MEDOCARDIL

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MЕDОCARDIL (MEDOCARDIL)

Composition:

Active substance: carvedilol;

1 tablet contains carvedilol 6.25 mg or 25 mg;

Excipients: lactose monohydrate, povidone, iron oxide yellow (E 172) (for 6.25 mg tablets), colloidal anhydrous silicon dioxide, crospovidone, sucrose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

6.25 mg tablets – yellow, flat, round tablets with a dividing groove. Diameter: approximately 7.0 mm. Thickness: 2.45 mm ± 8 %;

25 mg tablets – white, flat, round tablets with a dividing groove. Diameter: approximately 6.0 mm. Thickness: 2.7 mm ± 8 %.

Pharmacotherapeutic group. α- and β-adrenoreceptor blockers. ATC code C07AG02.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Carvedilol, a racemic mixture of two enantiomers (R- and S-carvedilol), is a multiple-action beta-blocker of alpha- and beta-adrenergic receptors. Blockade of beta-adrenergic receptors is associated with the S-enantiomer and is non-selective for beta1- and beta2-adrenergic receptors, whereas both enantiomers have equal blocking properties specific for alpha1-adrenergic receptors. At higher concentrations, carvedilol also has weak to moderate blocking activity against calcium channels. It has no intrinsic sympathomimetic activity and (like propranolol) possesses membrane-stabilizing properties.

Pharmacodynamic effects. Carvedilol reduces peripheral vascular resistance through selective blockade of alpha1-adrenergic receptors. Due to its beta-blocking action, carvedilol suppresses the renin-angiotensin-aldosterone system (RAAS), reducing renin release and causing minimal fluid retention. This attenuates the increase in arterial pressure induced by phenylephrine, an alpha1-adrenergic receptor agonist, but not that induced by angiotensin II. The calcium channel-blocking activity of carvedilol may enhance blood flow in certain vascular beds, such as the skin circulation.

Carvedilol has organ-protective effects, which are likely partly attributable to properties additional to its blocking action on adrenergic receptors. It has potent antioxidant properties associated with both enantiomers, acts as a scavenger of reactive oxygen species, and exerts anti-proliferative effects on human vascular smooth muscle cells. Carvedilol has no negative effect on the lipid profile.

Clinical efficacy and safety. Clinical studies have shown that the balance of vasodilation and beta-blockade provided by carvedilol leads to the following effects.

Hypertension. Carvedilol reduces arterial pressure in patients with hypertension through beta-blockade and alpha1-mediated vasodilation, without a concomitant increase in total peripheral resistance, as observed with pure beta-blockers. Heart rate is slightly reduced. Renal blood flow and renal function are maintained. It has been demonstrated that carvedilol maintains stroke volume and reduces total peripheral resistance without impairing blood supply to individual organs and vascular beds, such as the kidneys, skeletal muscles, forearm, legs, skin, brain, or carotid artery. The frequency of cold extremities and early fatigue during physical activity is reduced.

Hypertension with renal insufficiency. Several open-label studies have shown that carvedilol is effective in patients with renal hypertension, chronic renal insufficiency, on hemodialysis, or after kidney transplantation. Carvedilol causes gradual reduction in arterial pressure during dialysis and on non-dialysis days, and the blood pressure-lowering effects are comparable to those observed in patients with normal renal function.

Stable angina. In patients with stable angina, carvedilol has demonstrated anti-ischemic (improved total exercise time, time to 1 mm ST-segment depression, and time to angina) and anti-anginal properties, which are maintained during long-term treatment. Acute hemodynamic studies have shown that carvedilol significantly reduces myocardial oxygen demand and excessive sympathetic activity, as well as reduces preload (pulmonary artery pressure and pulmonary capillary wedge pressure) and afterload (total peripheral resistance) of the myocardium, resulting in improved systolic and diastolic left ventricular function without significant changes in cardiac output.

Carvedilol has no negative impact on metabolic risk factors for ischemic heart disease. It does not affect normal serum lipid levels, and in patients with hypertension and dyslipidemia, a favorable effect on serum lipids has been reported after 6 months of oral therapy.

In two studies, carvedilol at a dose of 25 mg twice daily was compared with other anti-anginal drugs with proven efficacy in patients with chronic stable exertional angina. The dosing regimens selected were widely used in clinical practice. Both trials had a double-blind, parallel-group design. The primary endpoint was total exercise time (TET).

The results of both studies clearly demonstrated that there was no significant difference in TET at the minimum blood level of the drug after 12 weeks of therapy. However, the risk ratios derived from the Cox proportional hazards model showed a trend in favor of carvedilol, indicating that on average carvedilol was 114% as effective as verapamil (90% CI: 85–152%) and 134% as effective as isosorbide dinitrate (90% CI: 96–185%). This also applied to time to angina (TTA) and ST-segment depression (TST). The increase in TET was approximately 50 seconds in all groups; improvements in TTA and TST were about 30 seconds, which is clinically significant.

In study 060, 48-hour Holter monitoring demonstrated a reduction in the number and duration of ST-segment depressions (silent myocardial ischemia) in both treatment groups. Carvedilol also reduced premature atrial and ventricular contractions (PAC, PVC), couples, and runs.

Chronic heart failure. Carvedilol significantly reduces mortality and hospitalizations and improves symptoms and left ventricular function in patients with ischemic or non-ischemic chronic heart failure. The effect of carvedilol is dose-dependent.

Patients with chronic heart failure and renal impairment. Carvedilol reduces morbidity and mortality in dialysis patients with dilated cardiomyopathy, as well as all-cause mortality, cardiovascular mortality, and mortality due to heart failure or first hospitalization in patients with heart failure and mild to moderate chronic kidney disease not requiring dialysis. A meta-analysis of placebo-controlled clinical trials, including a large number of patients (>4000) with mild to moderate chronic kidney disease, supports carvedilol treatment in patients with left ventricular dysfunction, with or without symptomatic heart failure, to reduce the incidence of all-cause mortality and heart failure-related events.

Pediatric population. The safety and efficacy of carvedilol in children and adolescents have not been established due to limited number and extent of studies. Available studies have focused on the treatment of pediatric heart failure, which differs from adult disease in characteristics and etiology. Due to the small number of participants compared to adult studies and the lack of an optimal dosing regimen for children and adolescents, available data are insufficient to establish a pediatric safety profile for carvedilol.

Pharmacokinetics.

Absorption. After oral administration, carvedilol is rapidly absorbed, with a peak plasma concentration (Cmax) of 21 µg/L reached approximately 1.5 hours (tmax) after dosing. Cmax values are linearly related to dose. Following oral administration, carvedilol undergoes extensive first-pass metabolism, resulting in an absolute bioavailability of approximately 25% in healthy males. Carvedilol is a racemate, and the S-enantiomer appears to be metabolized faster than the R-enantiomer, showing an absolute oral bioavailability of 15% compared to 31% for the R-enantiomer. The maximum plasma concentration of R-carvedilol is approximately twice that of S-carvedilol.

In vitro studies have shown that carvedilol is a substrate of the P-glycoprotein transporter. The role of P-glycoprotein in the distribution of carvedilol is also confirmed in vivo in healthy subjects. Food does not affect bioavailability, residence time, or maximum serum concentration, although the time to reach maximum serum concentration is delayed.

Distribution. Carvedilol is highly lipophilic, with plasma protein binding of approximately 95%. The volume of distribution ranges from 1.5 to 2 L/kg and is increased in patients with liver cirrhosis.

Biotransformation. In humans, carvedilol is extensively metabolized in the liver via oxidation and conjugation into various metabolites, which are primarily excreted in bile. Enterohepatic recirculation of the parent compound has been demonstrated in animals. Demethylation and hydroxylation on the phenolic ring produce three metabolites with beta-adrenergic receptor blocking activity.

Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent for beta-blockade than carvedilol. Compared to carvedilol, the three active metabolites exhibit weak vasodilatory activity. In humans, the concentration of the three active metabolites is approximately 10 times lower than that of the parent compound. Two of the hydroxycarbazole metabolites of carvedilol are extremely potent antioxidants, with activity in this regard 30–80 times greater than that of carvedilol.

Pharmacokinetic studies in humans have shown that the oxidative metabolism of carvedilol is stereoselective. In vitro study results suggest that various cytochrome P450 isoenzymes may be involved in oxidation and hydroxylation processes, including CYP2D6, CYP3A4, CYP2E1, CYP2C9, and CYP1A2. Studies in healthy volunteers and patients have shown that the R-enantiomer is predominantly metabolized by CYP2D6. The S-enantiomer is primarily metabolized by CYP2D6 and CYP2C9.

Genetic polymorphism. Results from clinical pharmacokinetic studies in humans have shown that CYP2D6 plays an important role in the metabolism of R- and S-carvedilol. As a result, plasma concentrations of R- and S-carvedilol are increased in CYP2D6 poor metabolizers. The importance of CYP2D6 genotype in the pharmacokinetics of R- and S-carvedilol has been confirmed in population pharmacokinetic studies, although other studies have not confirmed this observation. It has been concluded that CYP2D6 genetic polymorphism may have limited clinical significance.

Elimination. After a single oral dose of 50 mg carvedilol, approximately 60% is secreted into bile and excreted in feces as metabolites over 11 days. After a single oral dose, only about 16% is excreted in urine as carvedilol or its metabolites. Excretion of unchanged drug in urine is less than 2%. After intravenous infusion of 12.5 mg to healthy volunteers, the plasma clearance of carvedilol reaches approximately 600 mL/min, and the elimination half-life is about 2.5 hours. The half-life of a 50 mg capsule observed in the same individuals was 6.5 hours, which actually corresponded to the capsule's half-life. After oral administration, the total systemic clearance of S-carvedilol is approximately twice that of R-carvedilol.

Ageing. Age does not have a statistically significant effect on the pharmacokinetics of carvedilol in patients with arterial hypertension.

Liver disease. In studies of patients with liver cirrhosis, the bioavailability of carvedilol is 4 times higher, and the maximum plasma concentration is 5 times higher than in healthy volunteers.

Renal impairment. Since carvedilol is primarily excreted in feces, significant accumulation in patients with renal impairment is unlikely. In patients with arterial hypertension and renal impairment, the area under the plasma concentration-time curve, elimination half-life, and maximum plasma concentration do not change significantly. Renal excretion of unchanged drug is reduced in patients with renal impairment; however, changes in pharmacokinetic parameters are moderate. Carvedilol is not removed during dialysis, as it does not cross the dialysis membrane, likely due to its high plasma protein binding.

Clinical characteristics.

Indications.

Dosage of 6.25 mg

Adjunctive therapy for symptomatic chronic heart failure to reduce morbidity and improve well-being.

Treatment of hypertension.

Dosage of 25 mg

Adjunctive therapy for symptomatic chronic heart failure to reduce morbidity and improve well-being.

Treatment of hypertension.

Long-term treatment of stable angina pectoris.

Contraindications.

Hypersensitivity to carvedilol or to any of the excipients, unstable or decompensated heart failure requiring intravenous inotropic therapy, severe hepatic impairment, bronchial asthma or history of bronchospasm, second- or third-degree atrioventricular block (unless in patients with a permanent pacemaker), severe bradycardia (heart rate less than 50 beats/min at rest), cardiogenic shock, sick sinus syndrome (including sinoatrial block), severe hypotension (systolic blood pressure below 85 mm Hg).

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interactions. Carvedilol is both a substrate and an inhibitor of P-glycoprotein. Therefore, the bioavailability of drugs transported by P-glycoprotein may be increased when administered concomitantly with carvedilol. In addition, the bioavailability of carvedilol may be altered by inducers or inhibitors of P-glycoprotein.

Digoxin. In some studies involving healthy volunteers and patients with heart failure, an increase in digoxin exposure by up to 20% has been demonstrated. A significantly greater effect was observed in male patients compared to female patients. Therefore, monitoring of digoxin levels is recommended at the initiation of treatment, during dose adjustment, or discontinuation of carvedilol. Carvedilol did not affect intravenous digoxin administration.

Cyclosporine and tacrolimus. Two studies in heart and kidney transplant patients receiving oral cyclosporine showed increased cyclosporine plasma concentrations after initiation of carvedilol. Carvedilol appears to increase the exposure to oral cyclosporine by approximately 10–20%. To maintain therapeutic cyclosporine levels, cyclosporine dosage had to be reduced on average by 10–20%. The mechanism of interaction is unknown, but inhibition of intestinal P-glycoprotein by carvedilol is possible. Due to wide interindividual variability in cyclosporine levels, careful monitoring of cyclosporine concentration is recommended after initiation of carvedilol therapy, with appropriate adjustment of cyclosporine dosage. No interaction is expected with intravenous cyclosporine. Furthermore, data indicate that CYP3A4 is involved in the metabolism of carvedilol. Since tacrolimus is a substrate of both P-glycoprotein and CYP3A4, its pharmacokinetics may also be influenced by carvedilol via these interaction mechanisms.

Effect of other medicinal products and substances on the pharmacokinetics of carvedilol. Inhibitors and inducers of CYP2D6 and CYP2C9 may stereoselectively modify systemic and/or presystemic metabolism of carvedilol, leading to increased or decreased plasma concentrations of R- and S-carvedilol. Some examples observed in patients or healthy subjects are listed below, but the list is not exhaustive.

Rifampicin. In a study involving 12 healthy volunteers, the exposure to carvedilol decreased by approximately 60% during concomitant administration with rifampicin, and a reduction in the effect of carvedilol on systolic blood pressure was also observed. The mechanism of interaction is unknown but may be due to induction of intestinal P-glycoprotein by rifampicin. Careful monitoring of beta-blockade activity is advisable in patients receiving carvedilol and rifampicin concomitantly.

Amiodarone. In vitro studies with human liver microsomes showed that amiodarone and desethylamiodarone inhibit the oxidation of R- and S-carvedilol. The lowest concentration of R- and S-carvedilol increased significantly by 2.2-fold in patients with heart failure receiving carvedilol and amiodarone concomitantly, compared to patients receiving carvedilol monotherapy. The effect on S-carvedilol was attributed to desethylamiodarone, a metabolite of amiodarone, which is a potent inhibitor of CYP2C9. Monitoring of beta-blockade activity is recommended in patients receiving a combination of carvedilol and amiodarone.

Fluoxetine and paroxetine. In a randomized crossover study in 10 patients with heart failure, concomitant administration of fluoxetine, a potent CYP2D6 inhibitor, resulted in stereoselective inhibition of carvedilol metabolism, with a mean increase of 77% in AUC of the R-enantiomer and a slight increase of 35% in AUC of the S-enantiomer compared to placebo. However, no differences in adverse events, blood pressure, or heart rate were observed between treatment groups. The effect of a single dose of paroxetine, a potent CYP2D6 inhibitor, on the pharmacokinetics of carvedilol was investigated in 12 healthy volunteers after a single oral dose. Despite a significant increase in exposure to R- and S-carvedilol, no clinical effects were observed in these healthy subjects.

Alcohol. Alcohol consumption has an acute hypotensive effect, which may potentiate the blood pressure-lowering effect of carvedilol. Since carvedilol is soluble in ethanol, the presence of alcohol may affect the rate and/or extent of intestinal absorption of carvedilol. Additionally, carvedilol is partially metabolized by CYP2E1, an enzyme known to be induced and inhibited by alcohol.

Grapefruit juice. Consumption of a single 300 mL dose of grapefruit juice increases the AUC of carvedilol by 1.2-fold compared to water. Although the clinical significance is unclear, patients should avoid concomitant intake of grapefruit juice at least until a stable dose-response relationship is established.

Pharmacodynamic interactions.

Insulin or oral hypoglycemic agents. Agents with beta-blocking properties may potentiate the hypoglycemic effect of insulin and oral hypoglycemic agents. Signs of hypoglycemia may be masked or attenuated (particularly tachycardia). Therefore, patients receiving insulin or oral hypoglycemic agents should have regular monitoring of blood glucose levels.

Catecholamine agents. Patients receiving beta-blocking agents concomitantly with medicinal products that may reduce catecholamine levels (e.g., reserpine inhibitors and monoamine oxidase inhibitors) should be closely monitored for signs of hypotension and/or severe bradycardia.

Digoxin. Combined use of beta-blockers and digoxin may lead to additive prolongation of atrioventricular conduction time.

Non-dihydropyridine calcium channel blockers, amiodarone, or other antiarrhythmic agents. Combined use of non-dihydropyridine calcium channel blockers, amiodarone, or other antiarrhythmic agents with carvedilol may increase the risk of atrioventricular conduction disturbances. Isolated cases of conduction disturbances (rarely with hemodynamic impairment) have been observed with concomitant use of carvedilol and diltiazem. Similar to other agents with beta-blocking properties, when administering carvedilol orally together with non-dihydropyridine calcium channel blockers such as verapamil or diltiazem, amiodarone, or other antiarrhythmic agents, ECG and blood pressure monitoring are recommended.

Clonidine. Concomitant use of clonidine and beta-blocking agents may enhance the effects of lowering blood pressure and heart rate. When discontinuing concomitant therapy with beta-blocking agents and clonidine, beta-blocker therapy should be discontinued first. After several days, clonidine therapy may then be discontinued gradually by tapering the dose.

Antihypertensive agents. Like other beta-blockers, carvedilol may potentiate the effect of concomitantly administered antihypertensive agents (e.g., α1-receptor antagonists) or may lead to hypotension according to its adverse effect profile.

Anesthetics. Caution should be exercised during anesthesia due to synergistic negative inotropic and hypotensive effects of carvedilol and anesthetics.

Nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant use of NSAIDs and beta-blockers may lead to increased blood pressure and reduced blood pressure control.

β-agonists of bronchodilators. Non-cardioselective β-blockers antagonize the effects of β-agonist bronchodilators. Close monitoring of patients is recommended.

Dihydropyridines. Administration of dihydropyridines and carvedilol should be performed under close medical supervision, as there have been reports of heart failure and severe hypotension.

Nitrates. Concomitant use with carvedilol leads to an increased hypotensive effect.

Ergotamine. Vasoconstriction is enhanced.

Neuromuscular blocking agents (muscle relaxants). Carvedilol potentiates the effect of neuromuscular blocking agents.

Special precautions for use.

Chronic congestive heart failure. In patients with congestive heart failure, worsening of heart failure or fluid retention may occur during carvidilol titration. If such symptoms occur, diuretic dosage should be increased and carvidilol dose should not be escalated until clinical stability is restored. Sometimes it may be necessary to reduce the dose of carvidilol or, rarely, temporarily discontinue the drug. Such episodes do not preclude subsequent successful titration of carvidilol.

Carvedilol should be used with caution in combination with digitalis glycosides, as both drugs slow atrioventricular conduction.

Renal function in congestive heart failure. Reversible deterioration of renal function has been observed during carvedilol therapy in patients with chronic heart failure who have low blood pressure (systolic BP <100 mm Hg), ischemic heart disease, and diffuse vascular disease and/or renal insufficiency. In patients with chronic heart failure and these risk factors, renal function should be monitored during dose escalation of carvedilol, and the drug should be discontinued or the dose reduced if renal insufficiency worsens.

Chronic obstructive pulmonary disease. Carvedilol should be used cautiously in patients with chronic obstructive pulmonary disease (COPD) with a bronchospastic component who are not receiving oral or inhaled corticosteroids, and only if the potential benefit outweighs the potential risk. Close monitoring is required when initiating treatment and during dose escalation by titration, and the carvedilol dose should be reduced if any evidence of bronchospasm occurs during treatment.

Diabetes. Caution should be exercised when administering carvedilol to patients with diabetes, as it may impair glucose control. In addition, early signs and symptoms of acute hypoglycemia may be masked or attenuated. Alternatives to beta-blockers are generally preferred for insulin-dependent patients. Therefore, regular monitoring of blood glucose levels is necessary in diabetic patients when initiating or adjusting the dose of carvedilol, and hypoglycemic therapy should be adjusted accordingly.

Peripheral vascular disease and Raynaud's phenomenon. Carvedilol should be used with caution in patients with peripheral vascular disorders (e.g., Raynaud's phenomenon), as beta-adrenergic blockers may cause or exacerbate symptoms of arterial insufficiency.

Thyrotoxicosis. Carvedilol may mask symptoms of thyrotoxicosis.

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

Hypersensitivity. Caution is advised when using carvedilol in patients with a history of severe hypersensitivity reactions and in patients undergoing desensitization therapy, as beta-blockers may increase both sensitivity to allergens and the severity of hypersensitivity reactions.

Severe skin adverse reactions. Very rare cases of severe skin adverse reactions, such as toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported during carvedilol treatment. The drug should be permanently discontinued in patients who develop severe skin adverse reactions that may be related to carvedilol.

Psoriasis. Patients with a history of psoriasis associated with beta-blocker therapy should only take carvedilol after careful assessment of the risk-benefit ratio.

Interaction with other medicinal products. There are several important pharmacokinetic and pharmacodynamic interactions with other medicinal products (e.g., digoxin, cyclosporine, rifampicin, anesthetics, antiarrhythmics) (see section "Interaction with other medicinal products and other forms of interaction").

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

Prinzmetal's angina. Non-selective beta-adrenergic blockers may provoke 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; however, caution is advised when initiating carvedilol in patients suspected of having Prinzmetal's angina.

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

Withdrawal syndrome. As with other beta-adrenergic blockers, carvedilol therapy should not be abruptly discontinued, particularly in patients with ischemic heart disease. Carvedilol therapy should be gradually withdrawn over a two-week period, for example by reducing the daily dose by half every three days.

Excipients. The product contains sucrose and lactose. This medicine is not recommended for patients with the following conditions: fructose intolerance, lactase deficiency, galactosemia, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

There is insufficient clinical experience with the use of carvedilol in pregnant women. Animal studies have demonstrated effects on pregnancy, embryonic/fetal development, parturition, reproductive toxicity, and postnatal development. The potential risk to humans is unknown. Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential risk.

Beta-adrenergic blockers reduce placental perfusion, which may lead to intrauterine fetal death and premature delivery. In addition, adverse reactions (particularly hypoglycemia and bradycardia) may occur in the fetus and newborn. There is an increased risk of cardiac and pulmonary complications in newborns during the postnatal period. Animal studies have not shown significant evidence of teratogenicity with carvedilol.

Breastfeeding. Animal studies have shown that carvedilol and/or its metabolites are excreted in rat milk. Excretion of carvedilol into human breast milk has not been established. However, most beta-adrenergic blockers, particularly lipophilic compounds, are known to pass into human breast milk to varying degrees. Therefore, breastfeeding is not recommended after administration of carvedilol.

Ability to affect reaction speed when driving or operating machinery.

No studies on the effect on the ability to drive or operate machinery have been conducted.

Patients taking carvedilol should be advised not to drive or operate machinery if they experience dizziness or other symptoms related to the use of the drug. This is particularly important at the beginning of treatment, during dose escalation, when changing therapy, or when combining the drug with alcohol.

Dosage and Administration

Dosage

Chronic Heart Failure. The dose should be titrated according to individual needs, with gradual dose escalation carefully monitored. Patients receiving diuretics and/or digoxin and/or ACE inhibitors should have their therapy stabilized prior to initiating treatment with carvedilol.

Adults. The recommended starting dose is 3.125 mg (half of a 6.25 mg tablet) twice daily for 2 weeks. If tolerated, the dose may be gradually increased at intervals of at least 2 weeks to 6.25 mg twice daily, then to 12.5 mg twice daily, and eventually to 25 mg twice daily. The dose should be increased to the maximum level tolerated by the patient.

The maximum recommended dose is 25 mg twice daily for patients with severe chronic heart failure and for patients with mild to moderate heart failure and body weight below 85 kg. For patients with mild to moderate heart failure and body weight above 85 kg, the maximum recommended dose of carvedilol is 50 mg twice daily.

Prior to each dose increase, the physician should evaluate the patient for signs of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation, or fluid retention can be managed with increased doses of diuretics or ACE inhibitors, or by modification or temporary discontinuation of carvedilol therapy. Under such circumstances, the carvedilol dose should not be increased until symptoms of worsening heart failure or vasodilation have stabilized.

If treatment with carvedilol is interrupted for more than one week, therapy should be restarted at a lower dose level (twice daily) and titrated according to the above dosage recommendations.

If treatment with carvedilol is discontinued for more than two weeks, therapy should be restarted at 3.125 mg twice daily and titrated according to the above dosage recommendations.

Elderly Patients. As for adults.

Hypertension

Adults. The recommended initial dose for the first 2 days of treatment is 12.5 mg once daily. Treatment should then continue at a dose of 25 mg once daily. Although this is an adequate dose for most patients, the dose may be titrated, if necessary, to the recommended maximum daily dose of 50 mg, administered once daily or in divided doses. Dose titration should occur at intervals of at least two weeks.

Elderly Patients. The recommended initial dose is 12.5 mg once daily, which may be sufficient for continued treatment. If the therapeutic effect is inadequate, the dose may be titrated to the recommended maximum daily dose of 50 mg, administered once daily or in divided doses.

Angina Pectoris

Adults. The recommended starting dose is 12.5 mg twice daily for the first two days. Thereafter, the recommended dose is 25 mg twice daily. If necessary, the dose may be titrated up to 50 mg twice daily. Dose titration should occur at intervals of at least two weeks.

Elderly Patients. The recommended maximum daily dose is 50 mg, divided into two doses.

Special Dosage Instructions. As with all beta-blockers, treatment should not be abruptly discontinued, but gradually tapered with weekly intervals. This is particularly important in patients with concomitant ischemic heart disease.

Renal Impairment. Pharmacokinetic data and clinical studies in patients with impaired renal function (including renal insufficiency) indicate that dose adjustment is required in moderate to severe renal impairment.

Pediatric Patients. Safety and efficacy of carvedilol in children and adolescents under 18 years of age have not been established.

Route of Administration. The drug is intended for oral use only.

Tablets should be taken with water. In patients with chronic heart failure, the drug should be taken with food to slow the rate of absorption and reduce the frequency of orthostatic effects.

Children. The drug is not recommended for use in children due to lack of data on safety and efficacy in this patient population.

Overdose

Symptoms. Overdose may cause severe arterial hypotension, bradycardia, heart failure, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasm, vomiting, impaired consciousness, and generalized seizures may also occur.

Treatment. The patient's condition should be monitored and vital parameters corrected according to standard guidelines for managing overdose with β-adrenergic blockers (e.g., atropine, transvenous cardiac pacing, glucagon, phosphodiesterase inhibitors such as amrinone or milrinone, β-sympathomimetics). Within the first few hours, induce vomiting and perform gastric lavage.

In cases of severe overdose where the patient is in cardiogenic shock, supportive treatment should be continued for a sufficiently long period, as elimination or redistribution of carvedilol may be slower than usual.

Side effects.

The frequency of adverse reactions is dose-independent, except for dizziness, visual disturbances, and bradycardia. The adverse reactions listed below are categorized according to MedDRA terminology, with frequencies defined 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); frequency not known (cannot be estimated from available data).

Infections and infestations: common – bronchitis, pneumonia, upper respiratory tract infections, urinary tract infections.

Blood and lymphatic system disorders: common – anaemia; rare – thrombocytopenia; very rare – leukopenia.

Immune system disorders: very rare – hypersensitivity (allergic reactions).

Metabolism and nutrition disorders: common – weight gain, hypercholesterolemia, worsening of glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes mellitus.

Psychiatric disorders: common – depression, depressed mood; uncommon – sleep disorders.

Nervous system disorders: very common – dizziness, headache; common – presyncope, syncope; uncommon – paraesthesia.

Eye disorders: common – visual disturbance, decreased tear production (dry eyes), eye irritation.

Cardiac disorders: very common – heart failure; common – bradycardia, hypervolaemia (increased fluid volume); uncommon – atrioventricular block, angina pectoris.

Vascular disorders: common – orthostatic hypotension, peripheral circulation disorders (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Raynaud's phenomenon), arterial hypertension; very rare – arterial hypotension.

Respiratory, thoracic and mediastinal disorders: common – dyspnoea, pulmonary oedema, bronchial asthma in predisposed patients; rare – nasal congestion, rhinitis.

Gastrointestinal disorders: common – nausea, diarrhoea, vomiting, abdominal pain; uncommon – constipation; very rare – dry mouth.

General disorders and administration site conditions: very common – asthenia (increased fatigue), common – pain.

Hepatobiliary disorders: very rare – increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT).

Skin and subcutaneous tissue disorders: uncommon – skin reactions (e.g., allergic exanthema, dermatitis, urticaria, pruritus, psoriasiform or lichen planus-like skin lesions), alopecia.

Musculoskeletal and connective tissue disorders: common – limb pain.

Renal and urinary disorders: common – renal failure and impaired renal function in patients with diffuse vascular disease and/or pre-existing renal insufficiency; rare – urinary disorders; very rare – urinary incontinence in women.

Reproductive system and breast disorders: uncommon – erectile dysfunction.

General disorders at the site of administration: very common – asthenia (fatigue); common – pain, oedema.

Data on selected adverse reactions. The frequency of adverse effects is dose-independent, except for dizziness, visual disturbances, and bradycardia. Dizziness, loss of consciousness, headache, and asthenia are usually mild and more likely to occur at the beginning of treatment. 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 those receiving carvedilol (14.5% and 15.4%, respectively, in patients with left ventricular dysfunction following acute myocardial infarction). Reversible worsening of renal function has been observed during carvedilol therapy in patients with chronic heart failure, low blood pressure, ischaemic heart disease, and/or diffuse vascular disease and/or renal insufficiency.

Adverse effects identified during post-marketing use of carvedilol. Since reports on these reactions were voluntary and the population size is unknown, reliable estimation of frequency is not possible; therefore, these events are categorized as adverse reactions with unknown frequency.

Metabolism and nutrition disorders. As a class, beta-blockers may unmask latent diabetes mellitus, worsen manifest diabetes mellitus, and impair glucose regulation.

Psychiatric disorders. Carvedilol may cause hallucinations.

Cardiac disorders. Sinus node arrest may occur in patients predisposed to this condition (e.g., elderly patients or those with bradycardia, sinus node dysfunction, or atrioventricular block).

Skin and subcutaneous tissue disorders. Severe skin adverse reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome).

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

Special populations. Studies in elderly patients with hypertension or angina pectoris showed that the adverse effect profile was not different from that in younger patients. A further study including elderly patients with ischaemic arterial disease did not show significant differences in reported adverse effects compared to those reported in younger patients.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. In case of adverse reactions or questions regarding the safety of the medicine, please contact via the feedback form on the website: www.ukraine.medochemie.com.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging, out of reach of children.

Packaging. 10 tablets in a blister. 3 or 10 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Medochemie LTD (Central Factory)/Medochemie LTD (Central Factory).
2. Medochemie Limited/Medochemie Limited.

Manufacturer's location and address of operations.

1. 1-10 Constantinoupoleos Street, Limassol, 3011, Cyprus.
2. Michail Irakleous 2, Agios Athanassios Industrial Area, Agios Athanassios, Limassol, 4101, Cyprus.