INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KORIOL® (CORYOL®)

Composition:

Active substance: carvedilol;

1 tablet contains 3.125 mg or 6.25 mg of carvedilol;

Excipients: lactose monohydrate, sucrose, povidone, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics:

tablets of 3.125 mg: round, slightly biconvex, white tablets with a bevel;

tablets of 6.25 mg: oval, slightly biconvex, white tablets, with a score line on one side and the mark "S2" on the other.

Pharmacotherapeutic group. α- and β-adrenoreceptor blockers.

ATC code C07AG02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Carvedilol is a non-selective beta-blocker with vasodilating effects. It also possesses antioxidant and antiproliferative properties.

Pharmacodynamic effects

The active ingredient, carvedilol, is a racemate; the enantiomers differ in their effects and metabolism. The S(–) enantiomer has blocking activity against both α₁- and β-adrenoceptors, whereas the R(+) enantiomer has blocking activity only against α₁-adrenoceptors. Due to its cardioselective blockade of β-adrenoceptors, the drug reduces arterial blood pressure, heart rate, and cardiac output. Carvedilol reduces pressure in the pulmonary arteries and the right atrium. By blocking α₁-adrenoceptors, it causes peripheral vasodilation and reduces vascular resistance. These effects enable carvedilol to relax cardiac muscle and prevent angina attacks. In patients with heart failure, carvedilol promotes an increase in left ventricular ejection of blood and improves disease symptoms. Similar effects have been observed in patients with left ventricular dysfunction. Carvedilol has no intrinsic sympathomimetic activity and, like propranolol, possesses membrane-stabilizing properties. Plasma renin activity is reduced, and fluid retention is a rare occurrence.

Certain properties of traditional beta-adrenoceptor blockers appear to be absent in some vasodilating beta-blockers such as carvedilol.

Clinical efficacy and safety.

Clinical studies have shown that the balance between vasodilation and beta-blockade provided by carvedilol results in the following effects.

Hypertension. The effect on blood pressure and heart rate becomes evident within 1–2 hours after administration.

In hypertensive patients with normal renal function, carvedilol reduces renal vascular resistance. There are no significant changes in glomerular filtration rate, renal plasma flow, or electrolyte excretion.

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, forearms, legs, skin, brain, or carotid artery. The frequency of cold extremities and early fatigue during physical activity is reduced.

Hypertensive patients with renal impairment. Several open-label studies have shown that carvedilol is effective in patients with renal hypertension. The same applies to patients with chronic renal failure, those on hemodialysis, or after kidney transplantation. Carvedilol induces a gradual reduction in blood pressure both on dialysis and 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 effects (increased total exercise duration, time to 1 mm ST-segment depression, and time to onset of angina) and antianginal 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 decreases preload (pulmonary artery pressure and pulmonary capillary wedge pressure) and afterload (total peripheral resistance) of the myocardium, resulting in improved systolic and diastolic function of the left ventricle without significant changes in cardiac output.

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

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

Report No.	Control (dose)	Number of patients carvedilol / comparator drug	Treatment duration
060	Verapamil (120 mg three times daily)	126/122	12 weeks
061	Isosorbide dinitrate (40 mg twice daily)	93/94	12 weeks

The results of both studies clearly demonstrated that there was no significant difference in exercise duration at minimal plasma concentration after 12 weeks of therapy. However, hazard ratios derived from the Cox proportional hazards model showed a trend in favor of carvedilol, indicating that on average, carvedilol had an efficacy of 114% compared to verapamil (90% CI: 85–152%) and 134% compared to isosorbide dinitrate (90% CI: 96–185%). This also applied to the time to onset of angina and ST-segment depression. Exercise duration increased by approximately 50 seconds in all groups; improvements in time to onset of angina and ST-segment depression were about 30 seconds, which is clinically meaningful.

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, as well as couplets and runs.

Chronic heart failure. Carvedilol significantly reduces mortality and hospitalization rates 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 the need for 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 involving 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 risk of fatal outcomes and heart failure-related events.

Pediatric patients. 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 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 the pediatric safety profile of carvedilol.

Pharmacokinetics.

Absorption.

After oral administration of 25 mg capsules to healthy subjects, carvedilol is rapidly absorbed, with a maximum plasma concentration (Cmax) of 21 µg/L reached at approximately 1.5 hours (tmax). Cmax values are linearly dose-dependent. Following oral administration, carvedilol undergoes extensive first-pass metabolism, resulting in an absolute bioavailability of approximately 25% in healthy male subjects. Carvedilol is a racemate, and the S-(-)-enantiomer appears to be metabolized faster than the R-(+)-enantiomer, showing an absolute 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 efflux transporter P-glycoprotein. The role of P-glycoprotein in the distribution of carvedilol has also been confirmed in vivo in healthy subjects.

Food does not affect bioavailability, residence time, or maximum serum concentration, although the time to reach maximum plasma 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 increases in patients with hepatic 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-adrenoceptor blocking activity.

Preclinical studies indicate that the 4'-hydroxyphenol metabolite is approximately 13 times more potent than carvedilol for beta-blockade. 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 activities 30–80 times greater than that of carvedilol.

Pharmacokinetic studies in humans have shown that the oxidative metabolism of carvedilol is stereoselective. In vitro studies indicate 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.

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 increase 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 the genetic polymorphism of CYP2D6 may have limited clinical significance.

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. 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 approximately 2.5 hours. The half-life observed after oral administration of a 50 mg capsule in the same individuals was 6.5 hours, which corresponds to the elimination half-life of the capsule formulation. After oral administration, the total clearance of S-carvedilol is approximately twice that of R-carvedilol.

Special patient groups.

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

Pediatric patients. Studies in pediatrics have shown that weight-adjusted clearance is significantly higher in children compared to adults.

Hepatic impairment. In a study involving patients with hepatic cirrhosis, the bioavailability of carvedilol was four times higher, peak plasma concentration was five times higher, and volume of distribution was three times greater than in healthy volunteers.

Renal impairment. Since carvedilol is primarily eliminated in feces, significant accumulation in patients with renal impairment is unlikely.

In patients with arterial hypertension and renal impairment, the area under the concentration-time curve, elimination half-life, and maximum plasma concentration are not significantly altered. 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.

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

Preclinical safety data.

No particular hazard for humans was identified based on standard pharmacological safety, repeated-dose toxicity, genotoxicity, and carcinogenic potential studies.

Fertility impairment. When high doses of carvedilol were administered to pregnant rats (≥200 mg/kg—at least 100 times the maximum daily human dose), adverse effects on pregnancy and fertility were observed (poor mating, fewer corpora lutea, and fewer implants).

Teratogenicity. Animal studies do not indicate teratogenic effects of carvedilol.

Embryotoxicity (increased post-implantation embryo mortality) was observed, but no malformations were seen in rats and rabbits at doses of 200 mg/kg and 75 mg/kg, respectively (38–100 times the maximum daily human dose). The relevance of these findings to humans is unknown. Furthermore, animal studies have shown that carvedilol crosses the placental barrier, so potential effects of alpha- and beta-blockade on the fetus and newborn should also be considered (see section "Use in pregnancy or breastfeeding").

Thus, effects observed in preclinical studies occurred only at exposures significantly exceeding the maximum human exposure, indicating limited relevance for clinical use (see section "Use in pregnancy or breastfeeding").

Clinical characteristics.

Indications.

Essential arterial hypertension. Coriol® may be used alone or in combination with other antihypertensive agents (particularly thiazide diuretics);
chronic stable angina pectoris;
chronic stable heart failure (as an adjunct to standard therapy with diuretics, digoxin, or ACE inhibitors), for prevention of disease progression in patients with heart failure NYHA class II–III (New York Heart Association).

Contraindications.

Hypersensitivity to carvedilol or to any component of the medicinal product.
Decompensated heart failure – heart failure NYHA class IV requiring intravenous administration of inotropic agents.
Unstable heart failure.
Second- or third-degree atrioventricular block (unless 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 per minute).
Sinus node dysfunction (including sinoatrial block).
Cardiogenic shock.
Heart failure requiring intravenous administration of positive inotropic agents and/or diuretics.
Severe hypotension (systolic blood pressure < 85 mm Hg).
Pulmonary hypertension.
Cor pulmonale.
History of bronchial asthma or bronchospasm.
Clinically significant hepatic impairment.
Concomitant use of MAO inhibitors (except MAO-B inhibitors).
Metabolic acidosis.
Pheochromocytoma.
Prinzmetal’s angina.
Obstructive airway diseases.
Galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Pregnancy and lactation, pediatric age.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interactions.

Effect of carvedilol on the pharmacokinetics of other drugs

Carvedilol is 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: increased digoxin exposure by up to 20% has been demonstrated in some studies in healthy volunteers and patients with heart failure. The effect was significantly greater in male patients compared to female patients. Therefore, monitoring of digoxin levels is recommended during initiation, dose adjustment, or discontinuation of carvedilol (see section "Special precautions for use"). Carvedilol did not affect intravenous digoxin administration.

Cyclosporine and tacrolimus: Two studies in patients with renal or cardiac transplantation receiving oral cyclosporine showed increased plasma cyclosporine concentrations after initiation of carvedilol therapy. Carvedilol appears to increase the effect of 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 not known, but may involve inhibition of intestinal P-glycoprotein by carvedilol. Due to significant inter-individual variability in required dose adjustments, careful monitoring of cyclosporine concentrations is recommended after initiation of carvedilol therapy, with appropriate cyclosporine dose adjustment. No interaction with carvedilol is expected when cyclosporine is administered intravenously.

Additionally, evidence suggests that CYP3A4 is involved in the metabolism of carvedilol. Since tacrolimus is a substrate of both P-glycoprotein and CYP3A4, carvedilol may also affect its pharmacokinetics via these interaction mechanisms.

Effect of other drugs on the pharmacokinetics of carvedilol

Inhibitors and inducers of CYP2D6 and CYP2C9 may stereoselectively alter systemic and/or presystemic metabolism of carvedilol, resulting in increased or decreased plasma concentrations of R- and S-carvedilol. Some examples of such drug effects observed in patients or healthy subjects are listed below.

Rifampicin. In a study involving 12 healthy volunteers, the effect of 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 not known, but may involve induction of intestinal P-glycoprotein by rifampicin. Close 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 plasma concentrations of R- and S-enantiomers of 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 77% increase in mean AUC of the R(+) enantiomer and a non-statistically significant 35% increase 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 subjects after single oral administration. 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 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 is unclear, patients should avoid concomitant intake of grapefruit juice until a stable dose-response relationship has been established.

Pharmacodynamic interactions.

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

Agents reducing catecholamines: close monitoring for signs of arterial hypotension and/or severe bradycardia is required in patients receiving both beta-blocking agents and agents that reduce catecholamines (e.g., reserpine and monoamine oxidase inhibitors).

Digoxin.

Concomitant use of beta-adrenoblockers and digoxin may lead to additive prolongation of atrioventricular conduction time.

Non-dihydropyridine calcium channel blockers or other antiarrhythmic agents.

Combination with carvedilol may increase the risk of atrioventricular conduction disturbances (see "Special precautions for use"). Isolated cases of conduction disturbances (rarely with hemodynamic impairment) have been observed with concomitant use of carvedilol and diltiazem. As with other beta-blocking agents, if carvedilol is to be administered orally with non-dihydropyridine calcium channel blockers such as verapamil or diltiazem, amiodarone, or other antiarrhythmics, ECG and blood pressure monitoring are recommended.

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

Antihypertensive agents.

Like other beta-blocking agents, carvedilol may potentiate the effect of other concurrently administered antihypertensive agents (e.g., beta1-receptor antagonists) or may lead to arterial hypotension related to their adverse effect profile.

Anesthetics: extreme caution is required during anesthesia due to synergistic negative inotropic and hypotensive effects of carvedilol and anesthetics (see section "Special precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs), estrogens, and corticosteroids.

Concomitant use of NSAIDs, estrogens, or corticosteroids and beta-adrenergic blockers may lead to increased blood pressure, worsening of blood pressure control, and fluid and sodium retention.

Bronchodilator beta-agonists.

Non-cardioselective beta-blockers antagonize the effects of bronchodilator beta-agonists; therefore, such patients require careful monitoring.

Special precautions for use.

Chronic heart failure with congestion.

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

Carvedilol should be used with caution in combination with cardiac glycosides, as both agents slow AV conduction.

Renal dysfunction in congestive heart failure.

In patients with heart failure and low blood pressure (systolic < 100 mm Hg), ischemic heart disease or systemic atherosclerosis and/or underlying renal impairment, treatment with carvedilol has been associated with reversible worsening of renal function.

Left ventricular dysfunction following acute myocardial infarction.

Prior to initiation of carvedilol therapy, the patient must be clinically stable and have received ACE inhibitor therapy for at least 48 hours. Furthermore, the ACE inhibitor dose should have been stable for at least 24 hours.

Chronic obstructive pulmonary disease.

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

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

Diabetes mellitus.

Caution should be exercised when administering carvedilol to patients with diabetes, as it may be associated with impaired glucose control, and early signs of acute hypoglycemia may be masked or attenuated. Alternatives to beta-blockers are generally preferred in insulin-dependent patients. Therefore, regular monitoring of blood glucose levels is recommended at the start of carvedilol therapy or during dose titration, with appropriate adjustment of hypoglycemic therapy (see “Interaction with other medicinal products and other forms of interaction”).

Peripheral vascular disease and Raynaud’s syndrome.

Carvedilol should be used cautiously in patients with peripheral vascular disease and Raynaud’s syndrome, as beta-blockers may exacerbate symptoms of these conditions. However, since carvedilol also possesses alpha-blocking properties, this effect is largely counterbalanced.

Thyrotoxicosis.

Carvedilol, like other beta-blocking agents, may mask the symptoms of thyrotoxicosis.

Bradycardia.

If bradycardia develops (heart rate less than 55 beats/min), the dose of carvedilol should be reduced.

Hypersensitivity reactions.

Carvedilol should be administered with caution to patients with a history of severe hypersensitivity reactions and those undergoing desensitization therapy, as beta-blockers may increase reactivity during allergy testing, enhance sensitivity to allergens, and increase the severity of anaphylactic reactions.

Anaphylactic reaction risk.

Patients with a history of severe anaphylactic reactions to various allergens may be more susceptible to accidental, diagnostic, or therapeutic re-exposure while on beta-blockers. 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 therapy (see “Adverse reactions”). Patients who develop severe skin adverse reactions should discontinue carvedilol; carvedilol should be permanently discontinued.

Psoriasis.

Carvedilol should be prescribed to patients with a history of psoriasis associated with beta-blocker therapy only after careful consideration of the benefit-risk ratio. Carvedilol may exacerbate skin reactions.

Interaction with other medicinal products.

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

Concomitant use of debrisoquine.

Patients who are poor metabolizers of debrisoquine require caution at the start of treatment.

Pheochromocytoma.

In patients with pheochromocytoma, an alpha-blocker should be administered prior to any beta-blocker. Although carvedilol has both alpha- and beta-blocking pharmacological activity, there is no clinical experience with carvedilol in this condition. Therefore, caution is advised when prescribing carvedilol to patients suspected of having pheochromocytoma.

Prinzmetal’s angina.

In patients with Prinzmetal’s angina, non-selective beta-blockers may provoke chest pain (the alpha1-adrenergic blocking effect of carvedilol may prevent this, but there is insufficient clinical experience with carvedilol in Prinzmetal’s angina).

Contact lenses: Patients wearing contact lenses should be informed of the possibility of reduced tear production.

Withdrawal syndrome.

As with other beta-blockers, carvedilol therapy should not be abruptly discontinued, particularly in patients with ischemic heart disease. Carvedilol therapy should be tapered gradually over a period of two weeks.

Children.

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

Important information about excipients

The product contains sucrose and lactose. This medicine should not be taken by patients with the following conditions: fructose intolerance, lactase deficiency, galactosemia, glucose-galactose malabsorption syndrome, or sucrase-isomaltase deficiency.

Since the product contains sucrose, this should be taken into account in patients with diabetes mellitus.

Use during pregnancy or breastfeeding.

Pregnancy

There is insufficient clinical data on the effects of carvedilol during pregnancy.

Coriol® is contraindicated during pregnancy.

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

Breastfeeding

Animal studies have shown that carvedilol and/or its metabolites are excreted into the milk of rats.

Excretion of carvedilol into human milk has not been established. However, most beta-adrenergic blockers, particularly lipophilic compounds, are excreted into human breast milk to varying degrees. Breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

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

Due to variable individual responses (e.g., dizziness, fatigue), patients’ ability to drive, operate machinery, or perform tasks requiring sustained attention may be impaired. This is particularly important at the beginning of treatment, during dose escalation, when changing therapy, or when consuming alcohol concurrently.

Dosage and Administration

Tablets should be taken with sufficient amount of liquid. To slow absorption and prevent orthostatic effects, Coriol® should be administered after meals. Dosage must be individually adjusted. Treatment should be initiated with low doses – 3.125 mg (half of a 6.25 mg tablet), which should be gradually increased until optimal clinical response is achieved. After administration of the first dose and after each dose increase, blood pressure should be measured in the standing position 1 hour after dosing to rule out possible hypotension.

Treatment with Coriol® should be discontinued gradually by reducing the dose over 1–2 weeks. This is particularly important for patients with concomitant ischemic heart disease (see section "Special Warnings and Precautions for Use").

If treatment is interrupted for more than 1 week, it should be resumed with the lowest starting dose.

Essential Arterial Hypertension

The initial dose of Coriol® is 12.5 mg once daily in the morning after breakfast, or 6.25 mg twice daily (in the morning and evening). After 2 days of treatment, the dose may be increased to 25 mg once in the morning or 12.5 mg twice daily. The dose may be further increased after 14 days to 25 mg twice daily.

The maximum single dose of Coriol® in the treatment of arterial hypertension is 25 mg; the maximum daily dose should not exceed 50 mg.

The recommended initial dose of Coriol® for the treatment of hypertension in patients with heart failure is 3.125 mg twice daily.

Chronic Stable Angina

The initial dose of Coriol® is 12.5 mg twice daily (in the morning and evening), taken after meals. After 2 days of treatment, the dose may be increased to 25 mg twice daily.

The maximum dose of Coriol® in the treatment of chronic stable angina is 25 mg twice daily (in the morning and evening).

The recommended initial dose of Coriol® for the treatment of chronic angina in patients with heart failure is 3.125 mg twice daily.

Chronic Stable Heart Failure

Coriol® is recommended for the treatment of mild, moderate, and severe chronic stable heart failure as an additional therapy to standard medications such as diuretics, ACE inhibitors, or cardiac glycosides. It may also be prescribed to patients who are intolerant to ACE inhibitors. Coriol® should only be initiated in patients after diuretics, ACE inhibitors, and cardiac glycosides (if prescribed) have been appropriately titrated.

Dosage must be individually adjusted. Close medical supervision is required for the first 2–3 hours after initiation of treatment or after any dose increase, to monitor for tolerability. If the patient's heart rate decreases to less than 55 beats per minute, the dose of Coriol® should be reduced. If symptoms of hypotension occur, the first step is to consider reducing the dose of diuretic or ACE inhibitor; if these measures are insufficient, the dose of Coriol® usually needs to be reduced.

At the beginning of treatment with Coriol® or after dose escalation, transient worsening of heart failure may occur. In such cases, the diuretic dose should be increased. Occasionally, temporary reduction of the Coriol® dose or even discontinuation may be necessary. Once the clinical condition stabilizes, treatment with Coriol® can be resumed or the dose increased.

The initial dose for the first two weeks is 3.125 mg twice daily (in the morning and evening). The dose may be increased every 2 weeks to 6.25 mg twice daily (in the morning and evening), then to 12.5 mg twice daily (in the morning and evening), and finally to 25 mg twice daily (in the morning and evening), provided the patient tolerates the previous dose well. The patient should receive the highest maintenance dose that is well tolerated. The maximum daily dose is 25 mg twice daily for all patients with severe congestive heart failure and for patients with mild to moderate congestive heart failure weighing less than 85 kg, and 50 mg twice daily for patients weighing more than 85 kg.

Before each dose increase, the patient's condition should be evaluated for signs of worsening heart failure or vasodilation.

Elderly Patients

No dose adjustment is required.

Patients with Hepatic Impairment

Coriol® is not recommended for patients with severe hepatic impairment.

Patients with Renal Impairment

Based on pharmacokinetic data and clinical trial results in patients with renal impairment (including renal insufficiency), no dose adjustment is considered necessary in patients with moderate to severe renal impairment (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Children

Safety and efficacy of Coriol® in children have not been established; therefore, the use of this medication in children is contraindicated.

Overdose

Symptoms and Manifestations

In case of overdose, severe hypotension, bradycardia, heart failure, cardiogenic shock, sinus arrest, and cardiac arrest may occur. Other possible symptoms include respiratory difficulties, bronchospasm, vomiting, disturbances of consciousness, and generalized seizures.

Treatment

Patients should be closely monitored for the above-mentioned signs and symptoms and treated according to the best clinical judgment of the treating physicians and in accordance with standard management practices for beta-blocker overdose (e.g., atropine, transvenous pacing, glucagon, phosphodiesterase inhibitors such as amrinone or milrinone, beta-sympathomimetics).

Gastric lavage or induced vomiting may be beneficial within the first few hours after oral ingestion.

In cases of severe overdose with shock symptoms, supportive treatment as described should be continued for a sufficiently prolonged period—until the patient's condition stabilizes—due to the expected prolonged elimination half-life and redistribution of carvedilol from deep compartments.

Carvedilol cannot be removed by dialysis.

Adverse Reactions

The risk of most adverse reactions associated with carvedilol is similar across all indications. Exceptions are described below ("Description of certain adverse reactions").

The following are adverse effects of carvedilol identified during clinical trials, post-marketing safety studies, or spontaneous reporting.

Adverse reaction frequency is categorized as follows:

Very common ≥1/10; common ≥1/100 to <1/10; uncommon ≥1/1000 to <1/100; rare ≥1/10,000 to <1/1000; very rare <1/10,000.

Infections and infestations:

Common – bronchitis, pneumonia, upper respiratory tract infections, urinary tract infections.

Blood and lymphatic system disorders:

Common – anemia;

Rare – thrombocytopenia;

Very rare – leukopenia.

Immune system disorders:

Very rare – hypersensitivity (allergic reaction).

Metabolic and nutritional disorders:

Common – weight gain, hypercholesterolemia, impaired glucose control (hyperglycemia, hypoglycemia) in patients with pre-existing diabetes.

Psychiatric disorders:

Common – depression, depressed mood;

Uncommon – sleep disorders.

Central nervous system disorders:

Very common – headache, dizziness;

Common – fatigue, syncope;

Uncommon – paresthesia.

Eye disorders:

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

Cardiac disorders:

Very common – heart failure;

Common – bradycardia, edema, hypervolemia, fluid retention;

Uncommon – atrioventricular block, angina pectoris.

Vascular disorders:

Very common – arterial hypotension;

Common – orthostatic hypotension, peripheral circulation disorders (cold extremities, peripheral vascular disease, worsening of intermittent claudication, and Raynaud's syndrome).

Respiratory, thoracic and mediastinal disorders:

Common – dyspnea, pulmonary edema, asthma in predisposed patients;

Rare – nasal congestion, influenza-like symptoms.

Gastrointestinal disorders:

Common – nausea, diarrhea, vomiting, dyspepsia, abdominal pain;

Uncommon – constipation;

Rare – dry mouth.

Hepatobiliary disorders:

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

Skin and subcutaneous tissue disorders:

Uncommon – skin reactions (e.g., allergic exanthema, dermatitis, hyperhidrosis, urticaria, pruritus, psoriasiform and lichenoid skin lesions), alopecia.

Musculoskeletal and connective tissue disorders:

Common – limb pain.

Renal and urinary disorders:

Common – renal failure and impaired kidney function in patients with diffuse vascular disease and/or underlying renal insufficiency;

Rare – urinary disorders;

Very rare – urinary incontinence in women.

Reproductive system and breast disorders:

Uncommon – erectile dysfunction.

General disorders and administration site conditions:

Very common – asthenia (fatigue);

Common – edema, pain.

Description of certain adverse reactions.

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

Dizziness, syncope, headache, and asthenia are usually mild and occur most frequently 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 (see section "Dosage and administration").

Heart failure was reported very frequently as an adverse reaction in patients receiving placebo (14.5%) and carvedilol (15.4%), as well as 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, ischemic heart disease, diffuse vascular disease, and/or underlying renal insufficiency (see section "Dosage and administration").

Because these events are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency and/or establish a causal relationship to carvedilol use.

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

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).

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

Hyperhidrosis.

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

Reporting suspected adverse reactions.

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

Shelf life. 5 years.

Storage conditions.

No special storage conditions are required for this medicinal product. Keep out of reach of children.

Packaging.

7 tablets per blister, 4 blisters per cardboard box; 10 tablets per blister, 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's name and address of the place of business.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.