOLDER
Actavis UK Limited (Trading style: Actavis) Whiddon Valley BARNSTAPLE N Devon EX32 8NS
8. MARKETING AUTHORISATION NUMBERS
PL 0142/0082 R
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 16/08/2001
10 DATE OF REVISION OF THE TEXT
22/06/2015