Corvazan®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORVZAN® (CORVASAN)

Composition:

Active substance: carvedilol;

One tablet contains carvedilol equivalent to 100% substance 12.5 mg or 25 mg;

Excipients: microcrystalline cellulose; povidone; lactose monohydrate; potato starch; talc; calcium stearate; coating mixture "Opadry II Pink"*.

* Coating mixture "Opadry II Pink" contains triacetin; hypromellose; lactose monohydrate; titanium dioxide (E 171); polyethylene glycol; iron oxide yellow (E 172); iron oxide black (E 172); erythrosine (E 127); indigo carmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round-shaped, film-coated tablets of pink color, with a biconvex surface, with two perpendicular intersecting lines on one side of the tablet (for 12.5 mg dosage); or round-shaped, film-coated tablets of pink color, with a biconvex surface, with a single line and the inscription "KMP" on both sides of the line on one side of the tablet (for 25 mg dosage).

Pharmacotherapeutic group. Alpha- and beta-adrenoreceptor blockers. Carvedilol.

ATC code C07AG02.

Pharmacological properties.

Pharmacodynamics.

Carvedilol is a vasodilator and non-selective beta-adrenoblocker with antioxidant properties. The vasodilating effect is primarily due to selective blockade of alpha-1-adrenoreceptors. Carvedilol reduces peripheral vascular resistance by vasodilation and suppression of the renin-angiotensin-aldosterone system activity resulting from beta-adrenoreceptor blockade. Plasma renin activity thus decreases, and fluid retention in the body occurs only in isolated cases.

Carvedilol has no intrinsic sympathomimetic activity and, similar to propranolol, exhibits membrane-stabilizing properties.

Carvedilol is a racemic mixture of two stereoisomers. Studies in animal models have shown that both stereoisomers possess alpha-adrenoblocking properties. The beta-adrenoblocking effects are non-selective towards beta-1 and beta-2-adrenoreceptors and are associated with the levorotatory stereoisomer of carvedilol.

Carvedilol acts as a potent antioxidant, reducing the number of reactive oxygen species.

Clinical data indicate that the vasodilating and beta-adrenoblocking properties of carvedilol lead to the following effects.

In patients with arterial hypertension, reduction in arterial blood pressure is not accompanied by a concomitant increase in total peripheral vascular resistance, which is typically observed with true beta-adrenoblockers. Heart rate (HR) is only slightly reduced. Renal perfusion and kidney function remain unchanged. Since peripheral circulation is also unaffected, cold sensation in the extremities (commonly observed with true beta-adrenoblockers) occurs rarely.

In patients with ischemic heart disease, carvedilol demonstrates anti-ischemic and antianginal effects, which are maintained during long-term treatment. Carvedilol reduces both preload and afterload on the heart.

In patients with left ventricular dysfunction or chronic heart failure, the drug favorably affects hemodynamic parameters and improves left ventricular ejection fraction.

During treatment with carvedilol, the ratio of high-density lipoproteins to low-density lipoproteins (HDL/LDL) remains within normal limits. Electrolyte balance is not disturbed.

Pharmacokinetics.

In men, the absolute bioavailability of carvedilol is approximately 25%. Maximum serum concentration is reached about 1 hour after oral administration. The relationship between drug dose and its serum concentration is linear. Food intake does not affect the bioavailability or maximum serum concentration of the drug, but increases the time to reach peak plasma concentration. Carvedilol is a highly lipophilic compound: plasma protein binding is about 98–99%. The volume of distribution is approximately 2 L/kg, but is higher in patients with liver cirrhosis. Animal studies indicate enterohepatic circulation of the parent compound.

The mean elimination half-life of carvedilol ranges from 6 to 10 hours. Plasma clearance is about 590 mL/min. Elimination occurs predominantly via bile and feces. A small portion of the dose is excreted by the kidneys as various metabolites.

Carvedilol is extensively metabolized, forming a number of metabolites that are primarily excreted in bile. Metabolism occurs mainly in the liver, primarily through conjugation with glucuronic acid. Demethylation and hydroxylation of the phenolic ring lead to the formation of three active metabolites with beta-adrenoblocking activity. According to preclinical data, the 4-hydroxyphenolic metabolite is nearly 13 times more potent as a beta-adrenoblocker than carvedilol. Compared to carvedilol, these three active metabolites have weak vasodilating activity. In humans, their concentrations are 10 times lower than that of the parent compound. Additionally, two hydroxycarbazole metabolites of carvedilol are exceptionally potent antioxidants, with antioxidant activity 30–80 times greater than that of carvedilol.

Age does not significantly affect the pharmacokinetics of the drug: plasma levels of carvedilol in elderly patients are approximately 50% higher than in younger patients. Data indicate that the bioavailability of carvedilol in patients with liver cirrhosis is 4 times higher, and maximum plasma concentration is 5 times higher than in healthy individuals.

There is evidence that in patients with arterial hypertension and moderate (creatinine clearance 20–30 mL/min) or severe renal impairment (creatinine clearance < 20 mL/min), plasma concentrations of carvedilol are 40–55% higher compared to patients with arterial hypertension and normal kidney function.

Clinical characteristics.

Indications.

• Essential hypertension.
• Chronic stable angina.
• Chronic heart failure (additional therapy).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• Decompensated heart failure;
• Heart failure NYHA class IV requiring intravenous administration of inotropic agents;
• Second- and third-degree atrioventricular block (except when a permanent pacemaker is implanted);
• Concomitant intravenous administration of verapamil, diltiazem, or other antiarrhythmic agents (particularly antiarrhythmic agents of class I);
• Severe bradycardia (heart rate <50 beats/min);
• Severe arterial hypotension (systolic blood pressure below 85 mm Hg);
• Complicated myocardial infarction;
• Cardiogenic shock;
• Sick sinus syndrome (including sinoatrial block);
• Decompensated heart failure requiring intravenous administration of positive inotropic agents and/or diuretics;
• Cor pulmonale, pulmonary hypertension;
• Bronchial asthma or obstructive respiratory diseases associated with bronchospasm;
• Allergic rhinitis;
• Laryngeal edema;
• Pheochromocytoma (except when adequately controlled with alpha-blockers);
• Prinzmetal's angina;
• Severe hepatic impairment;
• Clinically manifest hepatic failure;
• Use in poor metabolizers of debrisoquine and mephenytoin type;
• Concomitant use of monoamine oxidase inhibitors (MAOIs) (except MAO-B inhibitors);
• Galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption;
• Metabolic acidosis;
• Pregnancy or breastfeeding;
• Pediatric age.

Interaction with other medicinal products and other types of interactions.

Some antiarrhythmic, narcotic, antihypertensive agents, antianginal drugs, other β-blockers (e.g., as eye drops), agents reducing catecholamine levels (e.g., monoamine oxidase inhibitors, reserpine), and cardiac glycosides may potentiate the effects of carvedilol. Therefore, the doses of these drugs and of Corvazan® should be carefully titrated.

Pharmacokinetic interactions.

P-glycoprotein, CYP2D6, CYP2D9 inducers or inhibitors.

Carvedilol is a P-glycoprotein inhibitor; therefore, the bioavailability of medicinal products transported by P-glycoprotein may increase when administered concomitantly with carvedilol.

Inhibitors and inducers of CYP2D6 and CYP2D9 may stereoselectively alter systemic or presystemic metabolism of carvedilol, increasing or decreasing plasma concentrations of R- and S-carvedilol.

Fluoxetine.

In studies of patients with heart failure, concomitant administration of fluoxetine, a potent CYP2D6 inhibitor, resulted in stereoselective inhibition of carvedilol metabolism, increasing the AUC of the R(+) enantiomer by 77%.

β-agonists bronchodilators.

Non-cardioselective β-blockers antagonize the effects of β-agonist bronchodilators; therefore, such patients require close monitoring.

Antiarrhythmic agents.

Isolated cases of conduction disturbances (rarely with hemodynamic compromise) have been observed when carvedilol and diltiazem were administered concurrently. For other agents with β-blocking properties, if carvedilol is administered orally with calcium channel blockers such as verapamil or diltiazem, ECG and blood pressure monitoring are recommended. These agents should not be administered intravenously.

Careful monitoring of the patient is required when carvedilol is used concomitantly with amiodarone (orally) or class I antiarrhythmic agents. Bradycardia, cardiac arrest, and ventricular fibrillation have been reported shortly after initiation of β-blocker therapy in patients receiving amiodarone concomitantly. There is a risk of developing heart failure when concomitant intravenous therapy with class Ia or Ic antiarrhythmic agents is administered.

Pharmacodynamic interactions.

Dihydropyridines.

Close monitoring of the patient is required when dihydropyridines and carvedilol are used concomitantly, as cases of heart failure and severe arterial hypotension have been reported.

Nitrates.

Potentiate the hypotensive effect.

NSAIDs, estrogens, and corticosteroids.

The antihypertensive effect of carvedilol is attenuated when used concomitantly with agents that promote fluid and sodium retention (due to reduced hypotensive effect resulting from decreased prostaglandin production).

Sympathomimetics, β-mimetics, and α-mimetics.

Concomitant use may result in arterial hypertension, severe bradycardia, asystole, and reduced beta-adrenergic blocking effect of carvedilol.

Ergotamine.

Vasoconstriction is potentiated when used concomitantly.

Myorelaxants.

Neuromuscular blockade is potentiated when carvedilol is combined with myorelaxants.

Xanthine derivatives.

Use with xanthine derivatives (aminophylline, theophylline) should be cautious due to reduced β-adrenergic blocking effect.

Digoxin.

Digoxin concentrations increase by approximately 15% when administered concomitantly with carvedilol. Both digoxin and carvedilol slow AV conduction. Increased monitoring of digoxin levels is recommended when initiating, adjusting, or discontinuing carvedilol therapy.

Insulin or oral hypoglycemic agents.

Medicinal products with β-blocking properties may enhance the glucose-lowering effect of insulin and oral hypoglycemic agents. Symptoms of hypoglycemia may be masked or attenuated (particularly tachycardia). Therefore, regular blood glucose monitoring is recommended for patients receiving insulin or oral hypoglycemic agents.

Agents reducing catecholamines.

Close monitoring for signs of hypotension and/or severe bradycardia is required in patients receiving both β-blocking agents and agents that may reduce catecholamines (e.g., reserpine, guanethidine, methyldopa, guanfacine, and monoamine oxidase inhibitors (except MAO-B inhibitors)).

Clonidine.

Concomitant use of clonidine and β-blocking agents may potentiate the effects of lowering blood pressure and heart rate. When discontinuing concomitant therapy with β-blocking agents and clonidine, the β-blocking agent should be discontinued first. Then, after several days, clonidine therapy may be gradually tapered and discontinued.

Anesthetics.

Extreme caution is required during anesthesia due to synergistic negative inotropic and hypotensive effects of carvedilol and anesthetics.

Agents affecting the central nervous system (CNS).

Use with agents affecting the CNS (sedatives, tranquilizers, tricyclic antidepressants, and ethanol) may result in mutual potentiation of effects.

Other antihypertensive medicinal products.

Like other β-blocking agents, carvedilol may potentiate the effect of other concurrently administered antihypertensive agents (e.g., α1-receptor antagonists) or may lead to hypotension due to their side effect profile.

Other interactions.

Concomitant use of carvedilol with clonidine, guanethidine, reserpine, α-methyldopa, guanfacine, and monoamine oxidase inhibitors (except MAO-B inhibitors) may potentiate hypotensive effects and reduce heart rate. Therefore, close monitoring for signs of hypotension and/or severe bradycardia is required.

Since carvedilol undergoes oxidative metabolism, its pharmacokinetics may be altered by induction or inhibition of the cytochrome P450 enzyme system; therefore, the following influences should be considered:

• Rifampicin (results in a 70% reduction in plasma concentration of carvedilol);
• Barbiturates (reduce the effectiveness of carvedilol);
• Cimetidine (increases the bioavailability of carvedilol by 30%);
• Digoxin: carvedilol increases digoxin plasma concentration;
• Inhibitors of the CYP2D6 isoenzyme (quinidine, fluoxetine, paroxetine, propafenone): increased concentration of the R(+) enantiomer of carvedilol may be expected;
• Carvedilol delays the metabolism of cyclosporine.

Cyclosporine and tacrolimus.

Two studies involving kidney and heart transplant patients receiving oral cyclosporine showed increased plasma concentrations of cyclosporine after initiation of carvedilol therapy. Apparently, carvedilol increases the effect of orally administered cyclosporine by approximately 10–20%. To maintain a therapeutic cyclosporine level, its dose should be reduced by an average of 10–20%. The mechanism of this interaction is unknown, but inhibition of intestinal P-glycoprotein may be involved. Due to wide individual variability in cyclosporine levels, careful monitoring of cyclosporine concentration is recommended after initiation of carvedilol therapy, with appropriate dose adjustments. There is also evidence that CYP3A4 is involved in the metabolism of carvedilol. Since tacrolimus is a substrate of P-glycoprotein and CYP3A4, carvedilol may also affect its pharmacokinetics via these interaction mechanisms.

Alcohol.

Concomitant alcohol consumption may affect the antihypertensive effect of carvedilol and cause various adverse effects. Alcohol intake has been shown to produce an acute hypotensive effect, which may potentiate the blood pressure-lowering effect of carvedilol. Since carvedilol is poorly water-soluble but soluble in ethanol, the presence of alcohol may affect the rate and/or extent of intestinal absorption of carvedilol by increasing its solubility. Furthermore, carvedilol has been shown to be partially metabolized by the enzyme CYP2E1, which is induced and inhibited by alcohol.

Grapefruit juice.

Consumption of a single 300 mL dose of grapefruit juice resulted in a 1.2-fold increase in the AUC of carvedilol compared to water intake. Since the clinical significance of this observation is not established, patients are advised to avoid concomitant intake of grapefruit juice until a stable dose-response relationship is established.

Nifedipine.

Concomitant use of nifedipine and carvedilol may lead to a significant reduction in blood pressure.

Special precautions for use.

Arterial hypotension.

The drug is not recommended for patients with low blood pressure.

Chronic heart failure.

In most cases, patients with chronic heart failure require additional therapy with diuretics, ACE inhibitors, digoxin, and/or vasodilators alongside carvedilol. Initiation of treatment should occur in a hospital setting under physician supervision. Therapy may only be initiated if the patient's condition has been stable for at least 4 weeks on standard background therapy. Patients with severe heart failure (above NYHA class III), electrolyte imbalances, low arterial pressure (less than 100 mm Hg), elderly patients (aged 70 years or older), or dehydration require continuous monitoring for approximately 2 hours after the first dose or after dose escalation, due to the risk of developing arterial hypotension. Arterial hypotension resulting from excessive vasodilation should initially be managed by reducing the diuretic dose; if symptoms persist, reduction of any ACE inhibitor dose may be considered. At the beginning of treatment or during dose escalation, worsening of heart failure or fluid retention may occur. In such cases, the diuretic dose should be increased. However, in some cases, dose reduction or discontinuation of the drug may be necessary. The dose of carvedilol should not be increased until symptoms related to worsening heart failure or arterial hypotension due to excessive vasodilation are controlled.

Carvedilol should be used with caution in patients with chronic heart failure who are taking digoxin, as this combination prolongs atrioventricular conduction.

Carvedilol may cause bradycardia. If heart rate is < 55 beats/min and symptoms related to bradycardia occur, the dose of the drug should be reduced.

Since carvedilol has a negative dromotropic effect, it should be administered with caution to patients with first-degree heart block.

If carvedilol is used for the treatment of arterial hypertension or angina in patients with heart failure, therapy should follow the dosing regimen recommended for heart failure: the initial dose should not exceed 3.125 mg twice daily, and any dose increase should be performed no sooner than after 2 weeks of treatment with the previous dose.

The use of carvedilol in patients with arterial hypertension who are already receiving digitalis preparations, diuretics, and/or ACE inhibitors requires close medical supervision, as all these drugs may reduce atrioventricular conduction.

Antiarrhythmic agents.

When carvedilol is used concomitantly with calcium channel blockers such as verapamil or diltiazem, or with other antiarrhythmic drugs, particularly amiodarone, blood pressure and ECG should be monitored. Concomitant intravenous administration should be avoided.

Hepatic impairment.

Carvedilol may very rarely cause worsening of liver function. If clinical deterioration is suspected, liver function should be evaluated. In cases of hepatic insufficiency, patients should discontinue taking Corvazan®. Typically, liver function normalizes after discontinuation of treatment.

Laboratory tests should be performed upon the first signs/symptoms of impaired liver function (e.g., pruritus, dark urine, persistent loss of appetite, jaundice, right upper quadrant pain, or unexplained flu-like symptoms). If laboratory results confirm liver injury or jaundice, carvedilol should be discontinued and not re-administered.

Orthostatic hypotension.

Especially at the beginning of treatment with Corvazan® and during dose escalation, orthostatic hypotension may occur, manifesting as dizziness and vertigo, and sometimes even loss of consciousness. Patients with heart failure, elderly patients, and those taking other antihypertensive agents or diuretics are at highest risk. These effects can be prevented by using a low initial dose of Corvazan®, careful titration of maintenance dose, and taking the drug after meals. Patients should be advised on measures to avoid orthostatic hypotension (caution when standing up; if dizziness occurs, the patient should sit or lie down).

Renal function in heart failure with congestion.

Worsening renal function has been observed during carvedilol therapy in patients with chronic heart failure who have low blood pressure (systolic pressure below 100 mm Hg), ischemic heart disease, diffuse vascular disease, and/or underlying renal insufficiency. In patients with congestive heart failure and such risk factors, renal function should be monitored during dose escalation by titration, and the drug should be discontinued or the dose reduced if worsening renal insufficiency occurs.

Left ventricular dysfunction after acute myocardial infarction.

Before initiating carvedilol therapy, the patient must be clinically stable and have received an ACE inhibitor for at least 48 hours prior to starting carvedilol. Furthermore, the ACE inhibitor dose should have been stable for at least 24 hours.

Prescribing the drug for unstable angina or first-degree atrioventricular block requires special caution, frequent ECG monitoring, and close medical supervision.

Chronic obstructive pulmonary disease (COPD).

Carvedilol should be used with caution in patients with chronic obstructive pulmonary disease with a bronchospastic component who are not receiving oral or inhaled medication, and only if the potential benefit outweighs the potential risk.

In patients with a tendency toward bronchospasm, respiratory arrest may occur due to possible increased resistance. Close monitoring is required during initiation and dose escalation of carvedilol by titration, and the carvedilol dose should be reduced if any evidence of bronchospasm occurs during treatment.

Diabetes mellitus.

Like other beta-adrenergic blockers, carvedilol may mask symptoms of hypoglycemia and adversely affect carbohydrate metabolism. Caution should be exercised when administering carvedilol to patients with diabetes mellitus, as early signs of acute hypoglycemia may be masked or diminished. In patients with chronic heart failure and diabetes mellitus, carvedilol use may be associated with worsening glycemic control; therefore, regular monitoring of blood glucose levels is recommended at the beginning of carvedilol therapy or during dose escalation by titration, along with appropriate adjustment of hypoglycemic therapy.

Peripheral vascular disease.

Carvedilol should be used with caution in patients with peripheral vascular disease, as beta-blockers may accelerate or exacerbate symptoms of arterial insufficiency. However, since carvedilol also possesses α-blocking properties, this effect is largely balanced.

Raynaud's phenomenon.

Carvedilol should be used with caution in patients suffering from peripheral circulatory disorders (e.g., Raynaud's phenomenon), as symptoms may worsen.

Thyrotoxicosis.

Carvedilol may mask symptoms of thyrotoxicosis. Abrupt discontinuation of the drug may lead to exacerbation of thyrotoxicosis and development of thyroid storm.

General anesthesia.

Beta-blockers reduce the risk of arrhythmias during anesthesia, but may increase the risk of arterial hypotension; therefore, certain anesthetics should be used cautiously.

Carvedilol should be used with particular caution in patients undergoing surgery under general anesthesia when anesthetics such as ether, cyclopropane, or trichloroethylene—known to depress myocardial function—are used.

Bradycardia.

Carvedilol may cause bradycardia. If pulse rate decreases to 55 beats per minute or less, the carvedilol dose should be reduced.

Hypersensitivity.

Caution should be exercised when administering carvedilol to patients with a history of severe hypersensitivity reactions and to those undergoing desensitization therapy, as beta-blockers may increase both sensitivity to allergens and the severity of anaphylactic reactions.

Very rare cases of serious skin reactions, such as toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported during carvedilol therapy. Carvedilol should not be prescribed to patients who have experienced serious skin reactions that may be attributed to carvedilol.

Psoriasis.

Treatment of patients with psoriasis with carvedilol requires careful assessment of the risk-benefit ratio, as carvedilol may exacerbate or provoke symptoms of psoriasis.

Concomitant use of calcium channel blockers or antiarrhythmic drugs.

Careful monitoring of ECG and blood pressure is necessary for patients receiving concomitant therapy with calcium channel blockers such as verapamil or diltiazem, or other antiarrhythmic drugs.

Pheochromocytoma.

In patients with pheochromocytoma, an alpha-receptor blocker should be initiated before any beta-receptor blocker. Although carvedilol has pharmacological blocking activity against both α- and β-receptors, there is no experience with the use of carvedilol in this condition. Therefore, caution should be exercised when administering carvedilol to patients suspected of having pheochromocytoma.

Prinzmetal's angina.

Nonselective beta-adrenergic blockers may cause chest pain in patients with Prinzmetal's angina. There is no clinical experience with carvedilol in such patients, although the α-blocking activity of carvedilol may prevent such symptoms. Nevertheless, caution should be exercised when administering carvedilol to patients suspected of having Prinzmetal's angina.

Contact lenses.

Patients wearing contact lenses should be informed that carvedilol reduces tear production.

Discontinuation of therapy.

Abrupt discontinuation of carvedilol (as with other beta-blockers) may result in sweating, tachycardia, dyspnea, worsening angina, and even myocardial infarction or ventricular arrhythmias. Patients with angina are at highest risk of cardiac events. The dose should be gradually reduced over 1–2 weeks. If necessary, replacement therapy may be initiated simultaneously to prevent disease exacerbation. If treatment has been interrupted for more than 2 weeks, reinitiation should begin with the lowest dose.

Important information about excipients.

The drug contains lactose monohydrate. In case of established intolerance to certain sugars, consult a physician before taking this medicinal product.

The drug is contraindicated in patients with the following health conditions: galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Alcohol.

Patients are advised not to consume alcoholic beverages during treatment, as alcohol may potentiate the effects of carvedilol.

Use during pregnancy or breastfeeding.

Clinical experience with the use of carvedilol during pregnancy is limited. Reproductive toxicity has been observed in animal studies. The potential risk to humans is unknown.

Beta-blockers reduce placental perfusion, which may lead to intrauterine fetal death, miscarriage, or premature delivery.

It is presumed that the use of carvedilol may lead to distress syndrome in the fetus or newborn (bradycardia, arterial hypotension, respiratory depression, hypoglycemia, and hypothermia). Newborns may be at increased risk of cardiac and pulmonary complications in the postnatal period.

Therefore, the use of carvedilol during pregnancy is contraindicated.

Animal studies have shown that carvedilol and/or its metabolites are excreted in the milk of rats. Excretion of carvedilol in human breast milk has not been established. However, most beta-adrenergic blockers, especially lipophilic agents, are known to pass into human breast milk to varying degrees.

It is unknown whether carvedilol passes into breast milk. Since carvedilol may have harmful effects on the infant, treatment with carvedilol should be discontinued during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

No specific studies have been conducted. Due to possible adverse reactions to carvedilol (e.g., dizziness, increased fatigue), caution should be exercised when driving or operating machinery during treatment. Particular caution is required at the beginning of therapy, after dose escalation, when changing medications, or when used concomitantly with alcohol.

Dosage and Administration

Tablets should be taken during meals with sufficient fluid.

Essential hypertension.

The recommended frequency of administration is once daily.

The recommended initial dose is 12.5 mg once daily for the first two days of treatment. Then the recommended dose is 25 mg once daily. If necessary, the dose may be gradually increased at intervals of at least two weeks up to the maximum recommended dose of 50 mg once daily, which may be taken as a single dose or divided into two doses.

The drug may be used either as monotherapy or in combination with other antihypertensive agents, particularly thiazide diuretics.

Elderly patients

The recommended starting dose is 12.5 mg once daily. If the therapeutic effect is inadequate, the dose may be gradually increased at intervals of at least two weeks up to the maximum recommended daily dose of 50 mg.

Chronic stable angina.

The recommended initial dose is 12.5 mg twice daily for the first two days of treatment. Then the recommended dose is 25 mg twice daily. If necessary, the dose may be increased at intervals of at least two weeks up to the maximum recommended daily dose of 100 mg, which should be divided into two doses.

Elderly patients

The recommended initial dose is 12.5 mg twice daily for two days.

Then treatment should continue at a dose of 25 mg twice daily, which is the recommended maximum daily dose.

Chronic heart failure.

The dose should be individually adjusted, and dose titration must be performed under close medical supervision.

Carvedilol may be used as an adjunct to standard therapy, but it may also be administered to patients intolerant to ACE inhibitors or to patients receiving digitalis, hydralazine, or nitrates.

Patients receiving digoxin, diuretics, or ACE inhibitors should continue these medications at their previously established doses prior to initiation of carvedilol therapy.

The recommended initial dose is 3.125 mg twice daily for two weeks. If this dose is well tolerated, it may be gradually increased at intervals of at least two weeks: first to 6.25 mg twice daily, then to 12.5 mg twice daily, and finally to 25 mg twice daily. The dose should be increased to the highest dose that is well tolerated by the patient.

The maximum recommended dose is 25 mg twice daily for all patients with severe chronic heart failure and for patients with mild to moderate chronic heart failure whose body weight does not exceed 85 kg. For patients with mild to moderate chronic heart failure and body weight exceeding 85 kg, the maximum recommended dose is 50 mg twice daily.

At the beginning of therapy or during dose escalation, transient worsening of heart failure symptoms may occur, particularly in patients with severe heart failure and/or those receiving high doses of diuretics. Although discontinuation of therapy is generally not required in such cases, the dose of carvedilol should not be increased. For the first two hours after initiation of carvedilol therapy or after dose escalation, the patient should be under the supervision of a cardiologist or other physician. Prior to each dose increase, the patient should be evaluated for possible signs of worsening heart failure or excessive vasodilation (e.g., assessment of renal function, body weight, blood pressure, heart rate, and cardiac rhythm). Worsening heart failure symptoms or fluid retention should be managed by increasing the diuretic dose; however, carvedilol dose escalation should not be performed until the patient's condition is stabilized. In case of bradycardia or atrioventricular conduction prolongation, plasma digoxin levels should first be checked. In some cases, it may be necessary to reduce the carvedilol dose or temporarily discontinue the drug. Even in such cases, successful continuation of carvedilol dose titration may be possible.

During dose titration, renal function, platelet count, and blood glucose levels (in patients with insulin-independent and/or insulin-dependent diabetes mellitus) should be monitored regularly. After completion of dose titration, the frequency of monitoring may be reduced.

If carvedilol therapy has been interrupted for more than two weeks, treatment should be resumed starting with a dose of 3.125 mg twice daily, followed by gradual dose escalation according to the recommendations above.

Elderly patients

Elderly patients may be more sensitive to the effects of carvedilol and therefore require closer monitoring.

Patients with hepatic impairment

Carvedilol is contraindicated in patients with severe hepatic impairment (see section "Contraindications"). Dose adjustment may be required in patients with moderate hepatic impairment.

Patients with renal impairment

The dose should be individually adjusted; however, there are no data indicating the need for dose adjustment of carvedilol in patients with renal impairment.

Discontinuation of therapy.

Carvedilol therapy must not be abruptly discontinued, especially in patients with ischemic heart disease. Discontinuation should be gradual over 7–10 days, for example, by halving the daily dose every three days.

Children.

The safety and efficacy of the drug in children have not been established; therefore, the drug is not intended for use in this patient population.

Overdose.

In case of overdose, severe arterial hypotension, bradycardia, heart failure, cardiogenic shock, or cardiac arrest may develop. Respiratory distress, bronchospasm, vomiting, impaired consciousness, generalized seizures, and exacerbation of other adverse reactions are also possible.

Treatment: within the first hours – induce vomiting and perform gastric lavage, followed by monitoring and correction of vital functions in an intensive care unit.

Supportive therapy

Atropine: 0.5–2 mg intravenously (for treatment of severe bradycardia).

Glucagon: initially 1–10 mg intravenously, followed by continuous infusion at 2–5 mg/hour (to support cardiovascular function).

Sympathomimetics – dobutamine, isoprenaline, orciprenaline, or adrenaline – should be administered according to patient body weight and treatment response.

If peripheral vasodilation predominates in the clinical picture of overdose, adrenaline or noradrenaline should be administered under continuous cardiovascular monitoring. In case of bradycardia resistant to pharmacological treatment, temporary cardiac pacing is indicated. In case of bronchospasm, administration of beta-sympathomimetics (by aerosol or intravenous route) or intravenous aminophylline is indicated. In case of generalized seizures, slow intravenous administration of diazepam or clonazepam is recommended.

Carvedilol is highly protein-bound and therefore cannot be removed by dialysis.

Note: In cases of severe overdose accompanied by shock symptoms, supportive therapy with antidotes should be continued for a prolonged period, as an increased elimination half-life and redistribution of carvedilol may be expected. The duration of treatment depends on the degree of overdose; supportive therapy should be continued until the patient's condition is stabilized.

Adverse Reactions

The frequency of adverse reactions is dose-independent, except for dizziness, visual disturbances, and bradycardia.

Frequency categories for adverse reactions are as follows:

• very common ≥ 1/10;
• common ≥ 1/100 to < 1/10;
• uncommon ≥ 1/1000 to < 1/100;
• rare ≥ 1/10000 to < 1/1000;
• very rare < 1/10000.

Infections and infestations

Common: bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection.

Blood and lymphatic system disorders

Common: anemia;

rare: thrombocytopenia;

very rare: leukopenia, decreased prothrombin levels, aplastic anemia.

Nervous system disorders

Very common: headache, dizziness, increased fatigue;

uncommon: paresthesia, hypesthesia, vertigo, pre-syncope, loss of consciousness.

Psychiatric disorders

Common: depression, depressed mood;

uncommon: sleep disturbances, nightmares, hallucinations, confusion;

very rare: psychoses.

Cardiac disorders

Very common: hypotension, worsening of heart failure;

common: bradycardia, peripheral edema, edema (including generalized, peripheral, dependent edema, and edema of genital organs and legs), orthostatic hypotension, hypervolemia, peripheral circulatory disorders (cold extremities), intermittent claudication or Raynaud's phenomenon, exacerbation of Charcot's syndrome;

uncommon: arterial hypertension, loss of consciousness – especially at the beginning of treatment, angina (including chest pain), tachycardia, atrioventricular block, left ventricular dysfunction following acute myocardial infarction.

Vascular disorders

Very common: arterial hypotension;

common: peripheral vascular disease.

Respiratory system disorders

Common: increased cough, wheezing, dyspnea, bronchial asthma (in patients predisposed to such conditions), flu-like symptoms;

rare: bronchospasm, nasal congestion, sneezing, interstitial pneumonitis.

Respiratory, thoracic and mediastinal disorders

Common: pulmonary edema, bronchial asthma in sensitive patients;

rare: rhinitis.

Gastrointestinal disorders

Common: nausea, diarrhea, vomiting, abdominal pain, dyspepsia, increased intestinal tone and motility;

uncommon: constipation;

rare: dry mouth, periodontitis, melena.

Hepatobiliary disorders

Rare: reactions presenting as acute liver failure and impaired liver function in patients with generalized atherosclerosis;

very rare: increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT).

Skin and subcutaneous tissue disorders

Uncommon: skin reactions (including allergic exanthema, dermatitis, increased sweating, urticaria, pruritus; skin lesions resembling psoriasis or lupus erythematosus), psoriatic skin lesions or worsening of pre-existing condition, alopecia, increased sweating.

Eye disorders

Common: decreased lacrimation (dry eyes), visual disturbances, eye irritation.

Metabolism and nutrition disorders

Common: hypoglycemia, impaired glucose regulation, anorexia/weight loss, weight gain, hypercholesterolemia, impaired blood glucose control (hyperglycemia, hypoglycemia) in patients with pre-existing diabetes, latent diabetes may become apparent, symptoms of existing diabetes may worsen during therapy, hyperkalemia, hypertriglyceridemia, hyponatremia, increased levels of alkaline phosphatase, creatinine, urea, hypervolemia, fluid retention.

Musculoskeletal and connective tissue disorders

Common: joint pain, limb pain;

rare: arthralgia, muscle cramps, muscle atrophy.

Reproductive system and breast disorders

Uncommon: erectile dysfunction.

Renal and urinary disorders

Common: acute renal failure and impaired kidney function in patients with diffuse vascular disease and/or renal insufficiency, urinary disorders;

very rare: urinary incontinence in women, hematuria, albuminuria, glucosuria, hyperuricemia.

Immune system disorders

Very rare: hypersensitivity reactions (allergic reactions), anaphylactic reactions;

uncommon: angioneurotic edema; Stevens-Johnson syndrome, toxic epidermal necrolysis, multiform erythema.

General disorders

Very common: asthenia (including fatigue);

common: pain, increased body temperature.

Laboratory findings

Common: hyperglycemia in diabetic patients, hypercholesterolemia, hyperkalemia, hypertriglyceridemia, hyponatremia, increased levels of alkaline phosphatase, creatinine, urea;

rare: thrombocytopenia;

very rare: elevated serum transaminase levels, leukopenia, anemia, decreased prothrombin levels, glucosuria, hyperuricemia.

Other adverse effects

Common: flu-like symptoms, increased body temperature; infections; bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection; anaphylactic reactions, possible manifestation of latent diabetes mellitus, symptoms of existing diabetes may worsen during therapy; hyperemia. Except for dizziness, visual disturbances, and bradycardia, none of the above-described adverse effects are dose-dependent.

Dizziness, loss of consciousness, headache, and asthenia are usually mild and more likely to occur at the beginning of treatment.

In addition, the following have been observed:

• worsening of symptoms in patients with intermittent claudication or Raynaud's syndrome;
• in isolated cases – exacerbation of pre-existing heart failure;
• rarely – mild liver injury (see "Special precautions");
• reactions similar to lichen planus;
• development or exacerbation of psoriasis.

Due to possible increased airway resistance, dyspnea or asthmatic attacks may occur in patients predisposed to bronchospastic reactions (see section "Special precautions").

Post-marketing experience

Stevens-Johnson syndrome, toxic epidermal necrolysis, and multiform erythema have been reported only when carvedilol was used concomitantly with other drugs that can cause such reactions.

In patients with congestive heart failure, worsening of heart failure and fluid retention may occur during dose escalation of carvedilol via titration.

Heart failure was frequently reported as an adverse event both in patients receiving placebo and in those receiving carvedilol (14.5% and 15.4%, respectively, in patients with left ventricular dysfunction after acute myocardial infarction).

Reversible worsening of renal function has been observed during carvedilol therapy in patients with chronic heart failure, low blood pressure, ischemic heart disease, diffuse vascular disease, and/or underlying renal insufficiency.

As a class, β-adrenergic receptor blockers may unmask latent diabetes mellitus, worsen manifest diabetes mellitus, and impair glucose regulation.

Carvedilol may cause urinary incontinence in women, which resolves after discontinuation of the drug.

Cardiac disorders

Sinus node arrest in susceptible patients (e.g., elderly patients or those with pre-existing bradycardia, sinus node dysfunction, or atrioventricular block).

Skin and subcutaneous tissue disorders

Alopecia, hyperhidrosis, severe skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome (see section "Special precautions").

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 10 tablets per blister, 3 blisters per carton.

Prescription category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of business activity.

139 Saksaganskogo St., Kyiv, 01032, Ukraine.