Digoxin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIGOXIN (Digoxin)

Composition:

Active substance: digoxin;

1 tablet contains digoxin (calculated as 100 % substance) 0.25 mg;

Excipients: microcrystalline cellulose, lactose monohydrate, corn starch, calcium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round-shaped tablets with a biconvex surface.

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

Pharmacological properties.

Pharmacodynamics.

Digoxin is a cardiac glycoside of intermediate duration of action, obtained from the leaves of Digitalis lanata. It exerts a positive inotropic effect, increases systolic and stroke volumes of the heart, prolongs the effective refractory period, slows AV conduction, and reduces heart rate. The use of digoxin in chronic heart failure leads to improved cardiac contractility. Digoxin also produces a moderate diuretic effect.

Pharmacokinetics.

The drug is rapidly and almost completely absorbed from the gastrointestinal tract. Therapeutic plasma concentrations of digoxin are achieved within 1 hour, and peak concentrations occur within 1.5 hours after administration. Onset of action occurs within 30 minutes to 2 hours after intake. Concomitant intake with food reduces the rate, but not the extent, of absorption.

A small amount undergoes hepatic biotransformation. Digoxin crosses the placenta and is excreted into breast milk in small amounts.

The elimination half-life averages 58 hours and depends on the patient's age and health status (36 hours in younger individuals, 68 hours in elderly individuals). It is considerably prolonged in renal insufficiency. In anuria, the half-life may extend to several days. 50–70% of the drug is excreted unchanged in the urine.

Clinical characteristics.

Indications.

• Congestive heart failure;
• Atrial fibrillation and atrial flutter (for control of ventricular rate);
• Supraventricular paroxysmal tachycardia.

Contraindications.

• Hypersensitivity to digoxin, other cardiac glycosides, or any component of the drug;
• Digitalis intoxication from previously administered digitalis preparations;
• Arrhythmias caused by glycoside intoxication in medical history;
• Marked sinus bradycardia, second- or third-degree AV block, Adams-Stokes-Morgagni syndrome;
• Carotid sinus syndrome;
• Hypertrophic obstructive cardiomyopathy;
• Supraventricular arrhythmias associated with accessory atrioventricular 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, acute myocardial infarction, constrictive pericarditis, cardiac tamponade;
• Hypercalcemia, hypokalemia.

Interaction with other medicinal products and other forms of interaction.

Digoxin is a substrate for P-glycoprotein. Medicinal products that induce or inhibit P-glycoprotein affect the pharmacokinetics of digoxin (intestinal absorption, renal clearance), altering its blood concentration.

Pharmacokinetic interactions

Medicinal products increasing digoxin blood concentration by > 50 %

Amiodarone, dronedarone, flecainide, disopyramide, propafenone, quinidine, quinine, captopril, prazosin, nitrendipine, ranolazine, ritonavir, verapamil, felodipine, tiapamil – digoxin dose should be reduced by 30–50 % when co-administered, with continued monitoring of plasma digoxin levels.

Medicinal products increasing digoxin blood concentration by < 50 %

Carvedilol, diltiazem, nifedipine, nicardipine, lercanidipine, rabeprazole, telmisartan – serum digoxin concentrations should be measured before initiating concomitant therapy. Reduce digoxin dose by approximately 15–30 % and continue monitoring.

Medicinal products increasing digoxin blood concentration (magnitude not established)

Alprazolam, diazepam, atorvastatin, azithromycin, clarithromycin, erythromycin, telithromycin, gentamicin, chloroquine, hydroxychloroquine, trimethoprim, cyclosporine, diclofenac, indomethacin, aspirin, ibuprofen, diphenoxylate, epoprostenol, esomeprazole, itraconazole, ketoconazole, lansoprazole, metformin, omeprazole, propantheline, nefazodone, trazodone, topiramate, spironolactone, tetracycline – measure serum digoxin concentrations before starting concomitant medications. Reduce digoxin dose if necessary and continue monitoring.

Loperamide: increased digoxin absorption due to reduced intestinal peristalsis.

Medicinal products decreasing digoxin blood concentration

Acarbose, adrenaline (epinephrine), activated charcoal, antacids, certain cytostatics, cholestyramine, colestipol, exenatide, kaolin-pectin, certain laxatives, sodium nitroprusside, hydralazine, metoclopramide, miglitol, neomycin, penicillamine, carbimazole, rifampicin, salbutamol, sucralfate, sulfasalazine, phenytoin, barbiturates, phenylbutazone, high-bran diet, St. John’s wort preparations – measure serum digoxin concentrations before initiating concomitant therapy. Increase digoxin dose if necessary by 20–40 % and continue monitoring.

Pharmacodynamic interactions

Diuretics (including acetazolamide, loop and thiazide diuretics, potassium-sparing diuretics): hypokalemia, hypomagnesemia, and hypercalcemia induced by diuretics may increase digoxin cardiotoxicity and the risk of arrhythmias. Diuretics may also slightly reduce renal tubular secretion of digoxin, leading to increased plasma levels. Potassium supplements should be administered as needed, and electrolyte imbalances corrected. Potassium-sparing diuretics (spironolactone, triamterene) may be intermittently prescribed to correct hypokalemia and arrhythmias. However, hyponatremia may develop. Optimal dosing should be maintained when combining diuretics with cardiac glycosides.

Potassium preparations: adverse effects of cardiac glycosides are reduced under the influence of potassium supplements.

Corticosteroids, corticotropin preparations, carbenoxolone cause potassium loss and sodium and fluid retention, thereby increasing digoxin toxicity and the risk of arrhythmias and heart failure. Patients on prolonged corticosteroid therapy should be closely monitored.

Amphotericin, lithium salts: hypokalemia induced by these agents may increase digoxin cardiotoxicity and the risk of arrhythmias.

Calcium preparations, especially with rapid intravenous administration, may lead to severe arrhythmias in digitalized patients. Intravenous calcium preparations enhance glycoside toxicity; therefore, their concomitant use is not recommended.

Vitamin D and its analogs (e.g., ergocalciferol), teriparatide may increase digoxin toxicity due to elevated plasma calcium levels.

Disopyramide: increased risk of torsades de pointes-type arrhythmia.

Moracizine: possible additive effects on cardiac conduction, significant QT interval prolongation, potentially leading to AV block.

Adrenergic agents: adrenaline (epinephrine), noradrenaline, dopamine, selective β2-receptor agonists (including salbutamol), tricyclic antidepressants, reserpine may increase the risk of arrhythmias.

Neuromuscular blocking agents (edrophonium, succinylcholine, pancuronium, tizanidine): possible exacerbation of arterial hypotension, excessive bradycardia, and atrioventricular block due to rapid potassium efflux from myocardial cells. Concomitant use should be avoided.

Beta-adrenergic blockers, 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.

ACE inhibitors and angiotensin II antagonists: may cause hyperkalemia, which may reduce digoxin tissue binding and result in higher serum digoxin levels. These drugs may also impair renal function and, due to reduced renal excretion, increase serum digoxin levels. Concomitant use of captopril has been associated with increased plasma digoxin levels, but this may be clinically significant only in patients with impaired renal function or severe congestive heart failure.

Use of telmisartan has also been associated with increased plasma digoxin levels; therefore, patients receiving this combination should be monitored.

No clinically significant interaction has been reported with other ACE inhibitors (cilazapril, enalapril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril) or with other angiotensin II antagonists (candesartan, eprosartan, irbesartan, losartan, valsartan), but monitoring the effects of digoxin when used concomitantly with these agents is still advisable.

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.

Xanthine derivatives: caffeine- or theophylline-containing preparations may occasionally induce arrhythmias.

Chlorpromazine and other phenothiazine derivatives: reduce the effect of cardiac glycosides.

Anticholinesterase agents: enhanced bradycardia. If necessary, this can be counteracted or reduced by administration of atropine sulfate.

Sodium adenosine triphosphate: should not be used concomitantly with cardiac glycosides in high doses, as this increases the risk of cardiovascular adverse reactions.

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

Disodium ethylenediaminetetraacetate: decreased efficacy and toxicity of cardiac glycosides have been observed.

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

Naproxen: as a representative of the NSAID class, may increase plasma concentrations of cardiac glycosides and may also exacerbate heart failure and impair renal function.

Paracetamol: clinical significance of this interaction is insufficiently studied, but data suggest reduced renal excretion of cardiac glycosides under the influence of paracetamol.

Thyroid hormones: dose adjustment of glycosides may be required when administered to hypothyroid patients.

Special precautions for use.

Digoxin therapy must be administered under the supervision of a physician. During prolonged treatment, the optimal individual dose is usually determined within 7–10 days.

If the patient has received other cardiac glycosides within the previous two weeks, digoxin therapy should be initiated at lower doses. If strophanthin is required, it should not be administered earlier than 24 hours after discontinuation of digoxin.

The drug should be used with particular caution in:

• Elderly patients – reduced renal function and low muscle mass commonly observed in elderly individuals affect digoxin pharmacokinetics: higher serum digoxin levels and prolonged elimination half-life, increasing the risk of adverse reactions, cumulative effects, and potential overdose;
• Weakened patients, patients with impaired renal function, and patients with implanted cardiac pacemakers, as toxic effects may develop even at doses usually well tolerated by others. Renal dysfunction is the most common cause of glycoside intoxication;
• Patients with concomitant atrial fibrillation and heart failure;
• Patients with thyroid disorders – in hypothyroidism, initial and maintenance doses of digoxin should be reduced; in hyperthyroidism, relative resistance to digoxin may occur, requiring higher doses. During treatment of thyrotoxicosis, digoxin doses should be reduced as the condition becomes controlled. Changes in thyroid function may affect sensitivity to digoxin independently of its plasma concentration;
• Patients with short bowel syndrome or malabsorption syndrome – impaired digoxin absorption may require higher doses;
• Patients with severe respiratory diseases – increased myocardial sensitivity to digitalis glycosides may occur;
• Patients with cardiovascular involvement in beriberi – inadequate response to digoxin may occur unless thiamine deficiency is simultaneously corrected;
• Patients with hypokalemia, hypomagnesemia, hypercalcemia, hypernatremia, hypothyroidism, hypoxia, or cor pulmonale – increased risk of digitalis intoxication and arrhythmias.

Electrolyte imbalances must be corrected. High single doses of digoxin should be avoided in such patients.

In patients receiving diuretics and ACE inhibitors, or diuretics alone, discontinuation of digoxin may lead to clinical deterioration.

Direct current cardioversion (DCCV) is the most effective method for treating atrial flutter. The risk of provoking dangerous arrhythmias during DCCV significantly increases in the presence of glycoside intoxication and is proportional to the energy level of the shock. Patients scheduled for cardioversion should discontinue digoxin 1–2 days prior to the procedure, if possible. If cardioversion is mandatory and digoxin has already been administered, the minimal effective energy level should be used. DCCV is inappropriate for treating arrhythmias provoked by cardiac glycosides.

During digoxin therapy, regular monitoring of ECG, renal function (serum creatinine concentration), and serum electrolyte levels (potassium, calcium, magnesium) is required.

Since digoxin slows sinoatrial and atrioventricular conduction, therapeutic doses may cause PR interval prolongation and ST segment depression on the electrocardiogram.

Digoxin intake may lead to false-positive ST-T changes on ECG during stress testing. These electrophysiological effects reflect the expected action of the drug and do not indicate toxicity.

Digoxin improves exercise tolerance in patients with systolic left ventricular dysfunction and normal sinus rhythm. This benefit may or may not be associated with improved hemodynamic profile. However, the benefit of digoxin in patients with supraventricular arrhythmias is most evident at rest and less apparent during physical exertion.

Serum digoxin concentration may sharply decrease during periods of physical activity due to increased binding in skeletal muscle, without any associated change in clinical efficacy.

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

Digoxin tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Use during pregnancy or breastfeeding.

There is no available information on the teratogenic effects of digoxin. It should be noted that digoxin crosses the placenta and its clearance is prolonged during pregnancy. The drug may be used during pregnancy under medical supervision only when the expected benefit to the mother outweighs the potential risk to the fetus.

Digoxin is excreted in 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.

Ability to affect reaction speed when driving or operating machinery.

Until individual response to the drug is established, patients should refrain from driving or operating machinery due to the potential for adverse effects on the nervous system and visual organs.

Method of Administration and Dosage.

Tablets should be swallowed whole, without chewing, and taken with sufficient water. It is recommended to administer the drug between meals.

Dosage is individually determined by a physician.

Adults and children aged 10 years and older: For rapid digitalization, administer 0.5–1 mg (2–4 tablets), followed by 0.25–0.75 mg every 6 hours for 2–3 days. After achieving therapeutic effect, maintain with maintenance doses of 0.125*–0.5 mg once or twice daily.

For slow digitalization, initiate treatment directly with maintenance doses of 0.125*–0.5 mg daily in 1–2 doses. Therapeutic saturation is typically achieved approximately 1 week after starting therapy. The maximum daily dose for adults is 1.5 mg (6 tablets).

Children aged 2 years and older: For rapid digitalization, administer Digoxin at a dose of 0.03–0.06 mg/kg body weight per day. For slow digitalization, use a dose equal to ¼ of the rapid loading dose.

Maximum daily loading dose: 0.75–1.5 mg; maximum daily maintenance dose: 0.125*–0.5 mg.

The loading dose in children should be administered in divided doses: approximately half of the total dose is given as the first dose, followed by fractions of the total dose at 4–8 hour intervals, with clinical response assessed before each subsequent dose. If the patient's clinical response requires adjustment of the initially calculated loading dose, the maintenance dose should be calculated based on the actual loading dose administered.

*When it is necessary to administer digoxin at a dose of 0.125 mg, a formulation allowing such dosing should be used.

Patients with renal impairment: Digoxin doses must be reduced, as the primary route of elimination is renal.

Elderly patients: Due to age-related decline in renal function and low muscle mass, doses should be carefully selected to prevent toxic reactions and overdosage.

Children.

This medicinal product in the given pharmaceutical form is indicated for children aged 2 years and older.

Overdose.

Symptoms of glycoside intoxication occur more frequently when serum digoxin concentration exceeds 2.0 ng/mL (2.56 nmol/L), although significant inter-individual variability exists. However, when assessing digoxin overdose, elevated serum digoxin levels are not the only consideration. Important factors also include the patient’s clinical condition, serum electrolyte levels, and thyroid function.

Overdose develops gradually over several hours. Cardiac manifestations are the most common and serious signs of both acute and chronic toxicity. Peak cardiac effects typically occur 3 to 6 hours after overdose and may persist for up to 24 hours or longer. Digoxin toxicity may result in virtually any type of arrhythmia.

Gastrointestinal symptoms are very common in both acute and chronic intoxication and precede cardiac manifestations in approximately half of patients (according to literature data).

Neurological and visual symptoms are also characteristic of acute and chronic intoxication.

In chronic toxicity, nonspecific extracardiac symptoms such as general malaise and weakness may predominate.

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, reduced visual acuity, scotoma, macropsia and micropsia, very rarely – confusion, syncope.

The most dangerous symptoms are rhythm disturbances due to the risk of fatal outcome from ventricular arrhythmias or complete heart block with asystole.

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 insulin in 500 mL of 5% glucose solution (infusion should be stopped when serum potassium concentration reaches 4–5.5 mmol/L). Potassium-containing agents are contraindicated in impaired atrioventricular conduction. In pronounced bradycardia, administer atropine sulfate solution. Oxygen therapy is indicated. Unithiol and ethylenediaminetetraacetic acid are also used as detoxifying agents. Symptomatic therapy is applied.

In hypokalemia, in the absence of complete heart block, potassium supplements should be administered. In complete heart block, cardiac pacing is indicated. For arrhythmias, lidocaine, procainamide, phenytoin, or propranolol may be used.

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

Hemodialysis and exchange transfusion are poorly effective in digoxin overdose.

Adverse Reactions.

Blood and lymphatic system: eosinophilia, thrombocytopenia, agranulocytosis.

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

Endocrine system: digoxin has estrogenic activity; therefore, gynecomastia in males is possible during prolonged use.

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

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

Eye organs: blurred vision, photophobia, halos around lights, disturbances in color vision (perception of surrounding objects in yellow, less frequently in green, red, blue, brown, or white).

Cardiovascular system: arrhythmias and conduction disturbances (sinus bradycardia, sinoatrial block, unifocal or multifocal extrasystoles (especially bigeminy, trigeminy), prolonged PR interval, ST segment depression, AV block, paroxysmal atrial tachycardia, ventricular fibrillation, ventricular arrhythmias), development or worsening of heart failure. These disturbances may be early signs of digoxin overdose.

Gastrointestinal tract: anorexia, nausea, vomiting, abdominal pain, diarrhea, particularly in elderly patients; disturbances in visceral circulation, intestinal ischemia, and necrosis have also been reported.

Adverse reactions of digoxin are dose-dependent and usually occur when doses exceed those required to achieve therapeutic effect. Dosage of the drug should be carefully selected and adjusted according to the patient's clinical condition.

Shelf life. 5 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

20 tablets in a blister pack, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific-Production Center "Borshchahivskyi Chemical-Pharmaceutical Plant".

Manufacturer's address and place of business.

17, Miru Street, Kyiv, 03134, Ukraine.