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Digoxin Tablets USP
Presentation

0.25 mg

 

For the use of a Registered Medical Practitioner or a Hospital or a Institution only. 

Used in
Cardiac Failure
Supraventricular Arrhythmias
DESCRIPTION:

DIGOXIN  TABLETS  USP (Digoxin) is a cardiotonic glycoside obtained from the leaves of Digitalis lanata Ehrhart (Family- Scrophulariaceae). Chemically, digoxin is 3β-[(O-2,6-Dideoxy- β-d-ribo-hexopyranosyl-(1®4)-O-2,6-dideoxy-β-d-ribo-hexopyranosyl-(1®4)-2,6-dideoxy-β-d ribo-hexopyranosyl)oxy]-12β,14 dihydroxy-5β-card-20(22)-enolide. The molecular formula is C41H64O14 and molecular weight is 780.94.

STRUCTURAL FORMULA :

Its structural formula is :

Digoxin Tablets USP

DESCRIPTION OF TABLET :

DIGOXIN  TABLETS  USP is blue coloured, circular, biconvex uncoated tablets having score line on one side and ‘SGP’ embossed on the other side.

COMPOSITION :

Each uncoated tablet contains :
Digoxin USP                                0.25 mg
Excipients                                           q.s.

 

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

Digoxin 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 such as diminished impulse conduction rate through the atria and atrio-ventricular node (vagotonic) and senzitisation of the carotid sinus nerves (sympathomimetic). 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 reduces activation of both the sympathetic nervous system and the (renin-angiotensin) system independently of its inotropic actions and may favourably influence survival. Whether this is achieved via direct sympathoinhibitory effects or by re-sensitizing baroreflex mechanisms remains unclear.

PHARMACOKINETICS : 
The absorption of digoxin from the gastrointestinal tract is variable depending upon the formulation used. About 70 % of a dose is absorbed from tablets which comply with B.P. or USP specifications. The generally accepted therapeutic plasma concentration range is       0.5 to 2.0 nanograms/ml but there is considerable inter individual variation. Digoxin has a large volume of distribution and is widely distributed in tissues, including the heart, brain, erythrocytes, and skeletal muscle. The concentration of digoxin in the myocardium is considerably higher than in plasma. From 20 to 30 % is bound to plasma proteins. Digoxin has been detected in cerebrospinal fluid (CSF) and breast milk; it also crosses the placenta. It has an elimination half-life of 1.5 to 2 days. 

Digoxin is mainly excreted unchanged in the urine by glomerular filtration and tubular secretion; reabsorption also occurs. Extensive metabolism has been reported in a minority of patients. Excretion of digoxin is proportional to the glomerular filtration rate. After intravenous injection 50 to 70 % of the dose is excreted unchanged. Digoxin is not removed from the body by dialysis, and only small amounts are removed by exchange transfusion and during cardiopulmonary bypass.

INDICATIONS :  
DIGOXIN  TABLETS  USP is indicated in :

Cardiac Failure :
DIGOXIN  TABLETS  USP is indicated in the management of chronic cardiac failure where the dominant problem is systolic dysfunction. Its therapeutic benefit is greatest in those patients with ventricular dilatation. DIGOXIN  TABLETS  USP is indicated in the management of chronic cardiac failure where the dominant problem is systolic dysfunction. Its therapeutic benefit is greatest in those patients with ventricular dilatation.
 
Supraventricular Arrhythmias :
DIGOXIN TABLETS USP is indicated in the management of certain supraventricular arrhythmias, particularly atrial flutter and fibrillation, where a major beneficial effect is reduction of the ventricular rate.
 
DOSAGE AND ADMINISTRATION :

Administration :
FOR ORAL USE.

Dosage :
Recommended dosages are average values that may require considerable modification because of individual sensitivity or associated conditions. Diminished renal function is the most important factor requiring modification of recommended doses.

In deciding the dose of digoxin, several factors must be considered :
1. The disease being treated. Atrial arrhythmias may require larger doses than heart failure.
2. The body weight of the patient. Doses should be calculated based upon lean or ideal body weight.
3. The patients renal function, preferably evaluated on the basis of creatinine clearance.
4. Age is an important factor in infants and children.
5. Concomitant disease states, drugs or other factors likely to alter the expected clinical response to digoxin.

Digitalization may be accomplished by either of two general approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount of digoxin accumulated in the body.
1. Rapid digitalization may be achieved by administering a loading dose based upon projected peak body dioxin then calculating the maintenance dose as a percentage of the loading dose.
2. More gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing dioxgoxin body stores to accumulate slowly. Stead-state serum digoxin concentrations will be achieved in approximately 5 half-lives of the drug for the individual patient. Depending upon the patients renal function, this will take between one and three weeks.
 
Adults :  Rapid Digitalization with a Loading Dose : Peak body digoxin stores of 8 to 12 μg/kg should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Larger stores (10 to 15 are often required for adequate control of ventricular rate in patients with atrial flutter or fibrillation. Because of altered digoxin distribution and elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e. 6 to 10 μg/kg).
The loading dose should be based on the projected peak body stores and administered in several portions with roughly half the total given as the first dose. Additional fraction of this planned total dose may be given at 6 to 8 hour intervals with careful assessment of clinical response before each additional dose.
 
If the patients clinical response necessitates a change from the calculated dose of digoxin, then the calculation of the maintenance dose should be based on the amount actually given. In previously undigitalized patients, a single initial DIGOXIN  TABLETS  USP dose of 500 to 750 μg (0.5 to 0.75 mg) usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2 to 5 hours. Additional doses of 125 to 375 mg (0.125 to 0.375 mg) may be given continuously at 6 to 8 hour intervals until clinical evidence of an adequate effect is noted. The usual amount of DIGOXIN  TABLETS  USP that a 70 kg patient requires to achieve 8 to 15 μg/kg per peak body stores is 750 to 1250 μg (0.75 to 1.25 mg).
Although peak body stores are mathematically related to loading doses and are utilized to calculate maintenance doses do not correlate with measured serum concentrations. This discrepancy is caused by digoxin distribution within the body during the first 6 to 8 hours following a dose. Serum concentrations drawn during this time are usually not interpretable. 
 
The maintenance dose should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use :
Maintenance Dose = Peak Body Stores (i.e. Loading Doses) x % Daily Loss / 100
Where : % Daily Loss = 14 + Ccr/5
 
Ccr is creatinine clearance, corrected to 70 kg body weight or 1.73 m2 body surface area. For adults, only if serum creatinine concentrations (Scr) are available, a Ccr (corrected to 70 kg body weight) may be estimated in men as 140- Age) /Scr. For women, this result should be a multiplied by 0.85. 
Note : This equation cannot be used for estimating creatinine clearance in infants or children.
 
A common practice involves the use of digoxin injection to achieve rapid digitalization, with conversion to DIGOXIN  TABLETS  USP for maintenance therapy. If patients are switched from intravenous to oral digoxin formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages 
 
Adults : Gradual Digitalization with a Maintenance Dose : The following table provides average DIGOXIN  TABLETS  USP daily maintenance dose requirements for patients with heart failure based upon lean body weight and renal function :
 
Usual DIGOXIN  TABLETS  USP Daily Maintenance Dose Requirements (μg)
For Estimated Peak Body Stores of 10 μg/kg
 
Lean Body Weight (kg/lbs)
 
Digoxin Tablets USP
 
*63 μg=0.063 mg.
+1/2 of 125 μg tablet or 125 μg every other day.
++1/1/2 of 125 μg tablet.
 
Example : Based on the above table, a patient in heart failure with an estimated lean body weight of 70 kg and a Ccr of 60 ml/min, should be given a 250 μg (0.25 mg) DIGOXIN  TABLETS  USP each day, usually taken after the morning meal. Steady-state serum concentrations should not be anticipated before 11 days.
 
Infants and Children : Digitalization must be individualized. Dividend daily dosing is recommended for infants and young children. Children over 10 years of age require adult dosages in proportion to their body weight. 
In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area. Digoxin Injection Paediatric can be used to achieve rapid digitalization, with conversion to an oral DIGOXIN  TABLETS  USP formulation for maintenance therapy. If patients are switched from intravenous to oral digoxin tablets or elixir, allowances must be made for differences in bioavailability when calculating maintenance dosages. 
 
Intramuscular injection digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.
Digitalizing and daily maintenance doses for each age group are given below and should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Larger doses are often required for adequate control of ventricular rate in patients with atrial flutter or fibrillation.
 
The loading dose should be administered in several portions, with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 6 to 8 hour intervals, with careful assessment of clinical response before each additional dose. If the patients clinical response necessitates a change from the calculated dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given. 
 
Digoxin Tablets USP
*I.V. digitalizing doses are 80 % of oral digitalizing doses.
+Divided daily dosing is recommended for children under 10 years of age.
++Projected or actual digitalizing dose providing clinical response.
 
More gradual digitalization can also be accomplished by beginning an appropriate maintenance dose. The range of percentages provided above can be used in calculating this dose for patients with normal renal function. In children with renal disease, digoxin dosing must be carefully titrated based upon clinical response. Long-term use of digoxin is indicated in many children who have been digitalized for acute heart failure, unless the cause is transient. Children with severe congenital heart disease, even after surgery, may require digoxin for prolonged periods.
 
It cannot be overemphasized that both the adult and paediatric dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, ultimate dosage selection must be based upon clinical assessment of the patient.
 
Serum Digoxin Concentrations :  Measurement of serum digoxin concentrations can be helpful to the clinician in determining the state of digitalization and in assigning certain probabilities to the likelihood of digoxin intoxication. Studies in adults considered adequately digitalized (without evidence of toxicity) show that about two-thirds of such patients have serum digoxin levels ranging from 0.8 to 2.0 ng/ml. Patients with atrial fibrillation or atrial flutter require and appear to tolerate higher levels than do patients with other indications. On the other hand, in adult patients with clinical evidence of digoxin toxicity, about two-thirds will have serum digoxin levels greater than 2.0 ng/ml. Thus, whereas levels less than 0.8 ng/ml are infrequently associated with toxicity, levels greater than 2.0 ng/ml are often associated with toxicity. Values in between are not very helpful in deciding whether a certain sign or symptom is more likely caused by digoxin toxicity or by something else. There are rare patients who are unable to tolerate digoxin even at serum concentrations below 0.8 ng/ml. Some researchers suggest that infants and young children tolerate slightly higher serum concentrations than do adults. 
 
To allow adequate time for equilibration of digoxin between serum and tissue, sampling of serum concentrations for clinical use should be at least 6 to 8 hours after the last dose, regardless of the route of administration or formulation used. On a twice daily dosing schedule, there will be only minor differences in serum digoxin concentrations whether sampling is done at 8 or 12 hours after a dose. After a single daily dose, the concentration will be 10 % to 25 % lower when sampled at 24 versus 8 hours, depending upon the patients renal function. Ideally, sampling for assessment of steady-state concentrations should be done just before the next dose.
 

If a discrepancy exists between the reported serum concentration and the observed clinical response, the clinician should consider the following possibilities :

1. Analytical problems in the assay procedure.
2. Inappropriate serum sampling time.
3. Administration of a digitalis glycoside other than digoxin.
4. Conditions causing an alteration in the sensitivity of the patient to digoxin.
5. The patient falls outside the norm in his response to or handling of digoxin. This decision should only be reached after exclusion of the other possibilities and generally should be confirmed by additional correlations of clinical observations with serum digoxin concentrations.
 
The serum concentration data should always be interpreted in the overall clinical context and an isolated serum concentration value should not be used alone as a basis for increasing or decreasing digoxin dosage.
 
Adjustment of Maintenance Dose in Previously Digitalized Patients : DIGOXIN  TABLETS  USP maintenance doses in individual patients on steady-state digoxin can be adjusted upward or downward in proportion to the ratio of the desired versus the measured serum concentration. For example, a patient at steady-state on 125 μg (0.125 mg) per day, with a measured serum concentration of 0.7 ng/ml, should have the dose increased to 250 μg (0.25 mg) per day to achieve a steady-state serum concentration of 1.4 ng/ml, assuming the serum digoxin concentration measurement is correct, renal function remains stable during this time and the needed adjustment is not the result of a problem with compliance.
 
Dosage Adjustment When Changing Preparations : The difference in bioavailability between injectable digoxin or digoxin capsule and digoxin Elixir Paediatric or DIGOXIN  TABLETS  USP must be considered when changing patients from one dosage form to another. digoxin Injection and digoxin capsule doses of 100 μg (0.1 mg) and 200 μg (0.2 mg) are approximately equivalent to 125 μg (0.125 mg) and 250 μg (0.25 mg) doses of DIGOXIN  TABLETS  USP and Elixir Paediatric  Intramuscular injection o f digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated.
 
CONTRAINDICATIONS : 
DIGOXIN  TABLETS  USP is contra-indicated in intermittent complete heart block or second degree atrioventricular block, especially if there is a history of Stokes-Adams attacks. DIGOXIN  TABLETS  USP is contra-indicated in arrhythmias caused by cardiac glycoside intoxication. DIGOXIN  TABLETS  USP is contra-indicated in supraventricular arrhythmias associated with an accessory atrioventricular pathway, as in the Wolff-Parkinson-White syndrome, unless the electrophysiological characteristics of the accessory pathway and any possible deleterious effect of digoxin on these characteristics have been evaluated. If an accessory pathway is known or suspected to be present and there is no history of previous supraventricular arrhythmias, DIGOXIN  TABLETS  USP is similarly contra-indicated. DIGOXIN  TABLETS  USP is contra-indicated in ventricular tachycardia or ventricular fibrillation.
DIGOXIN  TABLETS  USP is contra-indicated in hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure but even then caution should be exercised if DIGOXIN  TABLETS  USP is to be used. DIGOXIN  TABLETS  USP is contra-indicated in patients known to be hypersensitive to digoxin or other digitalis glycosides or to any component of the preparation. DIGOXIN  TABLETS  USP contains lactose which is contra-indicated in patients with galactosaemia, the glucose-galactose malabsorption syndrome, or lactase deficiency.
 
WARNINGS AND PRECAUTIONS :

Arrhythmias may be precipitated by digoxin 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 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. In some cases of sinoatrial disorder (i.e. Sick Sinus Syndrome) digoxin may cause or exacerbate sinus bradycardia or cause sinoatrial block. 

The administration of digoxin in the period immediately following myocardial infarction is not contra-indicated. 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 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.

Treatment with digoxin should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if alternative treatments are not appropriate, digoxin can be used to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation. Digoxin can rarely precipitate vasoconstriction and therefore should be avoided in patients with myocarditis. Patients with beri beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly. DIGOXIN TABLETS  USP should not be used in constrictive pericarditis unless it is used to control the ventricular rate in arterial fibrillation or to improve systolic dysfunction. Digoxin 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. In patients receiving diuretics and an ACE inhibitor, or diuretics alone, the withdrawal of digoxin has been shown to result in clinical deterioration. 

The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electro physiologic effects reflect an expected effect of the drug and are not indicative of toxicity. 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 dosing recommendations should be reconsidered if patients are elderly or there are other reasons for the renal clearance of digoxin being reduced. A reduction in both initial and maintenance doses should be considered. Patients receiving DIGOXIN  TABLETS  USP should have their serum electrolytes and renal function (serum creatinine concentration) assessed periodically; the frequency of assessments will depend on the clinical setting.

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, 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. DIGOXIN  TABLETS  USP should be used cautiously in diabetic patients.

Laboratory Tests : 
Patients receiving digoxin should have their serum electrolytes and renal function (BUN and/or serum creatinine) assessed periodically; the frequency of assessments will depend on the clinical setting.

PREGNANCY AND LACTATION :

Pregnancy : Category C

Teratogenic Effects :
Animal reproduction studies have not been conducted with digoxin. It is also not known whether digoxin can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Digoxin should be given to a pregnant woman only if clearly needed.

Nursing mothers :
Studies have shown that digoxin concentrations in the mother’s serum and milk are similar. However, the estimated exposure of a nursing infant to digoxin via breastfeeding will be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is administered to a nursing woman. 

Paediatric Use :
Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion. 

INTERACTIONS  AND  INCOMPATIBILITIES :
Potassium-depleting diuretics are a major contributing factor to digitalis toxicity. Calcium, particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. Quinidine, verapamil, amiodarone, propafenone, indomethacin, itraconazole, alprazolam, and spironolactone raise the serum digoxin concentration due to a reduction in clearance and/or volume of distribution of the drug, with the implication that digitalis intoxication may result. Erythromycin and clarithromycin (and possibly other macrolide antibiotics) and tetracycline may increase digoxin absorption in patients who inactivate digoxin by bacterial metabolism in the lower intestine, so that digitalis intoxication may result. Propantheline and diphenoxylate, by decreasing gut motility, may increase digoxin absorption. Antacids, kaolin-pectin, sulfasalazine, neomycin, cholestyramine, certain anticancer drugs, and metoclopramide may interfere with intestinal digoxin absorption, resulting in unexpectedly low serum concentrations. Rifampin may decrease serum digoxin concentration, especially in patients with renal dysfunction, by increasing the non-renal clearance of digoxin. There have been inconsistent reports regarding the effects of other drugs (e.g., quinine, Penicillamine) on serum digoxin concentration. Thyroid administration to a digitalized, hypothyroid patient may increase the dose requirement of digoxin. Concomitant use of digoxin and sympathomimetics increases the risk of cardiac arrhythmias. Succinylcholine may cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in digitalized patients. Although calcium channel blockers and digoxin may be useful in combination to control atrial fibrillation, their additive effects on AV node conduction can result in advanced or complete heart block. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15 % when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol. 

EFFECTS  ON  ABILITY  TO  DRIVE  AND  USE  MACHINES :
Since central nervous system and visual disturbances have been reported in patients receiving DIGOXIN  TABLETS  USP, patients should exercise caution before driving, using machinery or participating in dangerous activities.

SIDE  EFFECTS :
In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions. Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as : very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (1/10,000), including isolated reports. Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare (including isolated reports).

Blood and lymphatic system disorders : 
Very rare : Thrombocytopaenia

Metabolism and nutrition disorders :
Very rare : Anorexia

Psychiatric disorders :
Uncommon : Depression
Very rare : Psychosis, apathy, confusion.

Nervous system disorders :
Common : CNS disturbances, dizziness.
Very rare : Headache

Eye disorders :
Common : Visual disturbances (blurred or yellow vision)

Cardiac disorders :
Common : Arrhythmia, conduction disturbances, bigeminy, trigeminy, PR prolongation, sinus bradycardia.
Very rare : Supraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, ventricular premature contraction, ST segment depression.

Gastrointestinal disorders :
Common : Nausea, vomiting, diarrhoea.
Very rare : Intestinal ischaemia, intestinal necrosis.

Skin disorders :
Common : Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia.

Reproductive system and breast disorders :
Very rare : Gynaecomastia can occur with long term administration.

General disorders and administration site conditions :
Very rare : Fatigue, malaise, weakness.

Eye disorders :
Common : Visual disturbances (blurred or yellow vision)

Cardiac disorders :
Common : Arrhythmia, conduction disturbances, bigeminy, trigeminy, PR prolongation, sinus bradycardia.
Very rare : Supraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, ventricular premature contraction, ST segment depression.
 

OVERDOSAGE:

Symptoms and signs :
The systems and signs of toxicity are generally similar to those described in the Side effects section but may be more frequent and can be more severe. Signs and symptoms of digoxin toxicity become more frequent with levels above 3.0 nanograms/ml (3.84 nanomol/l) although there is considerable interindividual variation. However, in deciding whether a patient’s symptoms are due to digoxin, the clinical state, together with serum electrolyte levels and thyroid function are important factors. 

Adults :
In adults without heart disease clinical observation suggests that an overdose of digoxin of 10 -15 mg was the dose resulting in death of half of the patients. If more than 25 mg of digoxin was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments resulted.
 
Cardiac manifestations :
Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3 to 6 hours following overdosage and may persist for the ensuing 24 hours or longer. Digoxin toxicity may result in almost any type of arrhythmia. Multiple rhythm disturbances in the same patient are common. These include paroxysmal atrial tachycardia with variable atrioventricular (AV) block, accelerated junctional rhythm, slow atrial fibrillation (with very little variation in the ventricular rate) and bi directional ventricular tachycardia. Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmia. Bigeminy or trigeminy also occur frequently. Sinus bradycardia and other bradyarrhythmias are very common. First, second, third degree heart blocks and AV dissociation are also common. Early toxicity may only be manifested by prolongation of the PR interval. Ventricular tachycardia may also be a manifestation of toxicity. Cardiac arrest from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal. Acute massive digoxin overdosage 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 extracardiac symptoms, such as malaise and weakness, may predominate.
 
Children :
In children aged 1 to 3 years without heart disease, clinical observation suggests that an overdose of digoxin of 6 to 10 mg was the dose resulting in death in half of the patients. If more than 10 mg of digoxin was ingested by a child aged 1 to 3 years without heart disease, the outcome was uniformly fatal when Fab fragment treatment was not given. Most manifestations of toxicity in children occur during or shortly after the loading phase with digoxin.
 
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 should be assumed to be caused by digoxin, until further evaluation proves otherwise.
 
TREATMENT  OF  OVERDOSAGE :
In addition to cardiac monitoring, digoxin should be temporarily discontinued until the adverse reaction resolves and may be all that is required to treat the adverse reaction such as in asymptomatic bradycardia or digoxin related heart block. Every effort should also be made to correct factors that may contribute to the adverse reaction (such as electrolyte disturbances, thyroid function, or concurrent medications) Once the adverse reaction has resolved, therapy with digoxin may be reinstituted, following a careful reassessment of dose. When the primary manifestation of digoxin overdosage is a cardiac arrhythmia, additional therapy may be needed. If the rhythm disturbance is a symptomatic bradyarrhythmia or heart block, consideration should be given to the reversal of toxicity with Digoxin Immune Fab (Ovine), the use of atropine, or the insertion of a temporary cardiac pacemaker. Digoxin Immune Fab (Ovine) is a specific antidote for digoxin and may be used to reverse potentially life-threatening ventricular arrhythmias due to digoxin overdosage. 
 
Administration of Potassium : 
Before administering potassium in digoxin overdose for hypokalaemia, the serum potassium must be known and every effort should be made to maintain the serum potassium concentration between 4 and 5.5 mmol/l. Potassium salts should be avoided as they may be dangerous in patients who manifest bradycardia or heart block due to digoxin (unless primarily related to supraventricular tachycardia) and in the setting of massive digitalis overdosage. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and the serum potassium concentration is low, potassium may be administered cautiously by the intravenous route. The electrocardiogram should be monitored for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia.
 
Massive Digitalis Overdosage : 
Manifestations of life-threatening toxicity include ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias, or heart block. Digoxin Immune Fab (Ovine) should be used to reverse the toxic effects of ingestion of a massive overdose. The decision to administer Digoxin Immune Fab (Ovine) to a patient who has ingested a massive dose of digoxin but who has not yet manifested life-threatening toxicity should depend on the likelihood that life-threatening toxicity will occur. Digoxin is not effectively removed from the body by dialysis due to its large extravascular volume of distribution. Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation. Emesis may be indicated especially if ingestion has occurred within 30 minutes of the patient’s presentation at the hospital. Emesis should not be induced in patients who are obtunded. If a patient presents more than 2 hours after ingestion or already has toxic manifestations, it may be unsafe to induce vomiting because such maneuvers may induce an acute vagal episode that can worsen digitalis-related arrhythmias.
 
STORAGE : 
Store below 30°C (86° F), protected from moisture and light. 
Do not refrigerate.
 
SHELF  LIFE :
24 months from the date of manufacture.
 
PRESENTATION :
DIGOXIN TABLETS USP contains digoxin USP 0.25 mg.
10 Blisters of 10 Tablets per box.
 
 
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.
 
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