Digoxin-zdorovya

INSTRUCTION FOR MEDICAL USE OF DIGOXIN-ZDOROVYE

Composition:

Active substance: digoxin;

1 tablet contains digoxin 0.25 mg;

Excipients: refined sugar; potato starch; glucose monohydrate; mineral oil; talc; calcium stearate.

Dosage form. Tablets.

Main physicochemical properties: white-colored tablets, flat cylindrical or biconvex.

Pharmacotherapeutic group. Cardiology drugs. Cardiac glycosides. Digitalis glycosides.

ATC code C01A A05.

Pharmacological properties.

Pharmacodynamics. Digoxin is a cardiac glycoside of intermediate duration of action, derived from the leaves of Digitalis lanata. It exerts a positive inotropic effect, increasing systolic and stroke volume of the heart, prolongs the effective refractory period, slows atrioventricular (AV) conduction, and reduces heart rate. The use of digoxin in chronic heart failure enhances the force of cardiac contractions. Digoxin also exhibits 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 Cmax is reached 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 portion undergoes hepatic biotransformation. It crosses the placenta and is excreted into breast milk in small amounts.

The half-life (T½) averages 58 hours and depends on the patient's age and health status (36 hours in younger individuals, 68 hours in the elderly). It is considerably prolonged in renal insufficiency. In anuria, T½ 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 components of the drug or other cardiac glycosides;
• Digitalis intoxication from previously administered cardiac glycosides;
• Arrhythmias caused by glycoside intoxication in medical history;
• Marked sinus bradycardia, II–III degree AВ-blockade, Morgagni–Adams–Stokes syndrome;
• Carotid sinus syndrome;
• Hypertrophic obstructive cardiomyopathy;
• Supraventricular arrhythmias associated with accessory AВ-conduction pathways, including Wolff–Parkinson–White syndrome;
• Ventricular paroxysmal tachycardia/ventricular fibrillation;
• Thoracic aortic aneurysm;
• Hypertrophic subaortic 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 (absorption in the gastrointestinal tract, renal clearance), altering its blood concentration. Determination of digoxin concentrations in serum using chemiluminescent microparticle immunoassay (CMIA) during enzalutamide treatment may show falsely elevated serum digoxin levels. Results should be confirmed by another analytical method (see section «Special precautions for use»).

Pharmacokinetic interactions

Medicinal products that increase digoxin blood concentration by > 50 %

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

Medicinal products that increase 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 that increase digoxin blood concentration (magnitude unclear)

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 initiating concomitant therapy. Reduce digoxin dose as needed and continue monitoring.

Loperamide: increased digoxin absorption due to reduced intestinal peristalsis.

Medicinal products that decrease digoxin blood concentration

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

Pharmacodynamic interactions

Amphotericin, lithium salts, diuretics (including acetazolamide, loop and thiazide diuretics, potassium-sparing diuretics): hypokalemia, hypomagnesemia, hypercalcemia caused by these agents may increase digoxin cardiotoxicity and 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. When combining diuretics with cardiac glycosides, optimal dosing should be maintained. Potassium-sparing diuretics (spironolactone, triamterene) may be administered periodically to prevent hypokalemia and arrhythmias. However, hyponatremia may develop.

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

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

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

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

Dofetilide: increased risk of «torsades de pointes» arrhythmia.

Moracizine: possible additive effects on cardiac conduction, significant QT interval prolongation, which may lead to AВ-blockade.

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

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

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

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists: may cause hyperkalemia, which may reduce digoxin tissue binding and lead to 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 interactions have 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 concomitant digoxin use with these agents is still advisable.

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

Colchicine: possible increased risk of myopathy.

Mefloquine: possible increased risk of bradycardia.

Xanthine derivatives: caffeine or theophylline preparations may occasionally cause arrhythmias.

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

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

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

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

Disodium edetate (ethylene diamine tetraacetic acid disodium salt): decreased efficacy and toxicity of cardiac glycosides are observed.

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

Naproxen: as a representative of nonsteroidal anti-inflammatory drugs (NSAIDs), may increase plasma concentrations of cardiac glycosides; worsening of heart failure and reduced renal function are also possible.

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

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

Special precautions.

Digoxin therapy must be administered under medical supervision. During long-term treatment, the optimal individual dose is usually determined over a period of 7–10 days.

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

Digoxin should be used with particular caution in:

• Elderly patients – age-related decline in renal function and reduced muscle mass affect digoxin pharmacokinetics (higher serum digoxin levels, prolonged half-life), increasing the risk of adverse reactions, cumulative effects, and potential overdose;
• Debilitated patients, patients with impaired renal function, and patients with implanted cardiac pacemakers, as toxic effects may develop with doses that are generally well tolerated by others. Renal impairment 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 require higher doses. During treatment for thyrotoxicosis, digoxin dosage should be reduced once the condition is brought under control. Changes in thyroid function may affect sensitivity to digoxin independently of its plasma concentration;
• Patients with short bowel syndrome or malabsorption syndromes – impaired digoxin absorption may necessitate 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 toxicity 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 lowest effective energy shock should be used. DCCV is inappropriate for treating arrhythmias provoked by cardiac glycosides.

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

Since digoxin slows sinoatrial and AV 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 related to improved hemodynamic profile. However, the benefit of digoxin in patients with supraventricular arrhythmias is most evident at rest and less pronounced during physical exertion.

Serum digoxin concentration may decrease significantly during physical exercise due to increased uptake by skeletal muscles, but clinical efficacy remains unchanged.

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

If a patient has known sugar intolerances, consultation with a physician is recommended before taking this medication.

Interference with laboratory tests. In patients receiving enzalutamide, falsely elevated serum digoxin levels may be observed when samples are analyzed using a microparticle chemiluminescent immunoassay (CMIA), regardless of digoxin administration. In case of questionable results, confirmation of serum digoxin levels using an alternative assay method not subject to such interference is recommended to avoid unnecessary 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 the teratogenic potential 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 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 maternal plasma concentration). When digoxin is administered to breastfeeding women, the infant's heart rate should be monitored.

Ability to influence reaction speed when driving or operating machinery. Until individual response to the medication is established, patients should refrain from driving or operating machinery due to the potential for adverse nervous system and visual effects.

Dosage and Administration

Take orally, without chewing, with 150–200 ml of water. It is recommended to administer between meals.

Dosage is determined individually.

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 (1–3 tablets) every 6 hours for 2–3 days. After improvement in the patient's condition, switch to a maintenance dose of 0.125–0.5 mg daily in 1–2 divided doses.

For slow digitalization, start immediately with the maintenance dose of 0.125–0.5 mg daily in 1–2 divided doses; in this case, steady-state levels are achieved approximately 1 week after initiation of therapy.

The maximum daily dose for adults is 1.5 mg (6 tablets).

Children. The dosage for children should be determined based on the chosen digitalization regimen, age, and body weight.

Children aged 2 years and older: for rapid digitalization, administer a daily dose of 0.03–0.06 mg/kg body weight. 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 several divided doses: approximately half of the total dose initially, followed by the remainder in portions 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 received.

If digoxin administration at a dose of 0.125 mg is required, a formulation allowing such dosing should be used.

Patients with renal impairment require reduced digoxin doses, as the primary route of elimination is renal.

Elderly patients require particularly careful dose selection due to age-related decline in renal function and reduced muscle mass, to prevent development of toxic reactions and overdose.

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

Overdose.

Symptoms of glycoside toxicity occur more frequently when serum digoxin concentration exceeds 2.0 ng/mL (2.56 nmol/L), although significant inter-individual variability exists. However, digoxin overdose diagnosis is not based solely on elevated serum digoxin levels. Important factors also include the patient's clinical status, serum electrolyte levels, and thyroid function.

Overdose with digoxin 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 24 hours or longer. Digoxin toxicity may lead to 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 scientific literature).

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, AV block, ventricular tachycardias 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, 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 cardiac block with asystole.

Treatment: gastric lavage, administration of activated charcoal, cholestyramine, or colestipol. In case of arrhythmia, administer intravenous infusion of 2–2.4 g potassium chloride with 10 IU insulin in 500 mL of 5% glucose solution (discontinue infusion 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 may also be used as detoxifying agents. Symptomatic therapy is required.

In hypokalemia, in the absence of complete heart block, potassium preparations should be administered. In complete heart block, perform electrocardiostimulation. For arrhythmias, use lidocaine, procainamide, phenytoin, or propranolol.

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

Hemodialysis and exchange blood transfusion are poorly effective in digoxin overdose.

Adverse reactions.

Blood and lymphatic system: eosinophilia, thrombocytopenia, agranulocytosis.

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

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

Psychiatric disorders: disorientation, confusion, amnesia, depression, acute psychosis, delirium, visual and auditory hallucinations, especially in elderly patients, seizures.

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

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

Cardiovascular system: rhythm 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, especially in elderly patients; disturbances in visceral circulation, intestinal ischemia and necrosis.

Digoxin adverse reactions are dose-dependent and usually occur with doses exceeding those required to achieve therapeutic effect. Drug dosage 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. Tablets, 50 in blisters; 50, 10×5 in blisters in a carton.

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Prescription category. By prescription only.

Manufacturer: LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVYA".

Manufacturer's location and address of business activity.

22, Shevchenka Street, Kharkiv, Kharkiv Oblast, Ukraine, 61013.