Carvidex®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARVIDEX® (CARVIDEX)

Composition:

Active substance: carvedilol;

One film-coated tablet contains 6.25 mg or 12.5 mg or 25 mg of carvedilol;

Excipients: lactose monohydrate; crospovidone; colloidal anhydrous silicon dioxide; povidone; magnesium stearate; polysorbates; colorant Opadry OY-58900 White (hypromellose, titanium dioxide (E 171), polyethylene glycols).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, film-coated tablets with "R" on one side and, depending on the dose, on the other side: 6.25 mg tablets – "253", 12.5 mg tablets – "254", 25 mg tablets – "255".

Pharmacotherapeutic group. Agents acting on the cardiovascular system. Alpha- and beta-adrenoreceptor blockers. ATC code C07AG02.

Pharmacological Properties.

Pharmacodynamics.

Carvedilol is a non-selective beta-adrenergic receptor blocker with vasodilating activity. It possesses antioxidant properties. Vasodilation is primarily mediated through antagonism of alpha-adrenergic receptors. Carvedilol is a racemic mixture of two stereoisomers. Beta-adrenergic receptor blockade is attributed to the S(–) enantiomer. Carvedilol has no intrinsic sympathomimetic activity.

Carvedilol significantly improves myocardial function in patients with chronic heart failure due to left ventricular dysfunction, particularly by reducing afterload without adversely affecting left ventricular end-diastolic volume. In patients with mild to moderate essential hypertension, treatment with carvedilol leads to a reduction in left ventricular hypertrophy.

Pharmacokinetics.

After oral administration, carvedilol is rapidly absorbed. Absolute bioavailability of carvedilol is approximately 25–35% due to extensive first-pass metabolism in the liver. Maximum plasma concentration is reached within approximately 1 hour. The dose-concentration relationship in plasma is linear. Concomitant food intake does not affect bioavailability or maximum concentration, although the time to reach maximum concentration is reduced.

Administration of the drug with meals minimizes the risk of orthostatic hypotension. Carvedilol is a highly lipophilic substance. Approximately 98–99% of carvedilol is bound to plasma proteins, primarily to albumin.

Carvedilol is metabolized mainly in the liver, primarily via glucuronide formation. Demethylation and hydroxylation of the phenolic ring lead to the formation of three metabolites possessing beta-blocking activity. The mean elimination half-life ranges from 6 to 10 hours. The drug is excreted predominantly via bile and feces in the form of metabolites. A small portion is excreted in urine also as metabolites.

The pharmacokinetics of carvedilol are age-dependent. In elderly patients, plasma levels of carvedilol are approximately 50% higher than in younger individuals. In patients with liver cirrhosis, the bioavailability of the drug is four times greater than in individuals with normal liver function. Since carvedilol is primarily eliminated via feces, drug accumulation in patients with renal impairment is unlikely. In patients with hepatic impairment, bioavailability may increase by up to 80% due to reduced presystemic metabolism during first-pass liver metabolism.

Clinical characteristics.

Indications. Essential hypertension; chronic stable angina; moderate to severe chronic heart failure as adjunctive therapy.

Contraindications.

• Hypersensitivity to carvedilol or to any of the excipients.
• Decompensated heart failure – heart failure classified as NYHA class IV requiring intravenous administration of inotropic agents.
• Second- or third-degree atrioventricular block (unless 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 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.
• Obstructive respiratory diseases, including bronchospasm and history of bronchial asthma.
• Severe hepatic impairment.
• Concomitant use of monoamine oxidase inhibitors (MAOIs) (except MAO-B inhibitors).
• Metabolic acidosis.
• Pheochromocytoma (in the absence of adequate α-blocker control).
• Prinzmetal’s angina.
• Galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
• Pregnancy or breastfeeding.
• Pediatric age.

Interaction with other medicinal products and other forms of interaction.

Some antiarrhythmics, opioids, antihypertensives, antianginal agents, other β-blockers (e.g., in the form of eye drops), agents reducing catecholamine levels (e.g., monoamine oxidase inhibitors, reserpine), and cardiac glycosides may potentiate the effects of carvedilol. Therefore, the doses of these agents and of Carvidex® should be adjusted with caution.

Pharmacokinetic interactions.

P-glycoprotein, CYP2D6, CYP2C9 inducers or inhibitors.

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

Inhibitors and inducers of CYP2D6 and CYP2C9 may stereoselectively alter the systemic or presystemic metabolism of carvedilol, increasing or decreasing plasma concentrations of R- and S-carvedilol.

Fluoxetine.

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

β-agonists bronchodilators.

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

Antiarrhythmic agents.

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

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

Pharmacodynamic interactions.

Dihydropyridines.

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

Nitrates.

Enhance the hypotensive effect.

NSAIDs, estrogens, and corticosteroids.

The antihypertensive effect of carvedilol is attenuated when used concomitantly with agents that promote fluid and sodium retention.

Sympathomimetics, β-mimetics, and α-mimetics.

Concomitant use may result in arterial hypertension and marked bradycardia.

Ergotamine.

Vasoconstriction is enhanced when used concomitantly.

Neuromuscular blocking agents.

When carvedilol is combined with neuromuscular blockers, neuromuscular blockade is potentiated.

Xanthine derivatives.

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

Digoxin.

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

Cyclosporine and tacrolimus.

Two studies involving kidney and heart transplant patients receiving oral cyclosporine showed increased plasma cyclosporine concentrations after initiation of carvedilol. Carvedilol likely increases the effect of oral cyclosporine by approximately 10–20%. To maintain therapeutic cyclosporine levels, a dose reduction of cyclosporine by an average of 10–20% was necessary. 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 starting carvedilol therapy, with appropriate dose adjustments. No interaction is expected with intravenous cyclosporine.

Insulin or oral hypoglycemic agents.

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

Agents reducing catecholamines.

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

Clonidine.

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

Anesthetics.

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

Agents affecting the central nervous system (CNS).

With CNS-acting agents (sedatives, tranquilizers, tricyclic antidepressants, and ethanol) – due to possible mutual enhancement of effects.

Other antihypertensive medicinal products.

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

Other interactions.

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

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

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

Grapefruit juice.

A single intake of 300 mL of grapefruit juice increases the AUC of carvedilol by 1.2 times compared to water. Although the clinical significance of this interaction is not fully established, patients should avoid concomitant consumption of grapefruit juice, at least until a stable dose-response relationship is achieved.

Special precautions for use.

Arterial hypotension.

The drug is not recommended for use in patients with reduced arterial pressure.

Chronic heart failure.

In most cases, carvedilol should be administered to patients with chronic heart failure in addition to therapy with diuretics, ACE inhibitors, digitalis, and/or vasodilators. Initiation of treatment should occur in a hospital setting under medical supervision. Therapy may be initiated only if the patient's condition has been stable for at least 4 weeks on standard background therapy. Continuous monitoring is required for approximately 2 hours after the first dose or after dose escalation in patients with severe heart failure, electrolyte depletion or dehydration, elderly patients, or those with low baseline arterial pressure, as arterial hypotension may develop. Arterial hypotension due to excessive vasodilation should initially be managed by reducing the diuretic dose; if symptoms persist, the dose of any ACE inhibitor may be reduced. At the beginning of treatment or during dose escalation, heart failure may worsen or fluid retention may occur. In such cases, the diuretic dose should be increased. However, in some cases, dose reduction or discontinuation of the drug may be necessary. The dose of carvedilol should not be increased until symptoms related to worsening heart failure or arterial hypotension due to excessive vasodilation are controlled.

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

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

Since carvedilol has intrinsic negative dromotropic effects, it should be used cautiously in patients with first-degree heart block.

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

Antiarrhythmic agents.

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

Hepatic function.

Carvedilol may very rarely cause deterioration of liver function. In case of suspected clinical worsening, liver function tests should be performed. In the event of hepatic insufficiency, the patient should discontinue Carvidex®. Typically, liver function normalizes after discontinuation of treatment.

Orthostatic hypotension.

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

Renal function in heart failure with congestion.

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

Left ventricular dysfunction after acute myocardial infarction.

Before initiating carvedilol therapy, the patient must be clinically stable and have received an ACE inhibitor for at least 48 hours prior to starting carvedilol. The dose of the ACE inhibitor 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 possible increased resistance. Close monitoring is required during initiation and dose escalation of carvedilol via titration. The dose of carvedilol should be reduced if any signs of bronchospasm occur during treatment.

Diabetes mellitus.

Caution is advised when using carvedilol in patients with diabetes mellitus, as early signs of acute hypoglycemia may be masked or diminished. In patients with chronic heart failure and diabetes mellitus, carvedilol use may be associated with worsening glycemic control; therefore, regular monitoring of blood glucose levels is recommended at the beginning of carvedilol therapy or during dose titration, and appropriate adjustment of hypoglycemic therapy should be made.

Peripheral vascular disease.

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

Raynaud's phenomenon.

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

Thyrotoxicosis.

Carvedilol may mask symptoms of thyrotoxicosis.

General anesthesia.

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

Bradycardia.

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

Hypersensitivity.

Caution is advised when administering carvedilol to patients with a history of severe hypersensitivity reactions or those undergoing desensitization therapy, as β-blockers may increase both sensitivity to allergens and the severity of anaphylactic reactions.

Psoriasis.

The drug should be administered with caution to patients with psoriasis, as it may exacerbate skin reactions.

Concomitant use of calcium channel blockers or antiarrhythmic drugs.

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

Pheochromocytoma.

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

Prinzmetal's angina.

Nonselective β-blocking agents 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; nevertheless, caution is advised when administering carvedilol to patients suspected of having Prinzmetal's angina.

Contact lenses.

Patients wearing contact lenses should be informed about the possible reduction in tear production.

Discontinuation of treatment.

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

Important information about excipient.

The drug contains lactose monohydrate. Patients with known intolerance to certain sugars should consult their physician before taking this medication.

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

Alcohol.

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

Use during pregnancy or breastfeeding. The drug is contraindicated during pregnancy or breastfeeding. If use of the drug is necessary, breastfeeding should be discontinued.

Ability to affect reaction rate when driving or operating machinery. Driving and operating machinery should be avoided, especially at the beginning of treatment.

Method of Administration and Dosage

Tablets should be taken orally with sufficient fluid. Patients with heart failure are recommended to take carvedilol during meals to slow absorption and reduce the risk of orthostatic hypotension.

Essential Hypertension

Carvidex® can be used both as monotherapy and in combination with other antihypertensive agents, particularly thiazide diuretics. The drug is recommended to be administered once daily; however, the maximum recommended single dose is 25 mg, and the maximum recommended daily dose is 50 mg.

Adults. Dosage must be individually adjusted by a physician. The recommended initial dose for the first 2 days is 12.5 mg once daily. Treatment should then continue at a dose of 25 mg daily. Subsequently, if necessary, the dose may be gradually increased at intervals of 2 weeks or more.

Elderly patients. The recommended initial dose is 12.5 mg once daily, which may be sufficient for continued treatment. However, if the therapeutic effect of this dose is inadequate, it may be gradually increased at intervals of 2 weeks or more.

Chronic Stable Angina

The recommended dosing regimen is twice daily.

Adults. Dosage must be individually adjusted by a physician. The recommended initial dose for the first 2 days is 12.5 mg twice daily. Treatment should then continue at a dose of 25 mg twice daily. Subsequently, if necessary, the dose may be gradually increased at intervals of 2 weeks or more up to the recommended maximum dose of 100 mg daily, divided into two doses.

Elderly patients. Dosage must be individually adjusted by a physician. The recommended initial dose for the first 2 days is 12.5 mg twice daily. Treatment should then continue at a dose of 25 mg twice daily, which is the recommended maximum daily dose.

Chronic Heart Failure

Carvidex® should be used in moderate to severe heart failure as an additional therapy to standard background treatment with diuretics, ACE inhibitors, digoxin, and/or vasodilators. Patients must be clinically stable (no changes in NYHA class, no hospitalizations due to heart failure), and background therapy must have been stable for at least the last 4 weeks prior to initiating treatment. Additionally, patients must have reduced left ventricular ejection fraction, heart rate >50 beats/min, and systolic blood pressure >85 mm Hg.

Dosage must be individually adjusted by a physician. Initial dose for the first two weeks is 3.125 mg (if necessary, use the appropriate dosage form) twice daily. If tolerated, the dose may be slowly 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 well tolerated by the patient. The recommended maximum dose is 25 mg twice daily for patients with body weight below 85 kg and 50 mg twice daily for patients with body weight above 85 kg, provided heart failure is not of severe form. Increasing the dose to 50 mg twice daily should be done cautiously under close medical supervision.

At the beginning of treatment or during dose escalation, especially in patients with severe heart failure and/or those receiving high-dose diuretics, transient worsening of heart failure symptoms may occur. This is usually not a reason to discontinue treatment, but the dose should not be increased. The patient should be under the supervision of a physician/cardiologist for 2 hours after initiation of treatment or dose increase. Prior to each dose escalation, possible signs of worsening heart failure or symptoms indicating excessive vasodilation should be evaluated (e.g., kidney function, body weight, blood pressure, heart rate, and rhythm). Worsening heart failure or fluid retention should be managed by increasing the diuretic dose, and the carvedilol dose should not be increased until the patient's condition stabilizes. If bradycardia occurs or in case of prolonged atrioventricular conduction, digoxin levels should first be monitored. Sometimes it may be necessary to reduce the carvedilol dose or temporarily discontinue treatment. Nevertheless, even in such cases, treatment can often be successfully continued by careful dose titration of carvedilol. During dose titration, kidney function, platelet count, and glucose levels (in case of insulin-independent and/or insulin-dependent diabetes mellitus) should be monitored regularly. However, after completion of dose titration, the frequency of monitoring may be reduced.

If carvedilol has been discontinued for less than 2 weeks, treatment should be resumed at a dose of 3.125 mg (if necessary, use the appropriate dosage form) twice daily and gradually increased according to the above recommendations.

Renal Impairment

Dosage should be individually adjusted by a physician for each patient. However, according to pharmacokinetic data, dose adjustment is unlikely to be required in patients with renal impairment.

Mild to Moderate Hepatic Impairment

Dose adjustment may be necessary.

Elderly Patients

Elderly patients may be more sensitive to the effects of carvedilol and should therefore be under medical supervision.

When discontinuing carvedilol in patients receiving β-blockers, especially those with ischemic heart disease, the withdrawal should be gradual over 7–10 days, for example, by halving the daily dose every three days.

Children
The safety and efficacy of carvedilol in children (under 18 years of age) have not been established.

Overdose

Symptoms. Overdose may cause severe hypotension, bradycardia, heart failure, cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasm, vomiting, depressed consciousness, seizures, and exacerbation of other adverse reactions may also occur.

Treatment. In addition to standard supportive measures, vital signs should be monitored and corrected as needed in an intensive care unit. Supportive treatments may include: atropine 0.5–2 mg intravenously (for treatment of marked bradycardia); glucagon – initially 1–10 mg intravenously, followed if necessary by slow infusion of 2–5 mg/hour (to support cardiovascular function).

Sympathomimetics (dobutamine, isoprenaline, or adrenaline) should be used according to their efficacy and patient body weight. If peripheral vasodilation is the main symptom of overdose, noradrenaline or phenylephrine should be administered. Circulation must be continuously monitored in such patients. In case of bradycardia unresponsive to pharmacological treatment, cardiac pacing should be initiated. For treatment of bronchospasm, β-sympathomimetics or intravenous theophylline should be administered. In case of seizures, diazepam may be slowly administered intravenously.

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

Important! In cases of severe overdose with the patient in shock, supportive therapy should be prolonged, as elimination and redistribution of carvedilol are likely to be slower than usual. The duration of antidotal treatment depends on the severity of overdose; supportive treatment should be continued until the patient's condition stabilizes.

Adverse Reactions

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

The frequency categories of adverse reactions are 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 infection, urinary tract infection.

Blood and lymphatic system disorders.

Common: anemia;

Rare: thrombocytopenia;

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

Immune system disorders.

Very rare: hypersensitivity (allergic reaction), anaphylactic reactions.

Metabolism and nutrition disorders.

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

Psychiatric disorders.

Common: depression, depressed mood;

Uncommon: sleep disorders.

Central nervous system disorders.

Very common: dizziness, headache, fatigue;

Uncommon: pre-syncope, syncope, paresthesia, vertigo.

Eye disorders.

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

Cardiac and vascular disorders.

Very common: heart failure, hypotension;

Common: bradycardia, edema (including generalized, peripheral, dependent edema, and edema of genital organs and legs), hypervolemia, fluid overload, orthostatic hypotension, disorders of peripheral blood circulation (cold extremities, peripheral vascular disease, exacerbation of Charcot's syndrome and Raynaud's phenomenon);

Uncommon: atrioventricular block, angina (including chest pain), arterial hypertension, palpitations.

Respiratory, thoracic and mediastinal disorders.

Common: increased cough, wheezing, dyspnea, asthma (in patients predisposed to such pathology), pulmonary edema, influenza-like symptoms;

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

Gastrointestinal disorders.

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

Uncommon: constipation;

Rare: dry mouth, periodontitis, melena.

Hepatobiliary disorders.

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

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

Skin and subcutaneous tissue disorders.

Uncommon: skin reactions (e.g., allergic exanthema, dermatitis, increased sweating, urticaria, pruritus, psoriasiform and erythema multiforme-like skin lesions), exacerbation of existing skin lesions, alopecia, worsening of psoriasis, increased sweating, skin rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Musculoskeletal and connective tissue disorders.

Common: limb pain;

Rare: arthralgia, muscle cramps.

Renal and urinary disorders.

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

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

Reproductive system and breast disorders.

Uncommon: erectile dysfunction.

General disorders.

Very common: asthenia (fatigue);

Common: pain, increased body temperature.

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

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

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

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

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

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

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

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging. 10 tablets per strip, 2 strips per cardboard box.

Prescription status. Prescription only.

Manufacturer. Dr. Reddy’s Laboratories Ltd, Unit - II

Manufacturer's address and location of operations.

Plot Nos. 42, 45, 46, Bachupally, Medchal Malkajgiri District, Telangana State, Bachupally Mandal, India

Adverse reactions or lack of efficacy with the medicinal product can be reported via phone numbers:

+380 44 207 51 97 or +380 50 414 39 39; or by email: [email protected] (available 24/7).