Digoxin Actavis

Cardiac failure

Digoxin Actavis is indicated in the management of chronic cardiac failure where the dominant problem is systolic dysfunction. The therapeutic benefit of Digoxin Actavis is greater in patients with ventricular dilatation.

Digoxin Actavis is specifically indicated where cardiac failure is accompanied by atrial fibrillation.

Supraventricular arrhythmias

Digoxin Actavis 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 Actavis injection is indicated when emergency parenteral digitilisation is required in patients who have not been given cardiac glycosides within the preceding two weeks.

Posology:

Digoxin Actavis Injection is for administration by slow intravenous infusion (see Method of administration below).

The dose of Digoxin Actavis 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 Actavis 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):

Adults and paediatric populations over 10 years

Parenteral loading:

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 Actavis 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.

- Maintenance Dose:

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:

C_cr is creatinine clearance corrected to 70 kg body weight or 1.73 m² body surface area.

If only serum creatinine (S_cr) concentrations are available, a C_cr (corrected to 70 kg body weight) may be estimated in men as

NOTE: Where serum creatinine values are obtained in micromol/L these may be converted to mg/100 ml (mg %) as follows:

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 Actavis daily; however in those who show increased sensitivity to the adverse effects of Digoxin Actavis, a dosage of 62.5 microgram (0.0625 mg) daily or less may suffice. Conversely, some patients may require a higher dose.

Neonates, infants & paediatric populations up to 10 years of age:

if cardiac glycosides have been given in the two weeks preceding commencement of Digoxin Actavis therapy, it should be anticipated that optimum loading doses of Digoxin Actavis will be less than those recommended below.

In the newborn, particularly in the premature infant, renal clearance of Digoxin Actavis 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.

Parenteral Loading dose:

The I.V. loading dose in the above groups should be administered in accordance with the following schedule:

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.

Maintenance Dose:

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 Actavis levels should be used as a basis for adjustment of dosage in these paediatric patient groups.

Elderly.

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 Actavis levels and the risk of toxicity. The serum Digoxin Actavis levels should be checked regularly and hypokalaemia should be avoided.

Renal impairment

The dosage recommendations should be reconsidered if patients are elderly or if there are other reasons for the renal clearance of Digoxin Actavis being reduced. A reduction in both initial and maintenance doses should be considered.

Method of administration:

Dilution of Digoxin Actavis injection:

Digoxin Actavis 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 Actavis to 6 ml of injection solution. The use of less than a 4-fold volume of diluent could lead to precipitation of Digoxin Actavis.

Digoxin Actavis 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 Actavis added to 500ml of infusion solution), Digoxin Actavis 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.

Administration of Digoxin Actavis injection:

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.

Digoxin Actavis is contraindicated in

- intermittent complete heart block or second degree atrioventricular block, especially if there is a history of Stokes-Adams attacks.

- arrhythmias caused by cardiac glycoside intoxication.

- 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 Actavis 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 Actavis is similarly contra-indicated.

- ventricular tachycardia or ventricular fibrillation.

- hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure, but even then caution should be exercised if Digoxin Actavis is to be used.

Monitoring

Patients receiving Digoxin Actavis should have their serum electrolytes and renal function (serum creatinine concentration) assessed periodically; the frequency of assessments will depend on the clinical setting.

Serum concentrations of Digoxin Actavis may be expressed in Conventional Units of nanograms/ml or in SI units of nanomol/l. To convert nanograms/ml to nanomol/l, multiply nanograms/ml by 1.28.

The serum concentration of Digoxin Actavis can be determined by radioimmunoassay.

Blood should be taken 6 hours or more after the last dose of Digoxin Actavis.

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 Actavis serum level may be 0.5 nanograms/ml (0.64 nanomol/l) to 1.0 nanograms/ml (1.28 nanomol/l).

Digoxin Actavis toxicity is more commonly associated with serum Digoxin Actavis concentration greater than 2 nanograms/ml. However, serum Digoxin Actavis concentration should be interpreted in the clinical context. Toxicity may occur with lower Digoxin Actavis serum concentrations. In deciding whether a patient's symptoms are due to Digoxin Actavis, the clinical state together with the serum potassium level and thyroid function are important factors.

Determination of the serum Digoxin Actavis concentration may be very helpful in making a decision to treat with further Digoxin Actavis, but other glycosides and endogenous Digoxin Actavis-like substances, including metabolites of Digoxin Actavis, 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. Observations while temporary withholding of Digoxin Actavis might be more appropriate.

Arrhythmias

Arrhythmias may be precipitated by Digoxin Actavis 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.

Many beneficial effects of Digoxin Actavis 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.

Sinoatrial disorder

In some cases of sinoatrial disorder (i.e. Sick Sinus Syndrome) Digoxin Actavis may cause or exacerbate sinus bradycardia or cause sinoatrial block.

The administration of Digoxin Actavis 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 follow-up studies have suggested Digoxin Actavis 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 haemodynamically unstable must be borne in mind. The limitations imposed thereafter on direct current cardioversion must also be remembered.

Cardiac amyloidosis

Treatment with Digoxin Actavis should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if alternative treatments are not appropriate, Digoxin Actavis can be used with caution to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation.

Myocarditis

Digoxin Actavis can rarely precipitate vasoconstriction and therefore should be avoided in patients with myocarditis.

Beri beri heart disease

Patients with beri beri heart disease may fail to respond adequately to Digoxin Actavis if the underlying thiamine deficiency is not treated concomitantly. There is also some published information indicating that Digoxin Actavis may inhibit the uptake of thiamine in myocytes in beri beri heart disease.

Constrictive pericarditis

Digoxin Actavis should not be used in constrictive pericarditis unless it is used to control the ventricular rate in atrial fibrillation or to improve systolic dysfunction.

Exercise tolerance

Digoxin Actavis 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 Digoxin Actavis in patients with supraventricular arrhythmias is most evident at rest, less evident with exercise.

Withdrawal

In patients receiving diuretics and an ACE inhibitor, or diuretics alone, the withdrawal of Digoxin Actavis has been shown to result in clinical deterioration.

Electrocardiography

The use of therapeutic doses of Digoxin Actavis may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram.

Digoxin Actavis may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.

Severe respiratory disease

Patients with severe respiratory disease may have an increased myocardial sensitivity to digitalis glycosides.

Hypokalaemia

Hypokalaemia sensitises the myocardium to the actions of cardiac glycosides.

Hypoxia, hypomagnesaemia and hypercalcaemia

Hypoxia, Hypomagnesaemia and marked hypercalcaemia increase myocardial sensitivity to cardiac glycosides.

Thyroid disease

Administering Digoxin Actavis to a patient with thyroid disease requires care. Initial and maintenance doses of Digoxin Actavis should be reduced when thyroid function is subnormal. In hyperthyroidism there is relative Digoxin Actavis 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.

Malabsorption

Patients with malabsorption syndrome or gastro-intestinal reconstructions may require larger doses of Digoxin Actavis.

Chronic congestive cardiac failure

Although many patients with chronic congestive cardiac failure benefit from acute administration of Digoxin Actavis, 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 Actavis is continued long-term.

Direct current cardioversion

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 Actavis, 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.

Since central nervous system and visual disturbances have been reported in patients receiving Digoxin Actavis, patients should exercise caution before driving, using machinery or participating in dangerous activities.

In general, the adverse reactions of Digoxin Actavis are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect.

Hence, adverse reactions are less common when Digoxin Actavis is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions.

Tabulated list of adverse reactions

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 (> 1/1,000 and < 1/100),

rare (> 1/10,000 and < 1/1,000),

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).

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms and signs

Signs and symptoms of Digoxin Actavis 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 Actavis, the clinical state, together with serum electrolyte levels and thyroid function are important factors. In patients undergoing haemodialysis, Digoxin Actavis use is associated with increased mortality; patients with low predialysis potassium concentrations are most at risk.

Adults

In adults without heart disease, clinical observation suggests that an overdose of Digoxin Actavis of 10 to 15 mg was the dose resulting in death of half of the patients. If more than 25 mg of Digoxin Actavis was ingested by an adult without heart disease, death or progressive toxicity responsive only to Digoxin Actavis-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 over dosage and may persist for the ensuing 24 hours or longer. Digoxin Actavis 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 Actavis toxicity is usually fatal.

Acute massive Digoxin Actavis overdose can result in mild to pronounced hyperkalaemia due to inhibition of the sodium-potassium (Na⁺-K⁺) pump. Hypokalaemia may contribute to toxicity.

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 non-cardiac symptoms, such as malaise and weakness, may predominate.

Paediatric population

In children aged 1 to 3 years without heart disease, clinical observation suggests that an overdose of Digoxin Actavis of 6 to 10 mg was the dose resulting in death in half of the patients.

If more than 10 mg of Digoxin Actavis 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 Actavis overdose.

Cardiac manifestations

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 Actavis should be assumed to be caused by Digoxin Actavis, until further evaluation proves otherwise.

Non-cardiac manifestations

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.

Management

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 Actavis 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 Actavis has been ingested, hyperkalaemia may be present due to release of potassium from skeletal muscle. Before administering potassium in Digoxin Actavis 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 Actavis from the body in potentially life-threatening toxicity.

Digoxin Actavis-specific antibody Fab is a specific treatment for Digoxin Actavis toxicity and is very effective. Rapid reversal of the complications that are associated with serious poisoning by Digoxin Actavis, digitoxin and related glycosides has followed intravenous administration of Digoxin Actavis-specific (ovine) antibody fragments (Fab) when other therapies have failed.

For details, consult the literature supplied with antibody fragments.

Pharmacotherapeutic group:

Cardiac therapy, cardiac glycosides, digitalis glycosides.

ATC code: C01AA05

Mechanism of action

Digoxin Actavis 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 Actavis 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 Actavis may therefore appear considerably enhanced when the extracellular potassium concentration is low, with hyperkalaemia having the opposite effect.

Digoxin Actavis 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 atrio-ventricular node. Thus, the major beneficial effect of Digoxin Actavis is reduction of ventricular rate.

Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5 to 30 mins, while using the oral route the onset of effect occurs in 0.5 to 2 hours.

Pharmacodynamic effects

The PROVED trial designed to determine the effectiveness of Digoxin Actavis in 88 patients with chronic, stable mild to moderate heart failure. Withdrawal of Digoxin Actavis or its continuation was performed in a prospective, randomised, double-blind, placebo-controlled multicentre trial of patients with chronic, stable mild to moderate heart failure secondary to left ventricular systolic dysfunction who had normal sinus rhythm and were receiving long-term treatment with diuretic drugs and Digoxin Actavis. Patients withdrawn from Digoxin Actavis therapy showed worsened maximal exercise capacity (p = 0.003) an increased incidence of treatment failures (p = 0.039) and a decreased time to treatment failure (p = 0.037). Patients who continued to receive Digoxin Actavis had a lower body weight (p = 0.044) and heart rate (p = 0.003) and a higher left ventricular ejection fraction (p = 0.016). The overall percentage of participants having one or more adverse event was similar in the two groups: 59 % in the placebo group and 69 % in the Digoxin Actavis group. The types of adverse event were unspecified.

The RADIANCE trial examined the effects of discontinuation of Digoxin Actavis in stable NYHA class II and III patients who were receiving diuretics and ACE inhibitors. The 178 patients were initially stabilised on a combination of captopril or enalapril, diuretics and Digoxin Actavis, then randomised to continue Digoxin Actavis therapy or change to placebo. The relative risk of worsening disease in the placebo group was 5.9 compared to the Digoxin Actavis group. Withdrawal of Digoxin Actavis was accompanied by worsening symptoms, reduced exercise tolerance, and a deteriorating quality of life, indicating that patients with CHF were at considerable risk from discontinuation of the drug in spite of the continuation of therapy with diuretics and ACE inhibitors. Approximately 56 % in the placebo group and 49% in the Digoxin Actavis group experienced unspecified side effects.

In the DIG trial, 6800 patients with heart failure were randomised to receive Digoxin Actavis or placebo. No difference was found in all-cause mortality between patients who were treated with Digoxin Actavis and those who were given placebo. In the Digoxin Actavis group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio,0.88; 95% confidence interval, 0.77 to 1.01; p = 0.06). However, the patients who received Digoxin Actavis had significantly (p<0.001) fewer hospital admissions when the drug was given in addition to diuretics and ACE inhibitors. Digoxin Actavis therapy was most beneficial in patients with ejection fractions of ≤ 25%, patients with enlarged hearts (cardiothoracic ratio of >0.55), and patients in NYHA functional class III or IV. In the DIG study, 11.9 % of patients in the Digoxin Actavis arm and 7.9 % of patients in the placebo arm were suspected of having Digoxin Actavis toxicity, the most common symptoms being new episodes of ventricular fibrillation, supraventricular arrhythmia, tachycardia, or advanced atrioventricular block.

The AFFIRM study involved a total of 4060 patients recruited to a randomised, multicentre comparison of two treatment strategies in patients with atrial fibrillation and a high risk of stroke or death. The primary end point was overall mortality. There were 356 deaths among the patients assigned to rhythm-control therapy (amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, and combinations of these drugs) and 310 deaths among those assigned to rate-control [_β -blockers, calcium-channel blockers (verapamil and diltiazem), Digoxin Actavis, and combinations of these drugs) therapy (mortality at five years, 23.8% and 21.3%, respectively; hazard ratio, 1.15 [95% confidence interval, 0.99 to 1.34]; p=0.08). More patients in the rhythm-control group than in the rate control group were hospitalised, and there were more adverse drug effects in the rhythm-control group as well.

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 Actavis reduces activation of both the sympathetic nervous system and the (renin-angiotensin) system independently of its inotropic actions, and may thus favorably influence survival. Whether this is achieved via direct sympathoinhibitory effects or by re-sensitising baroreflex mechanisms remains unclear.

Absorption

The T_max following IV administration is approximately 1 to 5 hours, while the T_max for oral administration is 2 to 6 hours. Upon oral administration, Digoxin Actavis is absorbed from the stomach and upper part of the small intestine. When Digoxin Actavis is taken after meals, the rate of absorption is slowed, but the total amount of Digoxin Actavis absorbed is usually unchanged. When taken with meals high in fibre, however, the amount absorbed from an oral dose may be reduced.

The bioavailability of orally administered Digoxin Actavis is approximately 63 % in tablet form and 75 % as oral solution.

Distribution

The initial distribution of Digoxin Actavis 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 Actavis concentration, which is dependent upon Digoxin Actavis elimination from the body. The volume of distribution is large (Vd_ss = 510 litres in healthy volunteers), indicating Digoxin Actavis to be extensively bound to body tissues. The highest Digoxin Actavis 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 Actavis circulating in plasma, approximately 25% is bound to protein.

Biotransformation

The majority of Digoxin Actavis is excreted by the kidneys as an intact drug, although a small fraction of the dose is metabolised to pharmacologically active and inactive metabolites. The main metabolites of Digoxin Actavis are dihydroDigoxin Actavis and digoxygenin.

Elimination

The major route of elimination is renal excretion of the unchanged drug.

Digoxin Actavis is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of Digoxin Actavis. P-glycoprotein in renal proximal tubules appears to be an important factor in the renal elimination of Digoxin Actavis.

Following intravenous administration to healthy volunteers, between 60 and 75% of a Digoxin Actavis dose is recovered unchanged in the urine over a 6 day follow-up period. Total body clearance of Digoxin Actavis 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 Actavis have been found to be 193 ± 25 ml/min and 152 ± 24 ml/min in a healthy control population.

In a small percentage of individuals, orally administered Digoxin Actavis is converted to cardioinactive reduction products (Digoxin Actavis 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 Actavis 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 Actavis elimination is renal excretion of the unchanged drug.

The terminal elimination half-life of Digoxin Actavis in patients with normal renal function is 30 to 40 h.

Since most of the drug is bound to the tissues rather than circulating in the blood, Digoxin Actavis is not effectively removed from the body during cardiopulmonary by-pass. Furthermore, only about 3% of a Digoxin Actavis dose is removed from the body during five hours of haemodialysis.

Paediatric population

In the newborn period, renal clearance of Digoxin Actavis is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant since renal clearance reflects maturation of renal function. Digoxin Actavis clearance has been found to be 65.6 ± 30 ml/min/1.73m² at 3 months, compared to only 32 ± 7 ml/min/1.73 m² at 1 week. By 12 months Digoxin Actavis clearance of 88 ± 43 ml / min / 1.73m2 has been reported. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight and body surface area.

Renal impairment

The terminal elimination half-life of Digoxin Actavis is prolonged in patients with impaired renal function, and in anuric patients will be of the order of 100 hours.

Hepatic impairment

Hepatic impairment has little effect on Digoxin Actavis clearance.

Elderly

Age-related declines in renal function in elderly patients can result in a lower rates of Digoxin Actavis clearance than in younger subjects, with reported Digoxin Actavis clearance rates in the elderly of 53 ml/min/1.73m².

Gender

Digoxin Actavis clearance is 12% - 14% less in females than males and may need to be considered in dosing calculations.

Carcinogenesis, mutagenesis

Digoxin Actavis showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of Digoxin Actavis.

Not applicable.

If only part used, discard the remaining solution.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements