Each tablet contains:

active ingredients: Carvedilol– 6.25mg

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.

Symptomatic chronic heart failure (CHF).Carvedilol is indicated for the treatment of stable mild, moderate and severe chronic heart failure as adjunct to standard therapies e.g. diuretics, digoxin, and ACE inhibitors in patients with euvolemia.

Hypertension.Carvedilol is indicated for the treatment of hypertension.

Angina.Carvedilol is indicated for the prophylactic treatment of stable angina.

The tablets should be taken with fluid. For CHF patients Carvedilol should be given with food.Symptomatic chronic heart failure. Initiation of therapy with Carvedilol should only be under the supervision of a hospital physician, following a thorough assessment of the patient’s condition. Prior to any subsequent titration of the dose, the patient must be clinically evaluated on the day of uptitration by a health-care professional experienced in the management of heart failure to ensure that the clinical status has remained stable. The dose of carvedilol should not be increased in any patient with deteriorating heart failure since last visit or with signs of decompensated or unstable chronic heart failure. The dosage must be titrated to individual requirements.

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.

Adults
The recommended dose for the initiation of therapy is 3.125mg twice a day for two weeks. If this dose is tolerated, the dosage should be increased subsequently, at intervals of not less than two weeks, to 6.25mg twice daily, followed by 12.5mg twice daily and thereafter 25mg twice daily. Dosing should be increased to the highest level tolerated by the patient. The recommended maximum daily dose is 25mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85kg (187lbs). In patients with mild or moderate CHF weighing more than 85kg, the recommended maximum dose is 50mg twice daily. During up-titration of the dose in patients with systolic blood pressure < 100mmHg, deterioration of renal and/or cardiac functions may occur. Therefore, before each dose increase these patients should be evaluated by the physician for renal function and symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or fluid retention may be treated by adjusting doses of diuretics or ACE inhibitors or by modifying or temporarily discontinuing Carvedilol treatment. Under these circumstances, the dose of Carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised.If Carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125mg twice daily and up-titrated in line with the above dosing recommendation.

Elderly
As for adults.

Children
Safety and efficacy in children (under 18 years) has not been established.

 

Hypertension
Once daily dosing is recommended.

Adults
The recommended dose for initiation of therapy is 12.5mg once a day for the first two days. Thereafter the recommended dosage is 25mg once a day. Although this is an adequate dose in most patients, if necessary the dose may be titrated up to a recommended daily maximum dose of 50mg given once a day or in divided doses.

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

Elderly

An initial dose of 12.5mg daily is recommended. This has provided satisfactory control in some cases. If the response is inadequate the dose may be titrated up to the recommended daily maximum dose of 50mg given once a day or in divided doses.

Children
Safety and efficacy in children (under 18 years) has not been established.

 

Angina

Adults
The recommended dose for initiation of therapy is 12.5mg twice a day for the first two days. Thereafter, the recommended dosage is 25mg twice a day.

Elderly
The recommended maximum daily dose is 50mg given in divided doses.

Children
Safety and efficacy in children (under 18 years) has not been established.

 

Patients with co-existing hepatic disease
Carvedilol is contraindicated in patients with hepatic dysfunction

 

Patients with co-existing renal dysfunction
No dose adjustment is anticipated as long as systolic blood pressure is above 100mmHg

The frequency of adverse reactions is not dose-dependent, with the exception of dizziness, abnormal vision and bradycardia.

• Common: Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection

Blood and lymphatic system disorders

• Common: Anaemia.
• Rare: Thrombocytopaenia.
• Very rare: Leukopenia

Immune system disorders

• Very rare: Hypersensitivity (allergic reaction)

Metabolism and nutrition disorders

• Common: Weight increase, hypercholesterolaemia, impaired blood glucose control (hyperglycaemia, hypoglycaemia) in patients with pre-existing diabetes.

Psychiatric disorders

• Common: Depression, depressed mood.
• Uncommon: Sleep disorders.

Nervous system disorders

• Very common: Dizziness, headache.
• Uncommon: Presyncope, syncope, paraesthesia.

Eye disorders

• Common: Visual impairment, lacrimation decreased (dry eye), eye irritation.

Cardiac disorders

• Very common: Cardiac failure
• Common: Bradycardia, oedema (including generalized, peripheral, dependent and genital oedema, oedema of the legs), hypervolaemia, fluid overload
• Uncommon: Atrioventricular block, angina pectoris.

Vascular disorders

• Very common: Hypotension
• Common: Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Reynaud’s phenomenon).

Respiratory, thoracic and mediastinal disorders

• Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients
• Rare: Nasal congestion, wheezing and flu-like symptoms.

Gastrointestinal disorders

• Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain
• Uncommon: Constipation
• Rare: Dry mouth

Hepatobiliary disorders

• Very rare: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyltransferase (GGT) increased.

Skin and subcutaneous tissue disorders

• Uncommon: Skin reactions (e.g. allergic exanthema, dermatitis, increased sweating, urticaria, pruritus, psoriatic and lichen planus like skin lesions), alopecia.

Musculoskeletal and connective tissue disorders

• Common: Pain in extremities

Renal and urinary disorders

• Common: Renal failure and renal function abnormalities in patients with diffuse vascular disease and/or underlying renal insufficiency, micturition 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: Pain

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
In the event of overdose, there may be severe hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest. There may also be respiratory problems, bronchospasm, vomiting, disturbed consciousness and generalised seizures.

Treatment
Gastric lavage or induced emesis may be useful in the first few hours after ingestion.In addition to general supportive treatment, the vital parameters must be monitored and corrected, if necessary under intensive care conditions.Patients should be placed in the supine position. Atropine, 0.5mg to 2mg i.v. and/or glucagon 1 to 10mg i.v. (followed by a slow i.v. infusion of 2 to 5mg/hour if necessary) may be given when bradycardia is present. To support ventricular function intravenous glucagon or sympathomimetics (dobutamine, isoprenaline) are recommended. If positive inotrpopic effect is required phosphodiesterase inhibitors (PDE) should be considered. Pacemaker therapy may be necessary. For excessive hypotension, intravenous fluids may be administered. If peripheral vasodilation dominates the intoxication profile then norepinephrine or noradrenaline should be administered, with continuous monitoring of the circulation, either 5 to 10 micrograms i.v., repeated according to blood pressure response, or 5 micrograms per minute by infusion titrated to blood pressure. In the case of drug-resistant bradycardia, pacemaker therapy should be initiated. For bronchospasm, beta-sympathomimetics (as aerosol or intravenous) should be given, oraminophylline may be administered intravenously by slow injection or infusion. In the event of seizures, slow intravenous injection of diazepam or clonazepam is recommended.In cases of severe overdose with symptoms of shock, supportive treatment as described should be continued for a sufficiently long period of time, i.e. until the patient stabilises, since prolonged elimination half life and redistribution of carvedilol from deeper compartments can be expected.

• Hypersensitivity to the active substance or to any of the excipients.
• Unstable/decompensated heart failure.
• Marked fluid retention or overload requiring intravenous inotropic support.
• Obstructive airways disease.
• Clinically manifest liver dysfunction.
• History of bronchospasm or asthma.
• 2nd and 3rd degree A-V heart block, (unless a permanent pacemaker is in place).
• Severe bradycardia (< 50 bpm).
• Cardiogenic shock.
• Sick sinus syndrome (including sino-atrial block).
• Severe hypotension (systolic blood pressure < 85mmHg).
• Metabolic acidosis.
• Phaeochromocytoma (unless adequately controlled by alpha blockade).

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.

Pharmacokinetic interactions

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 .

Pharmacodynamic interactions

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.

Pregnancy

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

Lactation

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.