ATC categoryCardiology, angiology
Each tablet contains:
active ingredients: Carvedilol– 12.5mg
excipients microcrystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, magnesium stearate, sucrose, aerosil 200 .
Alpha and beta blocking agents. ATC code C07AG02.
(±)-1-(9Н-carbasol-4-yloxi-)-3-[[2-(2-metoxiphenoxi) ethyl-amino-propanol. 72956-09-3
Carvedilol is a vasodilating non-selective beta-blocking agent with antioxidant properties. Vasodilation is predominantly mediated through alpha1 receptor antagonism. Carvedilol reduces the peripheral vascular resistance through vasodilation and suppresses the renin-angiotensin-aldosterone system through beta-blockade. The activity of plasma renin is reduced and fluid retention is rare.Carvedilol has no intrinsic sympathomimetic activity and like propranolol, it has membrane stabilising properties.Carvedilol is a racemate of two stereoisomers. Beta-blockade is attributed to the S(-) enantiomer; in contrast, both enantiomers exhibit the same α1-blocking activity. Carvedilol is a potent antioxidant, a scavenger of reactive oxygen radicals and an anti-proliferative agent. The properties of carvedilol and its metabolites have been demonstrated in in vitro and in vivo animal studies and in vitro in a number of human cell types.
The absolute bioavailability of carvedilol is approximately 25% in humans. Bioavailability is stereo-selective, 30% for the R-form and 15% for the S-form. Serum levels peak at approximately 1 hour after an oral dose. There is a linear relationship between the dose and serum concentrations. Food does not affect bioavailability or the maximum serum concentration although the time to reach maximum serum concentration is delayed. Carvedilol is highly lipophilic, approximately 98% to 99% is bound to plasma proteins. The distribution volume is approximately 2 l/kg and increased in patients with liver cirrhosis. The first pass effect after oral administration is approximately 60 – 75%; enterohepatic circulation of the parent substance has been shown in animals.Carvedilol exhibits a considerable first pass effect. The metabolite pattern reveals intensive metabolism with glucuronidation as one of the major steps. Demethylation and hydroxylation at the phenol ring produce 3 metabolites with beta-receptor blocking activity.The average elimination half-life ranges from 6 to 10 hours. Plasma clearance is approximately 590ml/min. Elimination is mainly biliary. The primary route of excretion is via the faeces. A minor portion is eliminated via the kidneys in the form of various metabolites.The pharmacokinetics of carvedilol are affected by age; plasma levels of carvedilol are approximately 50% higher in the elderly compared to young subjects. In a study in patients with cirrhotic liver disease, the bioavailability of carvedilol was four times greater and the peak plasma level five times higher than in healthy subjects. Since carvedilol is primarily excreted via the faeces, significant accumulation in patients with renal impairment is unlikely. In patients with impaired liver function, bioavailability is raised to as much as 80% due to a reduced first pass effect.
Hypertension.Carvedilol is indicated for the treatment of hypertension.
Angina.Carvedilol is indicated for the prophylactic treatment of stable angina.
For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilised prior to initiation of Carvedilol treatment.
Once daily dosing is recommended.
Dose titration should occur at intervals of at least two weeks.
Patients with co-existing hepatic disease
Patients with co-existing renal dysfunction
Blood and lymphatic system disorders
Immune system disorders
Metabolism and nutrition disorders
Nervous system disorders
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Musculoskeletal and connective tissue disorders
Renal and urinary disorders
Reproductive system and breast disorders
General disorders and administration site conditions
Dizziness, syncope, headache and asthenia are usually mild and are more likely to occur at the beginning of treatment.
In patients with congestive heart failure, worsening cardiac failure and fluid retention may occur during up-titration of carvedilol dose .
Cardiac failure is a commonly reported adverse event in both placebo and carvedilol-treated patients (14.5% and 15.4% respectively, in patients with left ventricular dysfunction following acute myocardial infarction).
Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure, ischaemic heart disease and diffuse vascular disease and/or underlying renal insufficiency (see section 4.4).
As a class, beta-adrenergic receptor blockers may cause latent diabetes to become manifest, manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.
Carvedilol may cause urinary incontinence in women which resolves upon discontinuation of the medication.
Symptoms and signs
Chronic congestive heart failure: In congestive heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of Carvedilol. If such symptoms occur, diuretics should be increased and the Carvedilol. dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the Carvedilol.dose or in rare cases temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Carvedilol. Carvedilol should be used with caution in combination with digitalis glycosides since both drugs may slow A-V conduction.Renal function in congestive heart failure: Reversible deterioration of renal function has been observed with Carvedilol therapy in chronic heart failure patients with low blood pressure (systolic BP < 100mmHg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. In CHF patients with these risk factors, renal function should be monitored during up-titration of Eucardic and the drug discontinued or dosage reduced if worsening of renal failure occurs. Bronchospatic reactions: In patients with a tendency to bronchospastic reactions, respiratory distress can occur as a result of a possible increase in airway resistance.
Diabetes: Care should be taken in the administration of Carvedilol. to patients with diabetes mellitus as the early signs of acute hypoglycaemia may be masked or attenuated. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. In chronic heart failure patients with diabetes, the use ofCarvedilolmay be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when Carvedilol is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly.
Peripheral vascular disease: Carvedilol should be used with caution in patients with peripheral vascular disease since beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However as Eucardic also has alpha-blocking properties this effect is largely counterbalanced. Raynaud’s phenomenon Carvedilol should be used with caution in patients suffering from peripheral circulatory disorders (Raynaud’s phenomenon) as there may be exacerbation of symptoms.
Thyrotoxicosis: Carvedilol, as with other agents with beta-blocking activity, may mask the symptoms of thyrotoxicosis.Anaesthesia and major surgery: Caution should be exercised in patients undergoing general surgery, because of the synergistic negative inotropic effects of carvedilol and anaesthetic drugs . Bradycardia: Carvedilol may induce bradycardia. If the patient’s pulse rate decreases to less than 55 beats per minute, the dosage of Carvedilol should be reduced.
Hypersensitivity: Care should be taken in administering Carvedilol to patients with a history of serious hypersensitivity reactions and in those undergoing desensitisation therapy as beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.
Psoriasis: Patients with a history of psoriasis associated with beta-blocker therapy should be given Carvedilol only after consideration of the risk-benefit ratio.
Concomitant use of calcium channel blockers: Careful monitoring of ECG and blood pressure is necessary in patients receiving concomitant therapy with calcium channel blockers of the verapamil or diltiazem type or other antiarrhythmic drugs
Phaeochromocytoma: In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. Although carvedilol has both alpha and beta-blocking pharmacological activities, there is no experience of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of Carvedilol to patients suspected of having phaeochromocytoma.
Prinzmetal’s variant angina: Agents with non-selective beta-blocking activity may provoke chest pain in patients with Prinzmetal’s variant angina. There is no clinical experience with Carvedilol in these patients, although the alpha-blocking activity ofCarvedilol may prevent such symptoms. However, caution should be taken in the administration of Carvedilol to patients suspected of having Prinzmetal’s variant angina.
Contact lenses: Wearers of contact lenses should be advised of the possibility of reduced lacrimation.
Withdrawal syndrome: Carvedilol treatment should not be discontinued abruptly, particularly in patients suffering from ischaemic heart disease. The withdrawal of carvedilol should be gradual (over a period of 2 weeks).
Lactose: This medicinal product contains lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Sucrose: This medicinal product contains sucrose, therefore patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Digoxin: Digoxin concentrations are increased by about 16% when digoxin and carvedilol are administered concomitantly. Both digoxin and carvedilol slow AV conduction. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol.
Insulin or oral hypoglycaemics: Agents with beta-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycaemics. The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycaemics, regular monitoring of blood glucose is therefore recommended
Inducers and inhibitors of hepatic metabolism: Rifampicin reduced plasma concentrations of carvedilol by about 70%. Cimetidine increased AUC by about 30% but caused no change in Cmax. Care may be required in those receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels may be increased. However based on the relatively small effect of cimetidine on carvedilol drug levels the likelihood of any clinically important interaction is minimal.
Catecholamine-depleting agents: Patients taking both agents with beta-blocking properties and a drug that can deplete catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.
Ciclosporin: Modest increases in mean trough ciclosporin concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of ciclosporin had to be reduced in order to maintain ciclosporin concentrations within the therapeutic range, while in the remainder no adjustment was needed. On average, the dose of ciclosporin was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that ciclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate.
Verapamil, diltiazem or other antiarryhthmics: In combination with Carvedilol can increase the risk of AVconduction disturbances .
Clonidine: Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood pressure and heart rate lowering effects. When concomitant treatment with agents with beta-blocking properties and clonidine is to be terminated, the beta-blocking agent should be discontinued first. Clonidine therapy can then be discontinued several days later by gradually decreasing the dosage.
Calcium channel blockers: Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when Carvedilol and diltiazem were given concomitantly. As with other agents with beta-blocking properties, if carvedilol is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored. As with other agents with beta-blocking activity, Carvedilol may potentiate the effect of other concomitantly administered drugs that are anti-hypertensive in action (e.g. alpha1-receptor antagonists) or have hypotension as part of their adverse effect profile.
Careful attention must be paid during anaesthesia to the synergistic negative inotropic and hypertensive effects of carvedilol and anaesthetic drugs.
There is no adequate clinical experience with carvedilol in pregnant women.
Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development. The potential risk for humans is unknown.Carvedilol should not be used during pregnancy unless the potential benefit outweighs the potential risk.Beta blockers reduce placental perfusion, which may result in intrauterine foetal death, and immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in the foetus and neonate. There may be an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period. Animal studies have not shown substantive evidence of teratogenicity with carvedilol
Animal studies demonstrated that carvedilol or its metabolites are excreted in breast milk. It is not known whether carvedilol is excreted in breast milk. Breast feeding is therefore not recommended during administration of carvedilol.
White flat scored tablets.
1 blister packet with 40 tablets in each and leaflet inserted in the cardboard box.
3 years. Do not use after the expiration date.
Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from light.