Talliton

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TALLITON® (TALLITON®)

Composition:

Active substance: carvedilol;

1 tablet contains 6.25 mg or 12.5 mg or 25 mg of carvedilol;

Excipients:

tablets 6.25 mg: quinoline yellow (E 104), magnesium stearate, povidone, colloidal anhydrous silicon dioxide, sucrose, crospovidone, lactose monohydrate;

tablets 12.5 mg: yellow azo dye FCF (E 110), magnesium stearate, povidone, colloidal anhydrous silicon dioxide, sucrose, crospovidone, lactose monohydrate;

tablets 25 mg: magnesium stearate, povidone, colloidal anhydrous silicon dioxide, sucrose, crospovidone, lactose monohydrate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets 6.25 mg: pale yellow, flat, elongated tablets with beveled edges, a score line on one side and engraved stylized letter and number "E 341" on the other side, odorless or nearly odorless;

tablets 12.5 mg: pale orange (darker specks possible), flat, round tablets with beveled edges, a score line on one side and engraved stylized letter and number "E342" on the other side, odorless or nearly odorless;

tablets 25 mg: white or almost white, flat, round tablets with beveled edges, a score line on one side and engraved stylized letter and number "E 343" on the other side, odorless or nearly odorless.

Pharmacotherapeutic group. Combined alpha- and beta-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 alpha- and beta-adrenoceptor blocker. Blockade of beta-adrenergic receptors is associated with the S-enantiomer and is nonselective for beta-1- and beta-2-adrenoceptors, whereas both enantiomers have identical blocking properties specific for alpha-1-adrenoceptors. At higher concentrations, carvedilol also weakly or moderately blocks 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 alpha-1-adrenoceptors. Carvedilol reduces arterial blood pressure induced by phenylephrine, an alpha-1-adrenoceptor agonist, but not that induced by angiotensin II.

Blockade of calcium channels by carvedilol may enhance circulation in certain vascular beds, such as cutaneous circulation. Due to its beta-blocking action, carvedilol suppresses the renin-angiotensin-aldosterone system (RAAS), reducing renin release and rarely causing fluid retention.

Carvedilol has organoprotective effects, which are probably partly due to additional properties beyond its blockade of adrenergic receptors. It has potent antioxidant properties associated with both enantiomers and acts as a scavenger of reactive oxygen species. Clinical studies have demonstrated reduced oxidative stress, measured using various biomarkers, during long-term treatment with carvedilol. Furthermore, carvedilol exerts antiproliferative effects on human vascular smooth muscle cells.

Carvedilol does not affect lipid profile. It does not alter the ratio of high- and low-density lipoproteins (HDL/LDL).

Clinical efficacy

Arterial hypertension

Carvedilol reduces blood pressure in hypertensive patients through a combination of beta-blockade and alpha-1-mediated vasodilation. Its antihypertensive effect is not associated with an increase in total peripheral resistance, which is characteristic of drugs with pure beta-blocking activity.

Heart rate is slightly reduced during its use. Renal blood flow and kidney function remain unchanged in patients with arterial hypertension. Carvedilol does not affect cardiac stroke volume and reduces total peripheral vascular resistance. It does not impair blood supply to individual organs and their supplying vessels, including kidneys, skeletal muscles, forearms, legs, skin, brain, or carotid arteries. The frequency of cold extremities and early fatigue during physical exertion, commonly observed during treatment with beta-blockers lacking vasodilatory effects, is reduced.

The long-term effect of carvedilol on arterial hypertension has been confirmed in several clinical trials. The antihypertensive effect has a rapid onset, reaches maximum within 2–3 hours, and lasts for 24 hours. With prolonged treatment, maximum effect can be expected within 3–4 weeks.

Patients with arterial hypertension and renal impairment

Several clinical studies have demonstrated that carvedilol can be effectively used in renal hypertension, as well as in chronic renal failure, in patients undergoing hemodialysis, or who have undergone kidney transplantation. Carvedilol gradually reduces blood pressure both on dialysis and non-dialysis days, and its antihypertensive efficacy is similar to that observed in patients with normal kidney function.

Based on results from comparative studies, it has been concluded that in hemodialysis patients, carvedilol is more effective and better tolerated than calcium channel blockers.

Ischemic heart disease

In patients with ischemic heart disease, carvedilol has demonstrated anti-ischemic and antianginal properties during long-term treatment. Studies of acute hemodynamic effects showed that carvedilol significantly reduces myocardial oxygen demand and excessive sympathetic activity. Carvedilol also reduces ventricular preload (pulmonary artery pressure, pulmonary capillary pressure) and afterload (total peripheral resistance).

Chronic heart failure

In patients with chronic heart failure, carvedilol significantly reduced mortality and hospitalization rates in clinical trials. It has been proven effective and well tolerated even in patients with severe chronic heart failure. Carvedilol increased ejection fraction and alleviated symptoms of ischemic and non-ischemic chronic heart failure. The effect of carvedilol was dose-dependent. In another study, the addition of carvedilol to standard therapy significantly reduced mortality compared to the comparator drug metoprolol.

Chronic heart failure in patients with renal impairment

Carvedilol reduces morbidity and mortality in dialysis patients with dilated cardiomyopathy.

Additionally, a meta-analysis of pooled individual data from 4217 patients, including 2566 patients with chronic kidney disease, from two multinational double-blind placebo-controlled randomized trials showed that in patients with mild to moderate renal impairment associated with mild to moderate left ventricular dysfunction, with or without heart failure, carvedilol reduces the risk of all-cause mortality, cardiovascular mortality, death from heart failure, and the risk of first hospitalization due to heart failure. In patients with moderate renal dysfunction (GFR [glomerular filtration rate] < 45 mL/min/1.73 m²), there was no significant difference in these endpoints between the carvedilol and placebo groups.

Left ventricular dysfunction after acute myocardial infarction

In a double-blind placebo-controlled trial involving 1959 patients after myocardial infarction with left ventricular ejection fraction ≤ 40% or wall motion index ≤ 1.3 (with or without symptoms of heart failure), carvedilol did not show a statistically significant reduction in one of the primary endpoints, death or hospitalization due to cardiovascular complaints (8% reduction compared to placebo, p = 0.297), but significantly reduced overall mortality by 23% (p = 0.031), incidence of fatal and non-fatal myocardial infarction by 29% (p = 0.002), cardiovascular mortality by 25% (p = 0.024), and frequency of hospitalizations due to non-fatal myocardial infarction by 41% (p = 0.014). According to additional analysis, carvedilol significantly reduced mortality or hospitalization due to serious cardiovascular complications by 17% (p = 0.019).

Paediatric population

The safety and efficacy of carvedilol in children and adolescents have not been established due to limited number and scope of studies. Available studies have focused on the treatment of heart failure in children, which differs from adult disease in characteristics and etiology. Results from several preliminary and observational studies on heart failure, including heart failure due to muscular dystrophy, suggested possible beneficial effects of carvedilol, but evidence of efficacy from randomized controlled trials remains conflicting and unconvincing.

Safety data from these studies show that adverse events were generally similar between the carvedilol treatment group and the control group. 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 the paediatric safety profile of carvedilol.

Thus, the use of carvedilol in children and adolescents is not recommended due to lack of safety data and inability to assess the benefit-risk ratio.

Pharmacokinetics.

Absorption

After oral administration, carvedilol is rapidly absorbed in the gastrointestinal tract. Maximum plasma concentration is reached approximately 1 hour after intake. Absolute bioavailability is approximately 25%. Carvedilol is a substrate of the efflux transporter P-glycoprotein, which plays a key role in the bioavailability of certain drugs.

In healthy volunteers, after oral administration of a 25 mg capsule, carvedilol is rapidly absorbed, with maximum plasma concentration (Cmax) of 21 µg/L reached approximately 1.5 hours (tmax). Pharmacokinetics of carvedilol is linear (plasma concentration is proportional to the administered dose). After oral administration, carvedilol undergoes extensive first-pass metabolism, with bioavailability of approximately 25% in healthy male volunteers. Carvedilol is a racemic mixture, and the S-enantiomer appears to be metabolized faster than the R-enantiomer, resulting in absolute oral bioavailability of 15% compared to 31% for the R-enantiomer. Maximum plasma concentration of R-carvedilol is approximately twice that of S-carvedilol. Food does not affect bioavailability or maximum plasma concentration, but may prolong the time to reach maximum concentration.

In vitro studies showed that carvedilol is a substrate of the P-glycoprotein efflux transporter. The role of P-glycoprotein in carvedilol distribution was also confirmed in vivo in healthy volunteers.

Distribution

Carvedilol is a highly lipophilic compound, with plasma protein binding of approximately 95%. Volume of distribution ranges from 1.5 to 2 L/kg and increases in patients with hepatic impairment.

Biological transformation

In humans, carvedilol is metabolized in the liver, forming several metabolites that are primarily excreted via bile. Enterohepatic recirculation of carvedilol has been observed in animal studies.

Demethylation and hydroxylation of the phenolic ring lead to the formation of three active metabolites with beta-blocking activity. Preclinical studies indicate that the 4'-hydroxyphenol metabolite has 13 times greater beta-blocking activity than carvedilol. However, the three active metabolites are weaker vasodilators than carvedilol. Concentrations of the three active metabolites are about one-tenth of carvedilol concentrations. Two hydroxycarbazole metabolites are very potent antioxidants, with activity 30–80 times stronger than that of carvedilol.

Pharmacokinetic studies in humans have shown that oxidative metabolism of carvedilol is stereoselective. In vitro studies suggest that various cytochrome P450 isoenzymes, including CYP2D6, CYP3A4, CYP2E1, CYP2C9, and CYP1A2, may be involved in oxidation and hydroxylation processes.

Studies in healthy volunteers and patients have shown that the R-enantiomer is predominantly metabolized by CYP2D6. The S-enantiomer is mainly metabolized by CYP2D6 and CYP2C9.

Genetic polymorphism

Clinical pharmacokinetic studies in humans have shown that CYP2D6 plays an important role in the metabolism of R- and S-carvedilol. Thus, plasma concentrations of R- and S-carvedilol are higher in individuals who are poor CYP2D6 metabolizers. The importance of CYP2D6 genotype in the pharmacokinetics of R- and S-carvedilol was confirmed in a population pharmacokinetic study, although other studies did not confirm this observation. It has been concluded that CYP2D6 genetic polymorphism may have limited clinical significance. This is supported by observations that differences in pharmacokinetic characteristics due to CYP2D6 polymorphism did not significantly affect the pharmacodynamic response in healthy volunteers, and no association was found between CYP2D6 genotype or phenotype and carvedilol dose or frequency of adverse events in patients with heart failure.

Elimination

After a single oral dose of 50 mg carvedilol, approximately 60% is excreted in bile and eliminated in feces as metabolites within 11 days. After a single oral dose, only about 16% is excreted in urine as carvedilol or its metabolites. Less than 2% of the drug is excreted unchanged in urine. After intravenous infusion of 12.5 mg in healthy volunteers, plasma clearance of carvedilol was approximately 600 mL/min, and elimination half-life was about 2.5 hours. The elimination half-life in the same subjects after a 50 mg capsule was 6.5 hours, which corresponds to the half-life from the capsule. After oral administration, total clearance of S-carvedilol is approximately twice that of R-carvedilol.

Pharmacokinetic/pharmacodynamic relationships

Binding of carvedilol to adrenergic receptors was studied using radioreceptor assays. Enantiomer kinetics were dose-proportional. A linear relationship was found between therapeutic response, measured by ergometric heart rate, and logarithmically transformed dose and concentration of the S-enantiomer, as well as binding to beta-1-adrenergic receptors. As with other beta-blockers, there is a time lag between achieving a certain plasma concentration and pharmacodynamic effect: maximum effect on heart rate and blood pressure occurs later than peak plasma concentration. It has been established that metabolic differences characteristic of different CYP2D6 genotypes cause significant pharmacokinetic differences but do not affect heart rate, blood pressure, or side effects, likely due to compensation by active metabolites and the overall flat concentration-response curve. Overall, the dose-response relationship and kinetic-dynamic relationships of carvedilol are determined by complex interactions between enantiospecific kinetics and dynamics, protein binding, and the contribution of active metabolites, as outlined above in this section.

Pharmacokinetics in special populations

Renal impairment

During long-term treatment with carvedilol, renal blood flow was not impaired, and glomerular filtration rate remained unchanged.

In patients with arterial hypertension and renal impairment, plasma AUC levels, elimination half-life, and Cmax values were not significantly altered. In patients with renal impairment, renal excretion of carvedilol is reduced, but changes in pharmacokinetic parameters are minor.

Carvedilol is not removed during dialysis, as it does not pass through the dialysis membrane, likely due to its very high degree of plasma protein binding.

Hepatic impairment

In severe hepatic impairment, carvedilol bioavailability is significantly increased (up to 80%) due to reduced first-pass effect. Therefore, carvedilol is contraindicated in patients with severe hepatic impairment. A pharmacokinetic study in patients with liver cirrhosis showed that exposure (AUC) of carvedilol increases 6.8-fold in patients with hepatic impairment compared to healthy individuals.

Heart failure

In a study involving 24 Japanese patients with heart failure, clearance of R- and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results indicate that heart failure has a significant impact on the pharmacokinetics of R- and S-carvedilol.

Elderly patients

Age did not affect the pharmacokinetics of carvedilol in patients with arterial hypertension. A clinical study in elderly patients with arterial hypertension showed no difference in adverse effect profile compared to younger patients. Similarly, no difference in adverse effects was observed in another clinical study involving elderly patients with ischemic heart disease.

Paediatric population

Studies in paediatrics have shown that clearance, corrected for body weight, is significantly higher in the paediatric population than in adults.

Preclinical safety data.

Carcinogenicity

In carcinogenicity studies in rats and mice, carvedilol did not show carcinogenic effects when administered at doses 38–100 times higher than the recommended maximum human dose.

Mutagenicity

Carvedilol did not show mutagenic effects in in vitro and in vivo studies in mammals and other animals.

Fertility impairment and teratogenicity

In female rats, carvedilol administered at a toxic dose (100 times the human dose) caused fertility impairment, while a dose 30 times the human dose led to delayed growth/development of offspring. Embryotoxicity was observed in rats and rabbits at doses 38–100 times the human dose, but no developmental abnormalities were observed.

Clinical characteristics.

Indications.

• Essential arterial hypertension – as monotherapy or in combination with other antihypertensive agents (particularly with hydrochlorothiazide).
• Chronic stable angina pectoris (the drug is not suitable for treatment of acute angina attacks).
• Moderate to severe chronic heart failure – as an adjunct to standard therapy with diuretics, digoxin, or ACE inhibitors.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• Decompensated heart failure – NYHA (New York Heart Association) Class IV heart failure requiring intravenous administration of inotropic agents;
• Second- or third-degree atrioventricular block (except when a permanent pacemaker is implanted);
• Concomitant intravenous administration of verapamil, diltiazem, or other antiarrhythmic agents (particularly Class I antiarrhythmics);
• Severe bradycardia (heart rate < 50 beats/min);
• Severe arterial hypotension (systolic blood pressure below 85 mm Hg);
• Cardiogenic shock;
• Sinus node dysfunction (including sinoatrial block);
• Uncompensated 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;
• Pheochromocytoma (unless adequately controlled with alpha-blockers);
• Severe hepatic impairment / clinically evident liver dysfunction;
• Metabolic acidosis.

Interaction with other medicinal products and other types of interactions.

Pharmacokinetic interactions

Effect of carvedilol on the pharmacokinetics of other medicinal products

Carvedilol is both a substrate and an inhibitor of P-glycoprotein. Therefore, when carvedilol is administered concomitantly, the bioavailability of medicinal products transported by P-glycoprotein may increase. In addition, the bioavailability of carvedilol may be altered by inducers or inhibitors of P-glycoprotein.

Digoxin. In several studies involving healthy volunteers and patients with heart failure, an increase in digoxin exposure by almost 20% was observed. The effect was more pronounced in men than in women. Therefore, monitoring of digoxin levels is required at the initiation of treatment, during dose adjustment, or upon discontinuation of carvedilol therapy. Carvedilol did not affect the action of intravenously administered digoxin.

Cyclosporine and tacrolimus. Two studies in patients who had undergone kidney or heart transplantation and were receiving oral cyclosporine showed increased plasma concentrations of cyclosporine after initiation of carvedilol therapy. Carvedilol is likely to increase the exposure to oral cyclosporine by approximately 10–20%. About 30% of patients required a reduction in cyclosporine dose to maintain cyclosporine concentrations within the therapeutic range, while others did not require dose adjustment. On average, the cyclosporine dose needed to be reduced by approximately 20%. The mechanism of interaction is not fully understood, but inhibition of intestinal P-glycoprotein activity by carvedilol may play a role. Due to the significant interindividual variability in cyclosporine levels after initiation of carvedilol therapy, cyclosporine dosage should be carefully monitored and adjusted as necessary. No interaction with carvedilol is expected when cyclosporine is administered intravenously.

Additionally, 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 affected by carvedilol through these interaction mechanisms.

Effect of other medicinal products and substances on the pharmacokinetics of carvedilol

Inhibitors and inducers of CYP2D6 and CYP2C9 may stereoselectively alter systemic and/or pre-systemic metabolism of carvedilol, leading to increased or decreased plasma concentrations of R- and S-carvedilol. Below are some examples of such effects observed in healthy volunteers or patients.

Amiodarone. In vitro studies with human liver microsomes have shown that amiodarone and its metabolite desethylamiodarone inhibit the oxidation of R- and S-carvedilol. The minimum plasma concentration of R- and S-carvedilol was significantly increased by 2.2-fold in patients with heart failure receiving both carvedilol and amiodarone compared to those receiving carvedilol monotherapy. The effect on S-carvedilol is attributed to desethylamiodarone, a metabolite of amiodarone, which is a potent inhibitor of CYP2C9. Monitoring of beta-blocking activity is recommended in patients receiving combined therapy with carvedilol and amiodarone.

Rifampicin. In a study involving 12 healthy volunteers, the effect of carvedilol was reduced by approximately 60% when administered concomitantly with rifampicin, and a reduction in the effect of carvedilol on systolic blood pressure was also observed. The mechanism of interaction is not known, but it may be due to rifampicin-induced intestinal P-glycoprotein. Careful monitoring of beta-blocking activity is required in patients receiving both carvedilol and rifampicin.

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, increasing the mean AUC of the R(+)-enantiomer by 77% and causing a statistically non-significant increase in the AUC of the S(–)-enantiomer by 35% compared to the placebo group. 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 studied in 12 healthy volunteers after a single oral dose. Despite a significant increase in exposure to both R- and S-carvedilol, no clinical effects were observed in these healthy subjects.

Alcohol. Concomitant consumption of alcohol may affect the antihypertensive effect of carvedilol and cause various adverse reactions. Alcohol has been shown to have an acute hypotensive effect, which may potentiate the blood pressure-lowering effect of carvedilol. Since carvedilol is not water-soluble but soluble in ethanol, the presence of alcohol may influence the rate and/or extent of intestinal absorption of carvedilol by increasing its solubility. Additionally, carvedilol is partially metabolized by CYP2E1, an enzyme that is both 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 of this increase is not fully established, patients should avoid concomitant intake of grapefruit juice, at least until a stable dose-response relationship has been achieved.

Pharmacodynamic interactions

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

Insulin and oral antidiabetic agents. Beta-blocking agents may enhance the hypoglycemic effect of insulin and oral antidiabetic agents. Symptoms of hypoglycemia may be masked or attenuated (particularly tachycardia). Therefore, patients receiving insulin or oral antidiabetic agents are advised to monitor blood glucose levels regularly.

Digoxin. Concomitant 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. Concomitant administration of carvedilol with verapamil, diltiazem, or other antiarrhythmic agents may increase the risk of atrioventricular conduction disturbances.

Isolated cases of conduction disturbances (rarely with hemodynamic compromise) have been observed with concomitant use of carvedilol and diltiazem. Therefore, as with other beta-blocking agents, monitoring of blood pressure, heart rate, and ECG is recommended when carvedilol is used concomitantly with oral non-dihydropyridine calcium channel blockers such as verapamil or diltiazem, amiodarone, or other antiarrhythmic agents.

Concomitant intravenous administration of calcium channel blockers such as verapamil or diltiazem with carvedilol is contraindicated.

Clonidine. Concomitant use of clonidine with beta-blockers may potentiate the effects of lowering blood pressure and heart rate. When discontinuation of combined therapy with beta-blocking agents and clonidine is necessary, the beta-blocker should be discontinued first. Clonidine therapy may then be discontinued several days later by gradually reducing the dose.

Antihypertensive agents. Like other beta-blockers, carvedilol may enhance the effect of other concurrently administered antihypertensive agents (e.g., α1-receptor antagonists) or cause hypotension as a side effect.

Anesthetics. During anesthesia, careful monitoring of vital signs is recommended due to the synergistic negative inotropic and hypotensive effects of carvedilol and anesthetics.

Non-steroidal anti-inflammatory drugs (NSAIDs). Concomitant use of NSAIDs and beta-adrenergic blockers may lead to an increase in blood pressure and impaired blood pressure control.

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

Special precautions for use.

Chronic heart failure

In patients receiving carvedilol for the treatment of chronic heart failure, heart failure symptoms may worsen or fluid retention may occur during dose escalation. If such symptoms occur, the diuretic dose should be increased, and the carvedilol dose should not be changed until the clinical condition stabilizes. Sometimes temporary reduction of Talciton**®** dose or temporary discontinuation of treatment may be necessary. This does not preclude subsequent successful dose titration.

Treatment for chronic heart failure may only be initiated and continued in adequately compensated conditions.

In patients with arterial hypertension receiving digoxin, diuretics and/or angiotensin-converting enzyme (ACE) inhibitors for chronic heart failure, carvedilol should be used with caution, as both digoxin and carvedilol may slow atrioventricular conduction.

Renal function in congestive heart failure

Reversible worsening of 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 and diffuse vascular disease and/or renal insufficiency. In such patients, renal function should be monitored during dose titration of Talciton**®**. If renal function deteriorates, carvedilol should be discontinued or its dose reduced.

Left ventricular dysfunction after acute myocardial infarction

Prior to carvedilol treatment, the patient must be clinically stable and have been receiving an ACE inhibitor for at least 48 hours before starting carvedilol. Furthermore, the ACE inhibitor dose should have been stable for at least 24 hours.

Chronic obstructive pulmonary disease

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 increased airway resistance. Close monitoring is required during initiation and dose escalation of carvedilol through titration. The carvedilol dose should be reduced if bronchospasm occurs during treatment.

Diabetes mellitus

Like other beta-blockers, carvedilol may occasionally impair glycemic control or mask early signs of acute hypoglycemia in patients with diabetes mellitus; therefore, special caution and frequent monitoring of blood glucose levels are required when using carvedilol.

Like other beta-adrenergic blockers, carvedilol may cause manifestation of latent diabetes or exacerbation of existing diabetes.

In patients with chronic heart failure and diabetes mellitus, carvedilol use may be associated with worsening of blood glucose control.

In general, beta-blockers may increase insulin resistance and mask signs of hypoglycemia. However, several studies have shown that vasodilating beta-blockers such as carvedilol have a more favorable effect on glucose levels and lipid profile. Carvedilol has been shown to moderately increase insulin sensitivity and may alleviate some manifestations of metabolic syndrome.

Pheochromocytoma

In patients with pheochromocytoma, any beta-blocking agent should be administered only after prior treatment with alpha-blockers.

There is no experience with carvedilol, which has both alpha- and beta-blocking properties, in pheochromocytoma; therefore, Talciton**®** should be used with caution in patients suspected of having pheochromocytoma.

Prinzmetal's angina

Non-selective beta-adrenergic blockers may cause chest pain in patients with Prinzmetal's angina. Although the alpha-adrenergic blocking effect of carvedilol may prevent the development of such symptoms, there is no clinical experience with carvedilol in Prinzmetal's angina; therefore, it should be prescribed to such patients only with caution.

Peripheral vascular disease and Raynaud's phenomenon

Carvedilol should be used with caution in patients with peripheral vascular disease (e.g., Raynaud's phenomenon), as beta-blockers may precipitate or exacerbate arterial insufficiency or worsen its symptoms. Since carvedilol also has alpha-blocking properties, this effect is predominantly balanced.

Thyrotoxicosis

Like other beta-blockers, carvedilol may mask the symptoms of thyrotoxicosis.

Bradycardia

Carvedilol may cause bradycardia. If bradycardia develops (heart rate less than 55 beats/min), the dose of Talciton**®** should be reduced.

Hypersensitivity reactions

Carvedilol should be prescribed cautiously to patients with a history of severe hypersensitivity reactions and to patients undergoing desensitization therapy, as beta-adrenergic blockers may increase both sensitivity to allergens and the severity of hypersensitivity reactions.

Anaphylactic reaction risk

Patients taking beta-blockers who have a history of severe anaphylactic reactions to various allergens may be more susceptible to re-exposure to allergens, whether accidental, diagnostic, or therapeutic. Such patients may not respond to usual doses of epinephrine used to treat allergic 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.

Patients who develop severe skin adverse reactions possibly related to carvedilol should discontinue the drug and must never restart it.

Psoriasis

Carvedilol should be prescribed to patients with psoriasis or a family history of psoriasis only after careful assessment of the risk-benefit ratio.

Interaction with other medicinal products.

It should be noted that clinically significant pharmacokinetic and pharmacodynamic interactions of carvedilol with other medicinal products (e.g., digoxin, cyclosporine, rifampicin, anesthetics, antiarrhythmics) may occur when used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Contact lenses

Patients wearing contact lenses should be advised that carvedilol treatment may reduce tear production.

Discontinuation of treatment

Carvedilol treatment should not be stopped abruptly. Discontinuation (especially in ischemic heart disease and heart failure) should be done cautiously over a period of one or two weeks to avoid withdrawal effects.

Clonidine

When discontinuing combined treatment with clonidine, carvedilol should be discontinued first, followed by clonidine discontinuation a few days later.

Elderly patients

In a study of elderly patients with arterial hypertension, no differences in the adverse effect profile were observed compared to younger patients. Another study involving elderly patients with ischemic heart disease showed no significant difference in adverse effects compared to younger patients. Therefore, elderly patients do not require adjustment of the initial dose.

Renal impairment

During long-term carvedilol treatment, renal blood flow is preserved and glomerular filtration remains unchanged. There is no need to adjust the carvedilol dose in patients with renal impairment.

Hepatic impairment

Carvedilol is contraindicated in patients with clinically evident hepatic dysfunction.

Paediatric population

The safety and efficacy of Talciton**®** in patients under 18 years of age have not been established; therefore, Talciton**®** is not recommended for use in this population.

Alcohol

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

Important information about certain excipients of the medicinal product Talciton*®***

Talciton**®** contains lactose monohydrate. Patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Talciton**®** contains sucrose. Patients with rare hereditary forms of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product.

The sucrose content of the medicinal product should be taken into account when prescribing to patients with diabetes mellitus.

The medicinal product Talciton**®**, 12.5 mg tablets, contains the colorant "Yellow Sunset FCF" (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Animal studies have demonstrated reproductive toxicity. The potential risk to humans is unknown. Beta-blockers reduce placental perfusion, which may lead to intrauterine fetal death, miscarriage, and preterm delivery. There is an increased risk of cardiac and pulmonary complications in newborns during the postnatal period.

There is insufficient clinical experience with the use of carvedilol in pregnant women. Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential risk.

Animal studies have shown that carvedilol and/or its metabolites are excreted in breast milk. Excretion of carvedilol in human breast milk has not been established. However, most beta-blockers, particularly lipophilic compounds, pass into human breast milk in varying amounts. Therefore, breastfeeding is not recommended during carvedilol treatment.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of carvedilol on the ability to drive or operate machinery have not been conducted. Due to individual reactions (e.g., dizziness, fatigue), the ability to drive or operate machinery may be reduced.

Because of the antihypertensive effect of carvedilol, patients taking Talciton**®** should not drive or operate machinery if they experience dizziness or related symptoms. These symptoms occur more frequently at the beginning of treatment, after dose adjustment or changes in treatment regimen, and when alcohol is consumed concurrently.

Method of Administration and Dosage

Tablets should be taken with sufficient water, without chewing. For patients suffering from chronic heart failure, tablets should be taken during meals.

Essential Hypertension

Adults

The recommended initial dose is 12.5 mg once daily for the first two days of treatment. If well tolerated, this dose may be increased.

The recommended maintenance dose is 25 mg once daily. This dose is sufficient for most patients. If the response is inadequate, but not earlier than after 14 days of treatment, the dose may be increased to the maximum of 50 mg once daily or 25 mg twice daily.

Elderly Patients

The recommended starting dose is 12.5 mg once daily. This dose may be sufficient for adequate blood pressure control in some patients. If the response is inadequate, the dose may be gradually increased at intervals of at least two weeks up to the maximum dose of 50 mg, which should be taken in one or two divided doses daily.

Chronic Stable Angina

Adults

The recommended initial dose is 12.5 mg twice daily for the first two days of treatment. The recommended maintenance dose is 25 mg twice daily. If the response is inadequate, but not earlier than after 14 days, the dose may be increased to the maximum daily dose of 100 mg, divided into two doses.

Elderly Patients

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

Chronic Heart Failure

The dose of the medicinal product must be individually adjusted and gradually increased under close medical supervision.

Dose titration should be performed when the patient's condition is clinically stable. The dosage must be individually tailored.

Patients receiving digoxin, diuretics, or ACE inhibitors should continue these medications at previously established doses before starting carvedilol therapy.

The recommended initial dose is 3.125 mg twice daily for two weeks. The 3.125 mg dose can be obtained by splitting a 6.25 mg tablet in half. 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 maximum level that is well tolerated by the patient.

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

Before each dose increase, patients should be evaluated for possible signs of worsening heart failure or symptoms of excessive vasodilation (hypotension, dizziness). Worsening heart failure symptoms or fluid retention should be managed by increasing the diuretic dose. In some cases, it may be necessary to reduce the carvedilol dose or temporarily discontinue its administration.

If carvedilol treatment is interrupted for more than one week, therapy should be resumed at a lower dose twice daily and then titrated to the appropriate dose according to the standard titration schedule.

If carvedilol treatment has been interrupted for more than two weeks, it should be restarted at a dose of 3.125 mg twice daily and gradually increased according to the recommendations above.

Symptoms of potential vasodilation (arterial hypotension, warm extremities) should initially be managed by reducing the diuretic dose. If symptoms persist, the dose of ACE inhibitors should be reduced, followed by a reduction in the dose of Talciton®. In such cases, the carvedilol dose should not be increased until symptoms of heart failure exacerbation or vasodilation have resolved.

Special Populations

Elderly Patients

Dose adjustment is not required.

Children

The safety and efficacy of carvedilol in children and adolescents under 18 years of age have not been established; therefore, the medicinal product should not be used in this age group.

Patients with Hepatic Impairment

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

Patients with Renal Impairment

The dose should be individually adjusted for each patient; however, pharmacokinetic studies have not provided data indicating the need for dose adjustment of carvedilol in patients with renal impairment.

Discontinuation of Treatment

Carvedilol treatment is generally long-term.

As with other beta-blockers, treatment should not be stopped abruptly. The drug should be discontinued gradually, with weekly dose reductions. This is particularly important for patients with angina.

Children

The safety and efficacy of Talciton® in children and adolescents under 18 years of age have not been established; therefore, the medicinal product should not be used in this age group.

Overdose

Symptoms

In case of overdose, severe arterial hypotension, bradycardia, heart failure, cardiogenic shock, sinus node arrest, and cardiac arrest may occur. Respiratory distress, bronchospasm, vomiting, impaired consciousness, and generalized seizures have also been reported.

Treatment

Gastric lavage or induction of emesis may be beneficial within the first few hours after drug ingestion.

Patients should be closely monitored for the symptoms listed above. Treatment should be administered according to standard guidelines for beta-blocker overdose management (e.g., atropine, transvenous pacing, glucagon, phosphodiesterase inhibitors such as amrinone or milrinone, beta-sympathomimetics), if necessary, in an intensive care setting.

Note: In cases of severe overdose associated with shock symptoms, supportive therapy should be continued for a prolonged period, as the elimination half-life of carvedilol may be prolonged and redistribution may occur. The duration of treatment depends on the degree of overdose; supportive therapy should be continued until the patient's condition stabilizes.

Adverse Reactions

Adverse reactions are listed according to MedDRA (Medical Dictionary for Regulatory Activities) terminology, with frequency categories defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Below is a summary of adverse effects reported during clinical trials with carvedilol.

Central Nervous System Disorders:

• very common: headache, mild dizziness;
• common: loss of consciousness, pre-syncope;
• uncommon: paraesthesia.

Psychiatric Disorders:

• common: depression, depressed mood;
• uncommon: sleep disorders.

Cardiac Disorders:

• very common: heart failure;
• common: bradycardia, hypervolaemia (fluid overload);
• uncommon: atrioventricular block, angina pectoris.

Vascular Disorders:

• common: hypotension, orthostatic hypotension, peripheral circulation disorders (cold extremities, peripheral vascular disease, worsening of intermittent claudication, and Raynaud’s phenomenon), hypertension.

Respiratory, Thoracic and Mediastinal Disorders:

• common: dyspnoea, pulmonary oedema, bronchial asthma;
• rare: nasal congestion.

Infections and Infestations:

• common: bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection.

Blood and Lymphatic System Disorders:

• common: anaemia;
• rare: thrombocytopenia;
• very rare: leucopenia.

Metabolism and Nutrition Disorders:

• common: weight gain, hypercholesterolaemia, hyperglycaemia, hypoglycaemia, and worsening of glycaemic control in patients with diabetes mellitus.

Hepatobiliary Disorders:

• very rare: increased levels of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase.

Skin and Subcutaneous Tissue Disorders:

• uncommon: skin reactions (e.g., allergic exanthema, dermatitis, urticaria, pruritus, psoriasiform or erythema multiforme-like skin lesions, necrolysis).

Eye Disorders:

• common: decreased lacrimation (dry eyes), visual disturbance, eye irritation.

Gastrointestinal Disorders:

• common: nausea, diarrhoea, vomiting, dyspepsia, abdominal pain;
• uncommon: constipation;
• rare: dry mouth.

Musculoskeletal and Connective Tissue Disorders:

• common: limb pain.

Reproductive System and Breast Disorders:

• uncommon: erectile dysfunction.

Renal and Urinary Disorders:

• common: acute renal failure, renal impairment in patients with diffuse vascular disease and/or renal insufficiency;
• rare: urinary disorders.

Immune System Disorders:

• very rare: hypersensitivity (allergic reactions).

General Disorders:

• very common: asthenia (including fatigue);
• common: pain, oedema.

Description of Selected Adverse Reactions

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 titration of carvedilol.

Heart failure was frequently reported as an adverse event in both placebo- and carvedilol-treated patients (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.

Except for dizziness, visual disturbances, and bradycardia, none of the adverse effects listed above are dose-dependent.

Post-marketing Experience

The following adverse reactions have been reported during the post-marketing period of carvedilol use. Since these reports are voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug.

Metabolism and Nutrition Disorders

As with other beta-blockers, carvedilol may cause manifestation of latent diabetes or worsening of pre-existing diabetes.

Skin and Subcutaneous Tissue Disorders

Carvedilol may cause alopecia, severe skin reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome), and hyperhidrosis.

Renal and Urinary Disorders

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

Psychiatric Disorders

Carvedilol may cause hallucinations.

Cardiac Disorders

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

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf Life. 3 years.

Storage Conditions. Store at temperatures not exceeding 25 °C in a place protected from light and moisture. Keep out of reach of children.

Packaging.

For 6.25 mg dosage:

7 tablets per blister; 2 or 4 blisters per cardboard box.

For 12.5 mg and 25 mg dosages:

14 tablets per blister; 1 or 2 blisters per cardboard box.

Prescription Category. Prescription only.

Manufacturer. Egis Pharmaceuticals Ltd., Hungary.

Manufacturer’s Address and Place of Business.

1165 Budapest, Bekénytelep Street 118-120, Hungary.

9900 Kermend, Matyas Kiraly Street 65, Hungary.