DIXISOL (Digoxin) is a cardiotonic glycoside obtained from the leaves of Digitalis lanata Ehrhart (Family- Scrophulariaceae). Chemically, digoxin is 3b-[(2,6-Dideoxy-b-D-ribo-hexopyranosyl-(1®4)-2,6-dideoxy-b-D-ribo-hexopyranosyl-(1®4)-2,6-dideoxy-b-D-ribo-hexopyranosyl)oxy]-12b,14-dihydroxy-5b-card-20(22)-enolide. The molecular formula is C41H64O14 and molecular weight is 781.

STRUCTURAL  FORMULA : 
Its structural formula is :

DIXISOL is a sterile, nonpyrogenic, clear, colorless solution filled in amber ampoule of suitable size.

COMPOSITION :
Each ml contains :

Administration :
Recommended dosages of DIXISOL may require considerable modification because of individual sensitivity of the patient to the drug, the presence of associated conditions, or the use of concurrent medications. Parenteral administration of digoxin should be used only when the need for rapid digitalization is urgent or when the drug cannot be taken orally. Intramuscular injection can lead to severe pain at the injection site, thus intravenous administration is preferred. If the drug must be administered by the intramuscular route, it should be injected deep into the muscle followed by massage. No more than 500 mcg (2 ml) should be injected into a single site. DIXISOL Injection can be administered undiluted or diluted with a 4-fold or greater volume of Sterile Water for Injection, 0.9 % Sodium Chloride Injection, or 5 % Dextrose Injection. The use of less than a 4-fold volume of diluent could lead to precipitation of the digoxin. Immediate use of the diluted product is recommended. If tuberculin syringes are used to measure very small doses, one must be aware of the problem of inadvertent over administration of digoxin. The syringe should not be flushed with the parenteral solution after its contents are expelled into an indwelling vascular catheter. Slow infusion of DIXISOL Injection is preferable to bolus administration. Rapid infusion of digitalis glycosides has been shown to cause systemic and coronary arteriolar constriction, which may be clinically undesirable. Caution is thus advised and DIXISOL Injection should probably be administered over a period of 5 minutes or longer. Mixing of DIXISOL Injection with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended. 

       

Dosage :
In selecting a dose of digoxin, the following factors must be considered :
1. The body weight of the patient. Doses should be calculated based upon lean (i.e., ideal) body weight.
2. The patients renal function, preferably evaluated on the basis of estimated creatinine clearance.
3. The patients age. Infants and children require different doses of digoxin than adults. Also, advanced age may be indicative of diminished renal function even in patients with normal serum creatinine concentration (i.e., below 1.5 mg/dl).
4. Concomitant disease states, concurrent medications, or other factors likely to alter the pharmacokinetic or pharmacodynamic profile of digoxin.

Heart Failure

Adults :
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. If rapid digitalization is considered medically appropriate, it may be achieved by administering a loading dose based upon projected peak digoxin body stores. Maintenance dose can be calculated as a percentage of the loading dose.

2. More gradual digitalization may be obtained by beginning an appropriate maintenance dose, thus allowing digoxin body stores to accumulate slowly.Steady-state serum digoxin concentrations will be achieved in approximately five half-lives of the drug for the individual patient. Depending upon the patients renal function, this will take between 1 and 3 weeks. 

Rapid digitalization with a loading dose :
DIXISOL Injection is frequently used to achieve rapid digitalization, with conversion to digoxin tablets or digoxin capsules 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 Intramuscular injection of digoxin is extremely painful and offers no advantages unless other routes of administration are contraindicated. Peak digoxin body stores of 8 to 12 mcg/kg should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Because of altered digoxin distribution and elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e., 6 to 10 mcg/kg). 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 loading dose of digoxin, then calculation of the maintenance dose should be based upon the amount actually given. A single initial intravenous dose of 400 to 600 mcg  (0.4 to 0.6 mg) of DIXISOL Injection usually produces a detectable effect in 5 to 30 minutes that becomes maximal in 1 to 4 hours. Additional doses of 100 to 300 mcg (0.1 to 0.3 mg) may be given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate effect is noted. The usual 

amount of DIXISOL Injection that a 70-kg patient requires to achieve x8- to 12-mcg/kg peak body stores is  600  to 1,000 mcg (0.6 to 1.0 mg). 

 

Maintenance Dosing :

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 Dose) 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.)

Table 1 provides average daily maintenance dose requirements of DIXISOL Injection for patients with heart failure based upon lean body weight and renal function :

 

                 

 

^a Daily maintenance doses have been rounded to the nearest 25-mcg increment.
^b Ccr is creatinine clearance, corrected to 70-kg body weight or 1.73 m2 body surface area. For adults, if only 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 multiplied by 0.85. Note : This equation cannot be used for estimating creatinine clearance in infants or children. 
^c If no loading dose administered.
^d 75 mcg = 0.075 mg.

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 dose of 175 mcg (0.175 mg) daily of DIXISOL Injection. If no loading dose is administered, steady-state serum concentrations in this patient should be anticipated at approximately 11days.

Atrial Fibrillation

Peak digoxin body stores larger than the 8 to 12 mcg/kg required for most patients with heart failure and normal sinus rhythm have been used for control of ventricular rate in patients with atrial fibrillation. Doses of digoxin used for the treatment of chronic atrial fibrillation 

should be titrated to the minimum dose that achieves the desired ventricular rate control without causing undesirable side effects. Data are not available to establish the appropriate resting or exercise target rates that should be achieved.
 

CONTRAINDICATIONS :
DIXISOL is contra-indicated in intermittent complete heart block or second degree atrioventricular block, especially if there is a history of Stokes-Adams attacks. DIXISOL is contra-indicated in arrhythmias caused by cardiac glycoside intoxication. DIXISOL 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, DIXISOL is similarly contra-indicated. DIXISOL is contra-indicated in ventricular tachycardia or ventricular fibrillation. DIXISOL is contra-indicated in hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure but even then caution should be exercised if DIXISOL is to be used. DIXISOL is contra-indicated in patients known to be hypersensitive to digoxin or other digitalis glycosides or to any component of the preparation. 

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 ischemia, 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.

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 mothers 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. 

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 patients symptoms are due to digoxin, the clinical state, together with serum electrolyte levels and thyroid function are important factors.