Carvedilol aurobindo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CARVEDILOL AUROBINDO (CARVEDILOL AUROBINDO)

Composition:

Active substance: carvedilol;

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

Excipients: lactose monohydrate; colloidal anhydrous silicon dioxide; crospovidone; povidone; sucrose; magnesium stearate; macrogol 400; polysorbate 80; titanium dioxide (E 171); hypromellose.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

6.25 mg tablets: oval-shaped, film-coated tablets of white to almost white color, marked with "F 57" on one side and a deep score line on the other side;

12.5 mg tablets: oval-shaped, film-coated tablets of white to almost white color, marked with "F 58" on one side and a deep score line on the other side;

25 mg tablets: oval-shaped, film-coated tablets of white to almost white color, marked with "F 59" on one side and a deep score line on the other side.

Pharmacotherapeutic group. 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-adrenergic receptor blocker. Beta-adrenergic receptor blockade is associated with the S-enantiomer and is nonselective for beta1- and beta2-adrenergic receptors, whereas both enantiomers have equal blocking activity specific to alpha1-adrenergic receptors. At higher concentrations, carvedilol also has weak to moderate calcium channel blocking activity. It has no intrinsic sympathomimetic activity and, like propranolol, possesses membrane-stabilizing properties.

Pharmacodynamic effects

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

Carvedilol has organ-protective effects, which are likely partly attributable to additional properties beyond its blockade of adrenergic receptors. It has potent antioxidant properties associated with both enantiomers, acts as a scavenger of reactive oxygen radicals, and has antiproliferative effects on human vascular smooth muscle cells.

Carvedilol has no negative effect on the lipid profile.

Clinical efficacy and safety

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

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

Hypertension with renal impairment

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

Stable angina

In patients with stable angina, carvedilol has demonstrated anti-ischemic (improved total exercise time, time to 1 mm ST-segment depression, and time to angina) and 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 reduces 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 negative effect on metabolic risk factors for ischemic heart disease. It does not affect normal serum lipid levels, and in patients with hypertension and dyslipidemia, a favorable effect on serum lipids has been reported after 6 months of oral therapy.

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

Report No.	Control (dose)	Number of patients carvedilol/comparator drug	Duration of treatment
060	Verapamil (120 mg 3 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 ET at the minimal blood level of the drug after 12 weeks of therapy. However, the risk ratios obtained from the Cox proportional hazards model showed a trend in favor of carvedilol, indicating that on average carvedilol was 114% as effective as verapamil (90% CI: 85–152%) and 134% as effective as isosorbide dinitrate (90% CI: 96–185%). This also applied to time to angina (TTA) and ST-segment depression (TST). The increase in ET was approximately 50 seconds in all groups; improvement in TTA and TST was about 30 seconds, which is clinically significant.

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

Chronic Heart Failure

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

Patients with Chronic Heart Failure and Renal Impairment

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

Pediatric Population

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

Pharmacokinetics

Absorption

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

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

Food does not affect bioavailability, serum retention time, or maximum serum concentration, although the time to reach maximum serum concentration is delayed.

Distribution

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

Biological Transformation

In humans, carvedilol is extensively metabolized in the liver via oxidation and conjugation into various metabolites, which are primarily excreted in bile. Enterohepatic recirculation of the parent compound has been demonstrated in animals.

Demethylation and hydroxylation on the phenolic ring produce three metabolites with beta-adrenergic receptor blocking activity.

Based on preclinical studies, the 4'-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 activity in this regard 30–80 times greater than that of carvedilol.

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

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

Genetic Polymorphism

Results from clinical pharmacokinetic studies in humans have shown that CYP2D6 plays an important role in the metabolism of both 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 CYP2D6 genetic polymorphism may have limited clinical significance.

Elimination

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

Clinical characteristics.

Indications.

Dosage of 6.25 mg

• Adjunctive therapy of symptomatic chronic heart failure to reduce morbidity and improve well-being.
• Treatment of hypertension.

Dosages of 12.5 mg and 25 mg

• Adjunctive therapy of symptomatic chronic heart failure to reduce morbidity and improve well-being.
• Treatment of hypertension.
• Long-term treatment of stable angina pectoris.

Contraindications.

• Hypersensitivity to carvedilol or to any of the excipients;
• Unstable or decompensated heart failure (NYHA Class IV with significant fluid retention requiring intravenous inotropic therapy);
• Chronic obstructive pulmonary disease with bronchial obstruction;
• Bronchial asthma or bronchospasm;
• Clinically significant hepatic dysfunction;
• Second- or third-degree atrioventricular block (unless a permanent pacemaker is in place);
• Marked bradycardia (< 50 beats/min);
• Cardiogenic shock;
• Sick sinus syndrome (including sinoatrial block);
• Marked arterial hypotension (systolic blood pressure below 85 mmHg);
• Metabolic acidosis;
• Prinzmetal's angina;
• Severe peripheral arterial circulatory disorders;
• Untreated phaeochromocytoma;
• Concomitant intravenous administration of verapamil or diltiazem.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interactions

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

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

Cyclosporine and tacrolimus. Two studies in renal and heart transplant patients receiving oral cyclosporine showed increased plasma concentrations of cyclosporine after initiation of carvedilol. Carvedilol appears to increase the exposure to oral cyclosporine by approximately 10–20%. To maintain a therapeutic cyclosporine level, cyclosporine dosage had to be reduced on average by 10–20%. The mechanism of interaction is unknown, but inhibition of intestinal P-glycoprotein by carvedilol is possible. Due to wide inter-individual variability in cyclosporine levels, careful monitoring of cyclosporine concentration is recommended after initiation of carvedilol therapy, with appropriate adjustment of cyclosporine dosage. 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 influenced 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 modify systemic and/or pre-systemic metabolism of carvedilol, leading to increased or decreased plasma concentrations of R- and S-carvedilol. Some observed examples in patients or healthy subjects are listed below, but the list is not exhaustive.

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

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

Fluoxetine and paroxetine. In a randomized crossover study in 10 patients with heart failure, concomitant administration of fluoxetine, a potent CYP2D6 inhibitor, resulted in stereoselective inhibition of carvedilol metabolism, with a mean increase of 77% in the AUC of the R-enantiomer and a minor 35% increase in the 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 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. Alcohol consumption has an acute hypotensive effect, which may potentiate the blood pressure-lowering effect of carvedilol. Since carvedilol is soluble in ethanol, the presence of alcohol may affect the rate and/or extent of intestinal absorption of carvedilol. Additionally, carvedilol is partially metabolized by CYP2E1, an enzyme known to be induced and inhibited by alcohol.

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

Pharmacodynamic interactions

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

Catecholamine agents. Patients receiving concomitant treatment with beta-blocking agents and medicinal products that deplete catecholamines (e.g., reserpine inhibitors and monoamine oxidase inhibitors) should be closely monitored for signs of hypotension and/or marked bradycardia.

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

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

Clonidine. Concomitant use of clonidine with beta-blocking agents may potentiate the blood pressure-lowering effect and the heart rate-slowing effect. When discontinuing combined treatment with beta-blocking agents and clonidine, the beta-blocking agent should be discontinued first. Clonidine therapy may then be discontinued several days later, gradually reducing the dosage.

Antihypertensive agents. Like other beta-blockers, carvedilol may potentiate the effect of concomitantly administered medicinal products with antihypertensive activity (e.g., alpha1-receptor antagonists) or those having hypotension as a side effect.

Anaesthetics. During general anaesthesia, careful monitoring of the synergistic negative inotropic and hypotensive effects of carvedilol and anaesthetics is required.

Non-steroidal anti-inflammatory drugs (NSAIDs). Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and beta-adrenoblockers may lead to increased blood pressure and worsening of blood pressure control.

Beta-agonist bronchodilators. Non-cardioselective beta-adrenoblockers oppose the bronchodilator effect of beta-agonist bronchodilators. Close monitoring of patients is recommended.

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

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

Ergotamine. Vasoconstriction is potentiated.

Neuromuscular blockers. Carvedilol potentiates the effect of neuromuscular blocking agents.

Special precautions for use.

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

Carvedilol should be used with caution in combination with cardiac glycosides, as both drugs 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 BP <100 mm Hg), ischemic heart disease, and diffuse vascular disease and/or renal insufficiency. In patients with chronic heart failure and these risk factors, renal function should be monitored during dose escalation of carvedilol, and the drug should be discontinued or the dose reduced if renal function deteriorates.

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.

Close monitoring is required when initiating treatment and during dose escalation by titration, and the dose of carvedilol should be reduced if any evidence of bronchospasm occurs during treatment.

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

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

Thyrotoxicosis. Carvedilol may mask symptoms of thyrotoxicosis.

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

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

Severe skin adverse reactions. Very rare cases of severe skin adverse reactions, such as toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported during treatment with carvedilol.

The drug should be permanently discontinued in patients who experience severe skin adverse reactions possibly related to carvedilol.

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

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

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

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

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

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

Carvedilol contains lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

Patients who are poor metabolizers of debrisoquine should be closely monitored from the start of therapy (see section "Pharmacokinetic properties").

Due to limited clinical experience, carvedilol should not be used in patients with labile or secondary hypertension, orthostasis, acute inflammatory heart disease, hemodynamic obstruction of heart valves or outflow tract, end-stage peripheral arterial disease, or concomitant therapy with α1- or α2-receptor antagonists.

General anesthesia. Beta-blockers reduce the risk of arrhythmias during anesthesia, but may also increase the risk of arterial hypotension; therefore, some anesthetics should be used cautiously. However, recent studies indicate benefits of beta-blockers in preventing perioperative cardiac morbidity and reducing the incidence of cardiovascular complications.

Use during pregnancy or breastfeeding.

There is insufficient clinical experience with the use of carvedilol in pregnant women.

Animal studies have demonstrated effects on pregnancy, embryonic/fetal development, parturition, reproductive toxicity, and postnatal development. The potential risk to humans is unknown.

Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential risk.

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

Breastfeeding

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

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect on the ability to drive vehicles or operate machinery have not been conducted.

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

Dosage and Administration

Dosing

Chronic Heart Failure

The dose should be titrated according to individual needs, and dose escalation should be monitored gradually.

Patients receiving diuretics and/or digoxin and/or ACE inhibitors should have their therapy stabilized before initiating treatment with carvedilol.

Adults

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

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

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

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

Elderly Patients

As for adults.

Hypertension

Once-daily dosing is recommended.

Adults. The recommended initial dose for the first 2 days of treatment is 12.5 mg once daily. Treatment should then be continued at a dose of 25 mg once daily.

Although this dose is sufficient for most patients, the dose may be titrated, if necessary, to the recommended maximum daily dose of 50 mg, administered once daily or in divided doses.

Dose titration should occur at intervals of at least two weeks.

Elderly Patients.

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

Angina Pectoris

Adults

The recommended starting dose is 12.5 mg twice daily for the first two days. Thereafter, the recommended dose is 25 mg twice daily. If necessary, the dose may be titrated up to 50 mg twice daily.

Dose titration should occur at intervals of at least two weeks.

Elderly Patients.

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

Special Dosing Instructions

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

Renal Impairment

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

Children

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

Route of Administration

The medicinal product is intended for oral use only.

Tablets should be taken with water.

For patients with chronic heart failure, the drug should be administered with food to slow the rate of absorption and reduce the incidence of orthostatic effects.

Children.

The medicinal product should not be administered to children.

Overdose.

Symptoms: severe arterial hypotension, bradycardia, heart failure, cardiogenic shock, cardiac arrest; respiratory depression, bronchospasm, vomiting, confusion, generalized seizures may also occur.

Treatment. Patients should be monitored for the development of the above-mentioned symptoms. Treatment should be administered according to standard management of beta-blocker overdose (e.g., atropine, transvenous pacing, glucagon, phosphodiesterase inhibitor such as amrinone or milrinone, beta-sympathomimetics).

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

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

Adverse Reactions

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

The risk of most adverse reactions associated with carvedilol is similar across all indications. Exceptions are described below.

The following undesirable effects have been reported (during clinical trials, post-marketing safety studies, spontaneous reports) with the use of carvedilol:

Categories of adverse reaction frequency are 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.

Infections and infestations

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

Blood and lymphatic system disorders

Common: anaemia;
Rare: thrombocytopenia;
Very rare: leukopenia.

Immune system disorders

Very rare: hypersensitivity (allergic reactions).

Metabolism and nutrition disorders

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

Nervous system disorders

Very common: headache, dizziness;
Common: presyncope, loss of consciousness;
Uncommon: paresthesia, hypesthesia.

Psychiatric disorders

Common: depression, depressive mood;
Uncommon: sleep disorders.

Eye disorders

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

Cardiac disorders

Very common: heart failure;
Common: bradycardia, edema, hypervolemia;
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 phenomenon), hypertension.

Respiratory, thoracic and mediastinal disorders

Common: dyspnea, pulmonary edema, bronchial asthma in susceptible patients;
Rare: nasal congestion, influenza-like symptoms.

Gastrointestinal disorders

Common: nausea, diarrhea, vomiting, abdominal pain, dyspepsia;
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 (including allergic exanthema, dermatitis, urticaria, pruritus; skin lesions resembling psoriasis or lupus erythematosus); alopecia;
Very rare: severe skin adverse reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Musculoskeletal and connective tissue disorders

Common: limb pain.

Renal and urinary disorders

Common: acute renal failure and impaired renal function in patients with diffuse vascular disease and/or renal insufficiency;
Rare: urinary disorders;
Very rare: urinary incontinence in women.

Reproductive system and breast disorders

Very common: genital edema;
Uncommon: erectile dysfunction.

General disorders

Very common: asthenia (fatigue);
Common: pain, edema.

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 both in patients receiving placebo and in those receiving carvedilol (14.5% and 15.4%, respectively, in patients with left ventricular dysfunction after acute myocardial infarction).

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

The following adverse effects have been identified during post-marketing use of carvedilol. 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 drug exposure:

Metabolism and nutrition disorders

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

Skin and subcutaneous tissue disorders

Severe skin adverse reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome).

Renal and urinary disorders

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

Psychiatric disorders

Carvedilol may cause hallucinations.

Special populations

Studies in elderly patients with arterial hypertension or angina pectoris showed that the adverse effect profile did not differ from that in younger patients. A further study including elderly patients with ischemic arterial disease did not show a significant difference in reported adverse effects compared to those reported in younger patients.

Shelf life. 3 years.

Storage conditions. Store in a place inaccessible to children, at a temperature not exceeding 30 °C. Store in the original packaging to protect from light.

Packaging. 10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited - Unit III / Aurobindo Pharma Limited - Unit III.

Manufacturer's address and location of operations.

Survey No. 313, 314 - Blocks I, II, III, IV, Bachupally Village, Quthubullapur Mandal, Medchal District, Telangana, 500090, India.