Digoxin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIGOXIN

Composition:

Active substance: digoxin;

1 tablet contains digoxin equivalent to 100% content of the main substance 0.1 mg;

Excipients: sugar, potato starch, glucose, mineral oil, talc, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white tablets.

Pharmacotherapeutic group. Cardiology preparations. Cardiac glycosides. Digitalis glycosides. ATC code C01AA05.

Pharmacological Properties

Pharmacodynamics

Digoxin is a highly lipophilic cardiac glycoside with intermediate duration of action, derived from the leaves of Digitalis lanata. It exerts a positive inotropic effect by forming a complex with Na⁺-K⁺-ATPase, thereby disrupting the transport of sodium and potassium ions across the membranes of cardiomyocytes. As a result, transmembrane calcium ion transport increases and intracellular calcium release within cardiomyocytes is enhanced, leading to increased myofibrillar activity. Digoxin slows AV conduction, prolongs the effective refractory period, and reduces heart rate primarily by increasing parasympathetic tone and decreasing sympathetic tone of the autonomic nervous system.

Pharmacokinetics

The drug is well absorbed from the gastrointestinal tract. Its bioavailability ranges from 50% to 80%, depending on gastric acidity, intestinal motility, and blood supply to the stomach and intestines. Digoxin is 20–40% bound to plasma proteins. The ratio of digoxin concentration in serum to that in myocardium is approximately 1:67. About 80–85% of the drug is excreted unchanged by the kidneys (via glomerular filtration and tubular secretion), while the remainder undergoes hepatic biotransformation and is eliminated as inactive metabolites in feces. In children under 12 years of age, digoxin undergoes practically no biotransformation. After oral administration, the onset of action occurs within 1.5–3 hours, with peak effect reached at 4–6 hours. The elimination half-life of digoxin is 30–40 hours and depends on the patient's health status and age (the half-life is prolonged when the ratio of connective tissue to body mass increases). Impaired renal filtration and secretory function make digoxin administration hazardous due to drug accumulation (the half-life may extend to 6–8 days). A reduction in endogenous creatinine clearance to 50 mL/min necessitates a reduction in the maintenance dose by 1/3–1/2. Children under 10–12 years of age exhibit reduced sensitivity to cardiac glycosides, particularly digoxin, requiring higher doses compared to adolescents and adults to achieve a therapeutic effect.

Clinical characteristics.

Indications. Congestive heart failure, atrial fibrillation and atrial flutter (for control of ventricular rate), supraventricular paroxysmal tachycardia.

Contraindications.

• Hypersensitivity to components of the drug/other cardiac glycosides;
• Digitalis intoxication due to previously administered cardiac glycosides;
• History of glycoside-induced arrhythmias;
• Marked sinus bradycardia, second- or third-degree AV block, Adams-Stokes-Morgagni syndrome;
• Carotid sinus syndrome;
• Hypertrophic obstructive cardiomyopathy;
• Supraventricular arrhythmias associated with accessory AV conduction pathways, including Wolff-Parkinson-White syndrome;
• Ventricular paroxysmal tachycardia/ventricular fibrillation;
• Thoracic aortic aneurysm;
• Subaortic hypertrophic stenosis;
• Isolated mitral stenosis;
• Endocarditis, myocarditis, unstable angina pectoris, acute myocardial infarction, constrictive pericarditis, cardiac tamponade;
• Hypercalcemia, hypokalemia.

Interaction with other medicinal products and other forms of interaction. Agents causing hypokalemia may increase sensitivity to digoxin (e.g., certain diuretics, lithium salts, glucocorticosteroids).

Serum digoxin concentration measurements using microparticle chemiluminescent immunoassay (CMIA) during enzalutamide treatment may yield falsely elevated serum digoxin levels. Results should be confirmed by another analytical method (see section "Special precautions for use").

Serum digoxin concentrations may increase when co-administered with the following drugs: amiodarone, prazosin, propafenone, quinidine, spironolactone, tetracycline, erythromycin, gentamicin, indomethacin, quinine, trimethoprim, itraconazole, alprazolam, verapamil, felodipine, nifedipine.

Serum digoxin concentrations may decrease when co-administered with the following drugs: antacids, kaolin-pectin, certain laxatives, cholestyramine, sulfasalazine, neomycin, rifampicin, certain cytostatics, penicillamine, metoclopramide, adrenaline, salbutamol.

Adrenergic agents. Concomitant use of hydrochloride ephedrine, hydrochloride adrenaline, hydrochloride noradrenaline, or selective beta-adrenergic agents with cardiac glycosides may induce cardiac arrhythmias.

Chlorpromazine and other phenothiazine derivatives. The effect of cardiac glycosides is reduced.

Anticholinesterase agents. Concomitant use of anticholinesterase agents with cardiac glycosides intensifies bradycardia. If necessary, this can be counteracted or reduced by administration of atropine sulfate.

Glucocorticosteroids. Hypokalemia resulting from prolonged glucocorticosteroid therapy may increase the adverse effects of cardiac glycosides.

Diuretics. When diuretics (which cause hypokalemia and hypomagnesemia but increase serum calcium ion concentration) are combined with cardiac glycosides, the effect of the latter is enhanced. Optimal dosing should be maintained during concomitant use. Potassium-sparing diuretics (spironolactone, triamterene) may be administered periodically to correct hypokalemia and prevent arrhythmias. However, hyponatremia may develop under these conditions.

Potassium preparations. Undesirable effects of cardiac glycosides are reduced under the influence of potassium preparations.

Calcium preparations. Parenteral administration of calcium preparations during therapy with cardiac glycosides is dangerous, as cardiotoxic effects (arrhythmias) are intensified.

Disodium edetate (EDTA). Reduced efficacy and toxicity of cardiac glycosides may occur.

Corticotropic preparations. The action of cardiac glycosides may be enhanced under the influence of corticotropin.

Xanthine derivatives. Caffeine or theophylline preparations may occasionally induce cardiac arrhythmias.

Sodium adenosine triphosphate. Sodium adenosine triphosphate should not be administered concomitantly with cardiac glycosides.

Activated charcoal. Due to reduced gastrointestinal absorption, the action of cardiac glycosides is often diminished.

Ergocalciferol. In cases of ergocalciferol-induced hypervitaminosis, the effect of cardiac glycosides may be enhanced due to hypercalcemia.

Narcotic analgesics. The combination of fentanyl and cardiac glycosides may cause arterial hypotension.

Naproxen. In healthy individuals, combination of cardiac glycosides with naproxen does not affect results of psychological testing.

Paracetamol. The clinical significance of this interaction has not been fully studied, but data suggest decreased renal excretion of cardiac glycosides under the influence of paracetamol.

Dofetilide: increased risk of torsades de pointes arrhythmia.

Moracizine: possible additive effects on cardiac conduction, significant QT interval prolongation, which may lead to AV block.

Muscle relaxants (edrophonium, succinylcholine, pancuronium, tizanidine): possible potentiation of arterial hypotension, excessive bradycardia, and AV block due to rapid potassium efflux from myocardial cells. Concomitant use should be avoided.

β-adrenoblockers, including sotalol, and calcium channel blockers: increased risk of proarrhythmic events; additive effects on AV nodal conduction may lead to bradycardia and complete heart block.

Phenytoin: intravenous phenytoin should not be used to treat digoxin-induced arrhythmias due to the risk of cardiac arrest.

Colchicine: possible increased risk of myopathy.

Mefloquine: possible increased risk of bradycardia.

Etoricoxib, ketoprofen, meloxicam, piroxicam, and rofecoxib do not increase digoxin plasma levels.

Special precautions for use.

Patients receiving digoxin must be under medical supervision. During long-term therapy, the optimal individual dose is usually determined by the physician over 7–10 days.

Dosage must be selected particularly carefully in elderly and/or debilitated patients, patients with impaired renal function, or those with implanted cardiac pacemakers, as toxic effects may occur at doses that are generally well tolerated by other patients.

The risk of digoxin toxicity is increased in patients with hypokalemia, hypomagnesemia, hypercalcemia, hypernatremia, hypothyroidism, or cor pulmonale. Such patients should avoid high single doses of digoxin.

The drug is contraindicated in hypertrophic obstructive cardiomyopathy and should be used with caution in patients with concomitant atrial fibrillation and heart failure.

Digoxin should be used cautiously in patients with thyroid disorders. In patients with reduced thyroid function, initial and maintenance doses of digoxin should be reduced. In hyperthyroidism, there is relative resistance to digoxin, which may necessitate higher doses. During treatment of thyrotoxicosis, digoxin doses should be reduced once the thyrotoxic state is brought under control.

Higher doses of digoxin may be required in patients with short bowel syndrome or malabsorption syndrome due to impaired absorption.

During digoxin therapy, regular monitoring of ECG and serum electrolyte levels (potassium, calcium, magnesium) is necessary. Electrolyte imbalances should be corrected, as hypokalemia and hypomagnesemia enhance the toxicity of cardiac glycosides.

Digoxin should be used with particular caution in elderly patients. Given that elimination half-life is prolonged in elderly patients, there is an increased risk of adverse effects and potential overdose.

If strophanthin is required, it should not be administered earlier than 24 hours after discontinuation of digoxin.

During treatment, intake of hard-to-digest foods and products containing pectins should be limited.

If a patient has known sugar intolerance, medical advice should be sought before taking this medicinal product.

Interference with laboratory tests. In patients receiving enzalutamide, falsely elevated serum digoxin levels may be observed when samples are analyzed using a chemiluminescent immunoassay with microparticles (CMIA), regardless of digoxin administration. In case of questionable results, serum digoxin levels should be confirmed using an alternative assay method not subject to such interference, to avoid inappropriate discontinuation or dose reduction of digoxin (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding. Information regarding potential teratogenic effects of digoxin is lacking. It should be noted that digoxin crosses the placenta and its clearance is prolonged during pregnancy.

Digoxin may be used during pregnancy only if, in the physician’s opinion, the expected benefit to the mother outweighs the potential risk to the fetus.

Digoxin passes into breast milk in amounts that do not adversely affect the infant (digoxin concentration in breast milk is 0.6–0.9% of the maternal plasma concentration). When digoxin is administered to breastfeeding women, the infant’s heart rate should be monitored.

Effect on ability to drive and use machines. Generally, digoxin does not affect this ability. However, considering possible nervous system-related adverse effects, patients should be advised to avoid driving or operating machinery during treatment.

Method of administration and dosage.

Adults: for rapid digitalization, administer orally 0.5–1 mg initially, then 0.25–0.75 mg every 6 hours for 2–3 days. After the patient's condition improves, switch to a maintenance dose (0.125–0.5 mg daily in 1–2 doses). For slow digitalization, initiate treatment directly with the maintenance dose (0.125–0.5 mg daily in 1–2 doses); in this case, complete digitalization is achieved approximately 1 week after starting therapy. The maximum daily dose for adults is 1.5 mg.

Children:

The dosage for children must be determined individually, taking into account the chosen digitalization regimen, age, and body weight of the child.

Children. The drug can be used in children.

Overdose.

Symptoms:

Cardiovascular system: arrhythmias, including bradycardia, atrioventricular block, ventricular tachycardia or extrasystoles, ventricular fibrillation;

Gastrointestinal tract: anorexia, nausea, vomiting, diarrhea;

Central nervous system and sensory organs: headache, increased fatigue, dizziness, rarely – color vision disturbances, decreased visual acuity, scotoma, metamorphopsia (macropsia and micropsia), very rarely – confusion, syncope.

Treatment: gastric lavage, administration of activated charcoal, cholestyramine or colestipol. In case of arrhythmia, intravenous infusion of 2–2.4 g of potassium chloride with 10 IU of insulin in 500 ml of 5% glucose solution (infusion should be discontinued when serum potassium concentration reaches 5 mEq/L). Potassium-containing agents are contraindicated in atrioventricular conduction disturbances. In case of pronounced bradycardia, administer atropine sulfate solution. Oxygen therapy is indicated. For detoxification, unithiol (dimercaptopropanol) and ethylenediaminetetraacetic acid (EDTA) may also be used. Treatment is symptomatic.

In case of hypokalemia developing without complete heart block, potassium supplements should be administered. In complete heart block, cardiac pacing is required. For arrhythmias, lidocaine, procainamide, or phenytoin may be used.

In life-threatening digoxin overdose, administration of digoxin-specific ovine antibody fragments through a membrane filter is indicated (Digoxin immune Fab, Digitalis-Antidote BM); 40 mg of the antidote binds approximately 0.6 mg of digoxin.

Dialysis and exchange blood transfusion are poorly effective in poisoning with cardiac glycosides.

Adverse Reactions.

Cardiovascular system: rhythm and conduction disturbances (sinus bradycardia, extrasystoles, atrioventricular block, paroxysmal atrial tachycardia, ventricular fibrillation, ventricular arrhythmias).

Blood system: rarely – eosinophilia, thrombocytopenia, agranulocytosis.

Immune system: hypersensitivity reactions, including itching, hyperemia, rash, including erythematous, papular, maculopapular, vesicular; urticaria, angioedema (Quincke's edema).

Endocrine system: digoxin has estrogenic activity, therefore gynecomastia in men is possible with prolonged use.

Psychiatric disorders: disorientation, confusion, amnesia, depression; acute psychosis, delirium, visual and auditory hallucinations may occur, especially in elderly patients; seizures have been reported.

Nervous system: headache, neuralgia, increased fatigue, weakness, dizziness, drowsiness, unpleasant dreams, restlessness, nervousness, excitement, apathy.

Eye disorders: blurred vision, photophobia, halo effect, disturbances in visual perception (perceiving surrounding objects in green, white or yellow colors).

Gastrointestinal tract: anorexia, nausea, vomiting, abdominal pain, diarrhea, impaired visceral circulation, intestinal ischemia and necrosis.

Adverse reactions to digoxin are dose-dependent and usually occur with doses exceeding those required to achieve a therapeutic effect. Dosages should be carefully selected and adjusted according to the patient's clinical condition.

Shelf life. 4 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging. Tablets, 50 in bottles or containers; 50 in bottles or containers in a carton; 25 in blisters; 25x2 in blisters in a carton; 10x5 in blisters in a carton.

Prescription category. Prescription only.

Manufacturer.

Limited Liability Company "Experimental Plant 'GNCLC'", or

Limited Liability Company "FARMEKS GROUP", or

LIMITED LIABILITY COMPANY "CORPORATION 'ZDOROVIYA'".

Manufacturer's address and place of business.

Ukraine, 61057, Kharkiv region, city of Kharkiv, Vorobiova Street, building 8.

(Limited Liability Company "Experimental Plant 'GNCLC'")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, building 100.

(Limited Liability Company "FARMEKS GROUP")

Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, building 22.

(LIMITED LIABILITY COMPANY "CORPORATION 'ZDOROVIYA'")