1. Name of the medicinal product

Digoxin Tablets USP 62.5mcg Taj Pharma
Digoxin Tablets USP 125mcg Taj Pharma
Digoxin Tablets USP 250mcg Taj Pharma

  1. Qualitative and quantitative composition

a) Digoxin Tablets USP 62.5mcg Taj Pharma
Each uncoated tablet contains:
Digoxin USP 62.5mcg
Excipients: Q.S.

b) Digoxin Tablets USP 125mcg Taj Pharma
Each uncoated tablet contains:
Digoxin USP 125mcg
Excipients: Q.S.

c) Digoxin Tablets USP 250mcg Taj Pharma
Each uncoated tablet contains:
Digoxin USP 250mcg
Excipients: Q.S.

For full list of excipients (see section 6)

  1. Pharmaceutical form

White uncoated tablets.

White to off white, circular, flat bevelled-edge, uncoated tablets.

  1. Clinical particulars

Therapeutic indications

  • Digoxin Taj Pharma is indicated for the treatment of congestive cardiac failure.
  • Digoxin Taj Pharma may be used for certain supraventricular dysrhythmias, particularly atrial fibrillation.

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:

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 Taj Pharma 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%.

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:

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 1.73m2 body surface area. If only serum creatinine (Scr) concentrations are available, a Ccr (corrected to 70kg body weight) may be estimated in men as:

NB:

Serum creatinine values are in micromol/l, these can be converted to mg/100ml (mg/%) as follows:

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 Taj Pharma daily, however, in those who show increased sensitivity to the adverse effects of Digoxin Taj Pharma, 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:

In the newborn, particularly in the premature infant, renal clearance of Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma therapy, it should be anticipated that optimum loading doses of Digoxin Taj Pharma will be less than those recommended above.

Monitoring

Measurements of plasma levels of Digoxin Taj Pharma are useful in individualising therapy during the early stages of treatment, for detecting poor patient compliance and for diagnosing toxicity. Serum concentrations of Digoxin Taj Pharma 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 Taj Pharma can be determined by radioimmunoassay. Blood should be taken 6 hours or more after the last dose of Digoxin Taj Pharma. 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 Taj Pharma 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 Taj Pharma, the patent’s clinical state together with the serum potassium level and thyroid function are important factors. Other glycosides, including metabolites of Digoxin Taj Pharma, 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 Taj Pharma, such that high serum Digoxin Taj Pharma levels and associated toxicity can occur quite readily, unless dosages of Digoxin Taj Pharma lower than those in non-elderly patients are used. Serum Digoxin Taj Pharma levels should be checked regularly and hypokalaemia avoided.

Renal impairment

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

Method of Administration

For oral administration.

  • Contraindications
  • Patients known to be hypersensitive to Digoxin Taj Pharma, 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 Taj Pharma 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 Taj Pharma 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 Taj Pharma 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.
    • Special warnings and precautions for use

Monitoring

Patients receiving Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma can be determined by radioimmunoassay.

Blood should be taken six hours or more after the last dose of Digoxin Taj Pharma.

There are no rigid guidelines as to the range of serum concentrations that are most efficacious. Post hoc analyses of heart failure patients in the Digitalis Investigation Group trial suggest that the optimal trough Digoxin Taj Pharma serum level may be 0.5 nanogram/ml (0.64 nanomol/l) to 1.0 nanogram/ml (1.28 nanomol/l).

Digoxin Taj Pharma toxicity is more commonly associated with serum Digoxin Taj Pharma concentrations greater than 2 nanogram/ml. However, serum Digoxin Taj Pharma concentration should be interpreted in the clinical context. Toxicity may occur with lower Digoxin Taj Pharma serum concentrations. In deciding whether a patient’s symptoms are due to Digoxin Taj Pharma, the clinical state together with the serum potassium level and thyroid function are important factors (see Section 4.9).

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

  • Arrhythmias

Arrhythmias may be precipitated by Digoxin Taj Pharma 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).

Many beneficial effects of Digoxin Taj Pharma 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 Taj Pharma may cause or exacerbate sinus bradycardia or cause sinoatrial block.

The administration of Digoxin Taj Pharma 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 Taj Pharma to be associated with an increased risk of death. 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 Taj Pharma should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if alternative treatments are not appropriate, Digoxin Taj Pharma can be used to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation.

  • Myocarditis

Digoxin Taj Pharma 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 Taj Pharma if the underlying thiamine deficiency is not treated concomitantly.

  • Constrictive pericarditis

Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma 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 Taj Pharma has been shown to result in clinical deterioration.

  • Electrocardiograhy

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

Digoxin Taj Pharma 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.

  • Hypokalaemia, hypomagnesaemia, hypercalcaemia

Hypokalaemia sensitises the myocardium to the actions of cardiac glycosides. Digoxin Taj Pharma 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.

  • Thyroid disease

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

  • 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 Taj Pharma, 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 Taj Pharma 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 Taj Pharma, 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 Taj Pharma 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 Taj Pharma.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Digoxin Taj Pharma.

  • Interaction with other medicinal products 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 Taj Pharma. Consideration of the possibility of an interaction whenever concomitant therapy is contemplated is the best precaution and a check on serum Digoxin Taj Pharma level is recommended when any doubt exists.

Digoxin Taj Pharma is a substrate of P-glycoprotein. Thus, inhibitors of P-glycoprotein (e.g. clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) may increase blood concentrations of Digoxin Taj Pharma by enhancing its absorption and/or by reducing its renal clearance (see Section 5.2). Induction of P-glycoprotein can result in decreases in plasma concentrations of Digoxin Taj Pharma.

  • Antiarrhythmics

Amiodarone: plasma levels of Digoxin Taj Pharma are considerably increased by concurrent administration of amiodarone. This is due to a decrease in the renal and non-renal clearance of Digoxin Taj Pharma, a prolongation of its half life and a possible increase in absorption. Children are especially sensitive. The dose of Digoxin Taj Pharma should be reduced by a third to a half when it is given concurrently with amiodarone. Disopyramide may modify the cardiovascular effects of Digoxin Taj Pharma and reduce its volume of distribution. The loading dose of Digoxin Taj Pharma should be reduced in patients who are also receiving disopyramide. Flecainide: plasma levels of Digoxin Taj Pharma are increased by concurrent administration of flecainide. This is likely to be clinically significant only in patients with high plasma levels of Digoxin Taj Pharma or those with atrioventricular nodal dysfunction. Moracizine: Digoxin Taj Pharma and moracizine have additive effects on cardiac conduction. Propafenone: plasma levels of Digoxin Taj Pharma are increased by concurrent administration of propafenone. There is considerable interindividual variation in the extent of this interaction but the dose of Digoxin Taj Pharma should be reduced and patients monitored for signs of Digoxin Taj Pharma toxicity. Quinidine: the renal and non-renal excretion of Digoxin Taj Pharma is reduced by co-administration of Digoxin Taj Pharma. Excretion in bile and tissue binding of Digoxin Taj Pharma may also be reduced Significant effects occur as soon as quinidine is given to a patient stabilised on Digoxin Taj Pharma and plasma levels of Digoxin Taj Pharma are usually doubled within 5 days. The dose of Digoxin Taj Pharma 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 Taj Pharma to inactive metabolites in the gastrointestinal tract occurs in about 10% of patients. Co-administration of macrolide antibiotics (azithromycin, clarithromycin, erythromycin, telithromycin), gentamicin or tetracycline to this sub-group of patients can result in a clinically significant increase in plasma Digoxin Taj Pharma levels. Neomycin: absorption of Digoxin Taj Pharma from the gastrointestinal tract is inhibited by neomycin and plasma levels are reduced. Rifampicin: the metabolism of Digoxin Taj Pharma may be increased by co-administration with rifampicin. The interaction may be enhanced in patients with renal impairment. Trimethoprim: the renal excretion of Digoxin Taj Pharma is decreased by concurrent administration with trimethoprim. The interaction is more significant in elderly patients or those with renal impairment and Digoxin Taj Pharma plasma levels should be monitored. Amphotericin: hypokalaemia due to amphotericin administration may potentiate Digoxin Taj Pharma toxicity. Patients should be monitored and given potassium supplements when necessary. Itraconazole can cause a marked increase in plasma Digoxin Taj Pharma levels and toxicity may occur if the dose of Digoxin Taj Pharma is not reduced. Itraconazole may also oppose the positive inotropic effects of Digoxin Taj Pharma. Quinine, hydroxychloroquine and chloroquine can increase plasma levels of Digoxin Taj Pharma by decreasing non-renal clearance.

  • Calcium channel blockers

Diltiazem and Digoxin Taj Pharma co-administration can result in increased Digoxin Taj Pharma plasma levels and toxicity and patients should be monitored. Nifedipine may increase Digoxin Taj Pharma plasma levels but there is considerable interindividual variation. Patients taking high doses of Digoxin Taj Pharma or those with renal impairment are most at risk. Nisoldipine may also increase plasma levels of Digoxin Taj Pharma but amlodipine, felodipine, isradipine, lercanidipine, nicardipine, nimodipine and nitrendipine do not appear to have significant effects on Digoxin Taj Pharma plasma levels but it is prudent to monitor the effects of co-administration. Verapamil increases plasma Digoxin Taj Pharma levels by inhibiting the active tubular secretion and non-renal clearance of Digoxin Taj Pharma. The dose of Digoxin Taj Pharma should be reduced and plasma levels monitored. Verapamil may also increase atrioventricular block and tachycardia in patients taking Digoxin Taj Pharma.

  • Calcium salts and vitamin D analogues

Intravenous administration of calcium salts to patients taking Digoxin Taj Pharma can result in dangerous cardiac arrhythmias and should be avoided. Vitamin D analogues can also increase Digoxin Taj Pharma 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 Taj Pharma resulting in higher serum levels. These drugs may also cause a deterioration in renal function resulting in elevated serum levels of Digoxin Taj Pharma because of impaired renal excretion. Concurrent administration of captopril has been associated with increases in plasma Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma and beta blockers are taken concomitantly. Nitroprusside and hydralazine increase the renal clearance of Digoxin Taj Pharma by increasing renal blood flow and tubular secretion and lowering plasma Digoxin Taj Pharma levels.

  • Central nervous system drugs

St John’s wort: co-administration of Digoxin Taj Pharma with St John’s wort should be avoided because plasma levels are significantly reduced. Nefazodone, trazodone: Plasma levels of Digoxin Taj Pharma are increased by concomitant administration of nefazodone or trazodone and it may be necessary to reduce the dose of Digoxin Taj Pharma. Phenytoin increases total clearance of Digoxin Taj Pharma 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 Taj Pharma and topiramate reduces the bioavailability of Digoxin Taj Pharma and patients should be monitored. Alprazolam and diazepam can decrease Digoxin Taj Pharma clearance, resulting in increased plasma concentrations. Patients should be monitored for Digoxin Taj Pharma toxicity, especially those aged over 65. Digoxin Taj Pharma 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 Taj Pharma on the myocardium and may also have a small effect on reducing the renal tubular secretion of Digoxin Taj Pharma. Patients should be monitored for hypokalaemia and given potassium supplements when necessary. Spironolactone decreases renal excretion of Digoxin Taj Pharma, increasing plasma levels. The dose of Digoxin Taj Pharma should be decreased in susceptible patients.

  • Gastrointestinal drugs

Antacids and adsorbents, such as kaolin, can inhibit the absorption of Digoxin Taj Pharma from the gastrointestinal tract, resulting in a fall in Digoxin Taj Pharma 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 Taj Pharma toxicity. Metabolism of Digoxin Taj Pharma in the gastrointestinal tract is inhibited by omeprazole, resulting in increased plasma levels of Digoxin Taj Pharma. Smaller effects have been seen with pantoprazole and rabeprazoleSucralfate decreases the absorption of Digoxin Taj Pharma from the gastrointestinal tract, lowering plasma levels. Plasma levels of Digoxin Taj Pharma 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 Taj Pharma and another mesalazine prodrug, balsalazide.

  • Lipid regulating drugs

Increases in plasma levels of Digoxin Taj Pharma have been observed in patients taking atorvastatin and it may be necessary to reduce the dose of Digoxin Taj Pharma. Although fluvastatin, pravastatin and simvastatin do not appear to cause significant increases in plasma Digoxin Taj Pharma levels it is prudent to monitor the effects of co-administration. Colestipol and colestyramine bind to Digoxin Taj Pharma in the gastrointestinal tract, reducing its absorption and lowering plasma Digoxin Taj Pharma levels. The interaction can be prevented by separating the doses of Digoxin Taj Pharma 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 Taj Pharma as the combination may cause excessive bradycardia and atrioventricular block. Serious cardiac arrhythmias can develop in patients taking Digoxin Taj Pharma 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 Taj Pharma.

  • NSAIDs

NSAIDs have the potential to cause renal impairment, reducing the renal clearance of Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma levels. Patients being treated with Digoxin Taj Pharma often need to take NSAIDs and Digoxin Taj Pharma plasma concentrations should be monitored whenever an NSAID is initiated or discontinued. Phenylbutazone stimulates hepatic metabolism of Digoxin Taj Pharma so plasma levels should be monitored in these drugs are given concurrently.

  • Other drugs

Acarbose inhibits the absorption of Digoxin Taj Pharma in the gastrointestinal tract, resulting in lower plasma levels. Plasma levels of Digoxin Taj Pharma are increased by concomitant administration of prazosin. Carbimazole or penicillamine may reduce plasma levels of Digoxin Taj Pharma. Changes in thyroid function may affect sensitivity to Digoxin Taj Pharma independently of plasma levels. Increased plasma Digoxin Taj Pharma levels have been reported when ciclosporin has been administered to patients taking Digoxin Taj Pharma due to reduced renal elimination. Patients should be monitored closely and the Digoxin Taj Pharma dose adjusted when required. Corticosteroids cause potassium loss and sodium and water retention which increase the risk of Digoxin Taj Pharma 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 Taj Pharma and decreasing plasma levels. The effect is reversed shortly after discontinuing cytotoxic drug administration. Selective betaagonists may cause hypokalaemia which can increase susceptibility to Digoxin Taj Pharma induced arrhythmias. Concurrent administration of salbutamol has also been associated with increases in plasma Digoxin Taj Pharma levels.

Sympathomimetic drugs have direct positive chronotropic effects that can promote cardiac arrhythmias and may also lead to hypokalaemia, which can lead to or worsen cardiac arrhythmias. Concomitant use of Digoxin Taj Pharma and sympathomimetics may increase the risk of cardiac arrhythmias.

Combinations which can increase the effects of Digoxin Taj Pharma when co-administered:

Propantheline, epoprostenol (transient), vasopressin receptor antagonists (tolvaptan and conivaptan), carvedilol, ritonavir/ritonavir containing regimens, taleprevir, dronedarone, ranolazine, lapatinib and ticagrelor.

The concomitant use of Digoxin Taj Pharma and sennosides may be associated with a moderate increase in the risk of Digoxin Taj Pharma toxicity in heart failure patients.

Patients receiving Digoxin Taj Pharma are more susceptible to the effects of suxamethonium-exacerbated hyperkalaemia.

Co-administration of lapatinib with orally administered Digoxin Taj Pharma resulted in an increase in the AUC of Digoxin Taj Pharma.

Caution should be exercised when dosing Digoxin Taj Pharma concurrently with lapatinib.

Combinations which can decrease the effects of Digoxin Taj Pharma when co-administered:

Antacids, some bulk laxatives, kaolin-pectin, acarbose, neomycin, penicillamine, rifampicin, some cytostatics, metoclopramide, sulfasalazine, adrenaline, salbutamol, cholestyramine, phenytoin, St John’s wort (Hypericum perforatum), bupropion and supplemental enteral nutrition.

Bupropion and its major circulating metabolite, with and without Digoxin Taj Pharma, stimulated OATP4C1-mediated Digoxin Taj Pharma transport. Digoxin Taj Pharma has been identified as a substrate for aOATP4C1 in the basolateral side of the proximal renal tubules. Binding of bupropion and its metabolites to OATP4C1 could possibly increase the transport of Digoxin Taj Pharma and therefore, increase the renal secretion of Digoxin Taj Pharma.

Other interactions

Milrinone does not alter steady-state serum Digoxin Taj Pharma levels.

  • Fertility, pregnancy and lactation

Pregnancy

No data are available on whether or not Digoxin Taj Pharma has teratogenic effects.

There is no information available on the effect of Digoxin Taj Pharma on human fertility.

The use of Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma concentrations are maintained within the normal range. Although it has been speculated that a direct effect of Digoxin Taj Pharma 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 Taj Pharma has been used successfully to treat foetal bradycardia and congestive heart failure.

Adverse foetal effects have been reported in mothers with digitalis toxicity.

Breast feeding

Although Digoxin Taj Pharma is excreted in breast milk, the quantities are minute and breast feeding is not contraindicated.

Fertility

There is no information available on the effect of Digoxin Taj Pharma on human fertility.

No data are available on whether or not Digoxin Taj Pharma has teratogenic effects.

  • Effects on ability to drive and use machines

Neurological adverse effects and visual disturbances have been reported in patients receiving Digoxin Taj Pharma. Patients should make sure they are not affected before they drive or operate machinery.

  • Undesirable effects

The adverse effects produced by Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma is taken with other medications as many have the potential to affect plasma Digoxin Taj Pharma concentrations or electrolytes and cause toxicity (see section 4.5).

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 ≥ 1/1000 and < 1/100

Rare ≥ 1/10,000 and < 1/1000

Very rare < 1/10,000, including isolated reports.

System Organ ClassFrequencySide effects
Blood and lymphatic system disordersRareAgranulocytosis
Very rareThrombocytopaenia
Immune system disordersNot knownHypersensitivity reactions (pruritus, erythematous rashes, papules, vesicles and angioedema)
Metabolism and nutrition disordersVery rareAnorexia
Psychiatric disordersUncommonDepression
RareEpilepsy
Very rarePsychosis, confusion
Not KnownDisorientation, amnesia, delirium, visual and auditory hallucinations (especially in elderly patients)
Nervous system disordersCommonCNS disturbances, dizziness
Very rareHeadache, apathy
Not knownFatigue, weakness, drowsiness, bad dreams, restlessness,

nervousness, agitation

Eye disordersCommonVisual disturbances
Not KnownBlurred vision, photophobia, colour vision may be affected infrequently, with objects appearing yellow or, less frequently, green, red, blue, brown or white
Cardiac disordersCommonArrhythmia, conduction disturbances, bigeminy, trigeminy, PR prolongation, sinus bradycardia
Very rareSupraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, ventricular premature contraction, ST segment depression
Not KnownHeart failure or aggravation of heart failure, superventricular tachycardia, extrasystoles, sinoatrial block
Gastrointestinal disordersCommonNausea, vomiting, diarrhoea
Very rareIntestinal ischaemia, intestinal necrosis
Not KnownAnorexia, abdominal pain
Skin and subcutaneous tissue DisordersCommonSkin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia
Reproductive system and breast disordersVery rareGynaecomastia can occur with long term administration
General disorders and administration site conditionsVery rareFatigue, malaise, weakness

Paediatric population

Children are especially sensitive to the effects of Digoxin Taj Pharma (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 Taj Pharma. 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 Taj Pharma 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.

  • Overdose

Symptoms and signs

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 Taj Pharma 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 Taj Pharma, the clinical state, together with serum electrolyte levels and thyroid function are important factors (see Section 4.2). In patients undergoing haemodialysis, Digoxin Taj Pharma use is associated with increased mortality; patients with low pre-dialysis potassium concentrations are most at risk.

Adults

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

Acute massive Digoxin Taj Pharma 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).

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 Taj Pharma of 6 to 10 mg was the dose resulting in death in half of the patients.

If more than 10 mg of Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma should be assumed to be caused by Digoxin Taj Pharma, until further evaluation proves otherwise.

Non-cardiac manifestations

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.

Treatment

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

Digoxin Taj Pharma-specific antibody Fab is a specific treatment for Digoxin Taj Pharma toxicity and is very effective. Rapid reversal of the complications that are associated with serious poisoning by Digoxin Taj Pharma, digitoxin and related glycosides has followed I.V. administration of Digoxin Taj Pharma-specific (ovine) antibody fragments (Fab). For details, consult the literature supplied with antibody fragments.

  1. Pharmacological properties
  • Pharmacodynamic properties

Mechanism of action

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

Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma in 88 patients with chronic, stable mild to moderate heart failure. Withdrawal of Digoxin Taj Pharma 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 Taj Pharma. Patients withdrawn from Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma group. The types of adverse event were unspecified

The RADIANCE trial examined the effects of discontinuation of Digoxin Taj Pharma 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 Taj Pharma, then randomised to continue Digoxin Taj Pharma therapy or change to placebo. The relative risk of worsening disease in the placebo group was 5.9 compared to the Digoxin Taj Pharma group. Withdrawal of Digoxin Taj Pharma 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 Taj Pharma group experienced unspecified side effects.

In the DIG trial, 6800 patients with heart failure were randomised to receive Digoxin Taj Pharma or placebo. No difference was found in all-cause mortality between patients who were treated with Digoxin Taj Pharma and those who were given placebo. In the Digoxin Taj Pharma 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 Taj Pharma had significantly (p<0.001) fewer hospital admissions when the drug was given in addition to diuretics and ACE inhibitors. Digoxin Taj Pharma 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 Taj Pharma arm and 7.9 % of patients in the placebo arm were suspected of having Digoxin Taj Pharma 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 Taj Pharma, 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 Taj Pharma reduces activation of both the sympathetic nervous system and the (renin-angiotensin) system independently of its inotropic actions, and may thus favourably influence survival. Whether this is achieved via direct sympathoinhibitory effects or by re-sensitising baroreflex mechanisms remains unclear.

  • Pharmacokinetic properties

Absorption

The Tmax following IV administration is approximately 1 to 5 hours, while the Tmax for oral administration is 2 to 6 hours. Upon oral administration, Digoxin Taj Pharma is absorbed from the stomach and upper part of the small intestine. When Digoxin Taj Pharma is taken after meals, the rate of absorption is slowed, but the total amount of Digoxin Taj Pharma 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 Taj Pharma is approximately 63 % in tablet form and 75 % as oral solution.

Distribution

The initial distribution of Digoxin Taj Pharma from the central to the peripheral compartment generally lasts from 6 to 8 h. This is followed by a more gradual decline in serum Digoxin Taj Pharma concentration, which is dependent upon Digoxin Taj Pharma elimination from the body. The volume of distribution is large (Vdss = 510 litres in healthy volunteers), indicating Digoxin Taj Pharma to be extensively bound to body tissues. The highest Digoxin Taj Pharma 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 Taj Pharma circulating in plasma, approximately 25 % is bound to protein.

Biotransformation

The majority of Digoxin Taj Pharma 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 Taj Pharma are dihydroDigoxin Taj Pharma and digoxygenin.

Elimination

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

Digoxin Taj Pharma is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of Digoxin Taj Pharma. P-glycoprotein in renal proximal tubules appears to be an important factor in the renal elimination of Digoxin Taj Pharma (see Section 4.5).

Following I.V. administration to healthy volunteers, between 60 and 75 % of a Digoxin Taj Pharma dose is recovered unchanged in the urine over a six day follow-up period. Total body clearance of Digoxin Taj Pharma has been shown to be directly related to renal function, and percent daily loss is thus a function of creatinine clearance. The total and renal clearances of Digoxin Taj Pharma 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 Taj Pharma is converted to cardioinactive reduction products (Digoxin Taj Pharma 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 Taj Pharma 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 Taj Pharma elimination is renal excretion of the unchanged drug.

The terminal elimination half-life of Digoxin Taj Pharma 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 Taj Pharma is not effectively removed from the body during cardiopulmonary by-pass. Furthermore, only about 3 % of a Digoxin Taj Pharma dose is removed from the body during 5 h of haemodialysis.

Special patient populations

Paediatric population

In the newborn period, renal clearance of Digoxin Taj Pharma 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 Taj Pharma clearance has been found to be 65.6 ± 30 ml/min/1.73m2 at three months, compared to only 32 ± 7 ml/min/1.73m2 at one week. By 12 months Digoxin Taj Pharma 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 Taj Pharma is prolonged in patients with impaired renal function, and in anuric patients may be of the order of 100 h.

Hepatic impairment

Hepatic impairment has little effect on Digoxin Taj Pharma clearance.

Elderly

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

Gender

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

  • Preclinical safety data

Carcinogenesis, mutagenesis

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

  1. Pharmaceutical particulars

List of excipients

Also contains: lactose, magnesium stearate, maize starch, pregelatinised maize starch.

Incompatibilities

None known.

Shelf life

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.

Special precautions for storage

Store below 25°C in a dry place.

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) 250µm white rigid PVC. (ii) Surface printed 20µm 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: 5000.

Not all pack size may be marketed.

  • Special precautions for disposal and other handling

Not applicable.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Digoxin Tablets USP 62.5mcg Taj Pharma

Package Leaflet: Information for the User

Digoxin Taj Pharma

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions ask your doctor, pharmacist or nurse.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

  1. What Digoxin Taj Pharma is and what it is used for
  2. What you need to know before you use Digoxin Taj Pharma Tablets
  3. How to use Digoxin Taj Pharma Tablets
  4. Possible side effects
  5. How to store Digoxin Taj Pharma Tablets
  6. Contents of the pack and other information

1. What Digoxin Taj Pharma is and what it is used for

Digoxin Taj Pharma Tablets contains the active substance Digoxin Taj Pharma, which belongs to a group of medicines called cardiac glycosides. It is used to treat arrhythmias and heart failure. An arrhythmia is an irregularity in the heart-beat, which causes the heart to skip a beat, beat irregularly or beat at the wrong speed. This medicine works by correcting irregular heartbeats to a normal rhythm and strengthens the force of the heart-beat, which is why it is useful in heart failure.

  1. What you need to know before you use Digoxin Taj Pharma Tablets

Do not use Digoxin Taj Pharma Tablets if you:

  • Are allergic to Digoxin Taj Pharma, other cardiac glycosides or any of the other ingredients of this medicine (listed in section 6).
  • Have serious heart problems, such as those with the conduction of the electrical impulses in the heart, especially if you have a history of Stokes-Adams attacks (abrupt, short-lived loss of consciousness caused by a sudden change in heart rate or rhythm).
  • Have an irregular heart-beat caused by cardiac glycoside intoxication or conditions such as Wolff-Parkinson-White syndrome.
  • Have obstructive cardiomyopathy (enlargement of the heart muscle).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using this medicine:

  • If you are taking this medicine, your doctor may ask you to have regular blood tests to determine the amount of Digoxin Taj Pharma in the blood. This may be useful in the case of patients with kidney disorders.
  • If you develop Digoxin Taj Pharma toxicity, this can lead to various forms of heart rhythm disturbances, some of which resemble the rhythm disturbances for which the product was prescribed.
  • If you have abnormal heart rhythm (heart block) and you are taking this medicine, contact your doctor immediately if you feel one or more of the following symptoms: fainting, short-lasting loss of consciousness, dizziness or light-headedness, fatigue (tiredness), shortness of breath, chest pain, irregular heart-beat or confusion.
  • If you have a sinoatrial disorder (a disorder in the conduction of electrical impulses in the heart such as Sick Sinus Syndrome), in some patients with a sinoatrial disorder this medicine can cause a slow and/or irregular heart-beat. Sometimes this will cause tiredness, weakness and dizziness and when your heartbeat is very slow you may faint.
  • If you have recently suffered a heart attack.
  • When heart failure occurs along with the collection of an abnormal protein in the heart tissue (cardiac amyloidosis), an alternative therapy may be prescribed by the doctor.
  • If you have myocarditis (inflammation of the heart muscle) this may cause vasoconstriction (narrowing of the blood vessels) on rare occasions. Your doctor may prescribe you a different medicine.
  • If you have Beri-beri disease (caused by a vitamin B1 deficiency).
  • If you have constrictive pericarditis (inflammation of the sac which contains the heart).
  • If you are taking diuretics (drugs which promote urine production and help reduce the amount of water in your body) with or without an ACE inhibitor (mainly used to treat high blood pressure), your doctor will prescribe a lower dose of Digoxin Taj Pharma. Do not stop taking Digoxin Taj Pharma without talking to your doctor.
  • If you have a heart test called an ECG (electrocardiogram), tell the person doing the test that you are taking Digoxin Taj Pharma as it can affect the meaning of the results.
  • If you have severe respiratory (lung) disease (as you may have an increased sensitivity to Digoxin Taj Pharma).
  • If you have low levels of oxygen reaching certain parts of your body, low levels of potassium, abnormally low levels of magnesium or increased levels of calcium in your blood
  • If you have thyroid disease (such as an under-active or over-active thyroid) as you might require changes in the dose of this medicine.
  • If you have malabsorption syndrome (you cannot absorb minerals from your food properly) or if you have ever had gastrointestinal reconstruction surgery.
  • If you will receive electric shock treatment to correct an abnormal heart-beat.

Other medicines and Digoxin Taj Pharma Tablets

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Taking several medicines can sometimes have harmful consequences or lead to unwanted interactions.

Sensitivity to Digoxin Taj Pharma can be increased by medicines which lower the level of potassium in the blood. These include:

  • diuretics,
  • lithium salts (antidepressants),
  • corticosteroid based products,
  • carbenoxolone (a product which strengthens the gastric mucosa).

The following medicines increase the level of Digoxin Taj Pharma in the blood, which can increase the risk of toxicity:

  • certain products which affect the heart: amiodarone, flecainide, prazosin, propafenone, quinidine,
  • canagliflozin (used to treat of type 2 diabetes mellitus),
  • certain antibiotics: erythromycin, clarithromycin, tetracycline, gentamicin, trimethoprim,
  • daclatasvir (used in combination with other medications to treat hepatitis C),
  • flibanserin (used to treat low sexual desire in women who have not gone through menopause),
  • isavuconazole (used to treat fungal infections),
  • itraconazole (used to treat fungal infections),
  • ivacaftor (used to treat cystic fibrosis),
  • spironolactone (a drug which increases the amount of urine you produce),
  • alprazolam (a sedative which may be used to treat anxiety),
  • indomethacin (used to treat inflammation),
  • quinine (may be used to prevent malaria infection),
  • propantheline (used to prevent muscle spasms),
  • mirabegron (used to treat overactive bladder that causes a sudden urge to urinate resulting in involuntary loss of urine),
  • nefazodone (an antidepressant),
  • atorvastatin (lowers blood cholesterol),
  • cyclosporine (an immunosuppressant often used to prevent transplant rejection),
  • epoprostenol (used to treat pulmonary arterial hypertension),
  • tolvaptan (used to treat low blood sodium levels),
  • conivaptan (used to treat low blood sodium levels),
  • carvedilol (used to treat mild to severe congestive heart failure and high blood pressure),
  • ritonavir (used to treat HIV infection and AIDS),
  • taleprevir (used to treat hepatitis C infection),
  • dronedarone (used to treat irregular heart-beat),
  • ranolazine (used to treat chest pain),
  • simeprevir (used in combination with other medications to treat hepatitis C),
  • telmisartan (used to treat high blood pressure),
  • lapatinib (used to treat breast cancer),
  • ticagrelor (used to prevent heart attack or stroke),
  • verapamil (used to treat high blood pressure),
  • felodipine (used to treat high blood pressure),
  • tiapamil (used to treat chest pain),
  • vandetanib (used to treat certain cancers of the thyroid gland),
  • velpatasvir (used in combination with other medications to treat hepatitis C),
  • P-glycoprotein inhibitors.

The following medicines may increase or have no effect on the levels of Digoxin Taj Pharma in the blood:

  • nifedipine, diltiazem, angiotensin receptor blockers (ARBs) and ACE inhibitors (used to treat high blood pressure and congestive heart failure),
  • non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 enzyme (COX-2) inhibitors (used to treat pain and inflammation).

If you have heart failure and are taking sennosides (increase the amount of stools you produce to help you have bowel movements) along with Digoxin Taj Pharma you may have a moderately increased risk of Digoxin Taj Pharma toxicity.

The following medicines reduce the level of Digoxin Taj Pharma in the blood:

  • antacids (used to treat gastric acidity),
  • some bulk-forming laxatives (increase the amount of stools you produce to help you have bowel movements),
  • kaolin-pectin (used to treat diarrhoea),
  • acarbose (used to treat some types of diabetes),
  • certain antibiotics: neomycin, penicillamine, rifampicin,
  • some cytostatic drugs (used as chemotherapy for cancer treatment),
  • metoclopramide (a product for treating nausea and vomiting),
  • sulfasalazine (a product to counteract inflammatory diseases of the intestine),
  • adrenaline (used to treat severe allergic reactions),
  • salbutamol (a product used to treat asthma),
  • colestyramine (lowers blood cholesterol),
  • phenytoin (used to treat epilepsy),
  • John’s wort (Hypericum perforatum) (used to treat depression),
  • bupropion (used to treat depression),
  • P-glycoprotein inducers,
  • supplemental enteral nutrition (being fed by a feeding tube).

If you are taking Digoxin Taj Pharma along with the following medicines you may have an increased risk of irregular heart rhythm:

  • intravenous calcium
  • beta-blockers
  • sympathomimetics (used to treat heart attack and low blood pressure),

If you are taking Digoxin Taj Pharma and suxamethonium (used to help muscle relaxation and treat short-term paralysis), you may have an increased risk of high potassium levels in the blood.

Digoxin Taj Pharma Tablets with food and drink

This medicine may be taken on an empty stomach or with most meals. However, you should avoid taking Digoxin Taj Pharma tablets with foods that are high in fibre, also known as ‘dietary fibre’, because the level of Digoxin Taj Pharma absorbed by the body can be reduced.

Pregnancy, breastfeeding and fertility

Pregnancy

Your doctor will prescribe this medicine with caution during pregnancy.

You may require a higher dose of this medicine if you are pregnant.

This medicine could be given to the mother to treat abnormally high heart rate and congestive heart failure in the unborn child.

Side effects of Digoxin Taj Pharma treatment affecting the mother may also affect the unborn child.

Breastfeeding

This medicine is excreted in breast milk, but in very small amounts. Therefore, this medicine can be used by women who are breast-feeding.

Fertility

There is no information available on the effect of Digoxin Taj Pharma on fertility.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Since dizziness and blurred or yellow vision have been reported, you should exercise caution before driving a vehicle, using machinery or participating in dangerous activities.

Digoxin Taj Pharma tablets contain lactose

Digoxin Taj Pharma tablets contain lactose (a sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

  1. How to take Digoxin Taj Pharma Tablets

This medicine is available as a tablet taken orally.

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Your doctor will have decided how much of this medicine is right for you:

  • It depends on what heart problem you have and how serious it is.
  • It also depends on your age, weight and how well your kidneys work.
  • While you are taking this medicine, your doctor will take regular blood tests. This is to determine how you are responding to treatment.
  • Your doctor will adjust your dose based on your blood test results and on how you are responding to treatment. This is why you must strictly adhere to the treatment course prescribed your doctor.
  • If you have taken another cardiac glycoside in the past 2 weeks, your doctor may prescribe a lower dose.
  • If you feel that the effect of this medicine is too strong or too weak, talk to your doctor or pharmacist.

Taking this medicine

You usually take this medicine in two stages:

  • Stage 1 – loading dose
    The loading dose gets your Digoxin Taj Pharma levels up to the correct level quickly. You will either:
  • take one large single dose and then begin your maintenance dose or
  • take a smaller dose each day for a week and then begin your maintenance dose
  • Stage 2 – maintenance dose
    After your loading dose you will take a much smaller dose every day, until your doctor tells you to stop.

Oral Administration

Adults and children over 10 years

Loading dose

    • Usually between 0.75 and 1.5 mg as a single dose
    • For some patients, this may be given in divided doses 6 hours apart
    • Alternatively, between 0.25 and 0.75 mg may be given each day for a week

Maintenance dose

  • Your doctor will decide this, depending on your response to Digoxin Taj Pharma
  • It is usually between 0.125 and 0.25 mg daily

Children under 10 years

loading dose

  • This is worked out using your child’s weight
  • Usually between 0.025 and 0.045 mg per kg of body weight
  • This should be given in divided doses between 4 and 8 hours apart

maintenance dose

  • The doctor will decide this, depending on your child’s response to Digoxin Taj Pharma
  • It is usually a 1/5 (fifth) or a 1/4 (quarter) of the loading dose, to be taken daily

Elderly

Elderly people may be given a lower dose than the usual adult dose. This is because older people may have reduced kidney function. Your doctor will check the levels of Digoxin Taj Pharma in your blood and may change your dose if necessary.

If you use more Digoxin Taj Pharma Tablets than you should

If you have taken too much of the Digoxin Taj Pharma tablets or a child has taken the medicine by accident, contact your doctor, hospital or poison centre to evaluate the risks and get more information.

The main symptoms of Digoxin Taj Pharma toxicity are heart rhythm disturbances and gastrointestinal symptoms which may happen before heart rhythm disturbances. Gastrointestinal symptoms include loss of appetite, nausea and vomiting. Other symptoms of Digoxin Taj Pharma toxicity include dizziness, fatigue, a general feeling of being unwell and various neurological disturbances including visual disturbances (more yellow-green than usual). The neurological and visual symptoms may persist even after other signs of toxicity have been resolved. In chronic toxicity, non-heart related symptoms, such as weakness and a general feeling of being unwell, may be the main symptoms.

If you forget to use Digoxin Taj Pharma Tablets

Do not take a double dose to make up for the forgotten dose.

If you stop using Digoxin Taj Pharma Tablets

Your doctor will tell you how long you should take Digoxin Taj Pharma. Do not stop your treatment early without consulting your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you get any of the following, talk to your specialist doctor straight away or seek urgent medical advice:

Very rare (may affect up to 1 in 10,000 people)

  • palpitations, chest pain, shortness of breath or sweating. These can be symptoms of a serious heart problem caused by new irregular heartbeats.

Other side effects may include:

Common (may affect up to 1 in 10 people)

  • allergic reactions of the skin may occur (rash, urticaria)
  • abnormal heart-beat
  • nausea, vomiting, diarrhoea
  • central nervous system disturbances such as dizziness
  • visual disturbances (blurred or yellow vision)

Uncommon (may affect up to 1 in 100 people)

  • depression

Very rare (may affect up to 1 in 10,000 people)

  • decrease in blood platelets (symptoms include bruises and nose bleeds)
  • loss of appetite (anorexia)
  • psychosis, apathy, confusion
  • headache
  • stomach pain caused by lack of blood supply or damage to your intestines (ischaemia and necrosis)
  • enlarged breast tissue in men (gynaecomastia)
  • lack of energy (fatigue), a general feeling of being unwell and weakness

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

By reporting side effects, you can help provide more information on the safety of medicine.

  1. How to store Digoxin Taj Pharma Tablets
  • Keep out of the reach and sight of children.
  • Do not use Digoxin Taj Pharma after the expiry date on carton or bottle label (Exp.). The expiry date refers to the last day of that month.
  • Store below 25°C.
  • Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
  1. Contents of the pack and other information

What Digoxin Taj Pharma Tablets contains

  • The active ingredient is Digoxin Taj Pharma, each tablet contains 62.5mcg, 125mcg and 250mcg.
  • The other ingredients are lactose monohydrate, maize starch, modified maize starch, rice starch and magnesium stearate.

What Digoxin Taj Pharma Tablets looks like and contents of the pack

Within the carton is an amber glass bottle that contains 500 white tablets. A white to off white, round, biconvex tablet.

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm 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

Not all pack size may be marketed.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at: Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com