Alpha and beta blocking agents - ATC code: C07AG02

carvedilol

Each tablet contains 25mg carvedilol. Excipients: lactose, sucrose. Each tablet contains 10mg lactose and 25mg sucrose.

Tablet. Round white to pale yellowish beige tablet, scored on both sides, marked BM on one side and D5 on the other.

Symptomatic chronic heart failure (CHF)

Eucardic 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

Eucardic is indicated for the treatment of hypertension.

Angina

Eucardic is indicated for the prophylactic treatment of stable angina.

The tablets should be taken with fluid. For CHF patients Eucardic should be given with food.

Symptomatic chronic heart failure

Initiation of therapy with Eucardic 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 Eucardic 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 Eucardic treatment. Under these circumstances, the dose of Eucardic should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised.

If Eucardic 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.

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.

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.

Patients with co-existing hepatic disease

Eucardic 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.

Symptomatic chronic heart failure

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

Hypertension

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

Angina

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

Symptomatic chronic heart failure

As for adults.

Hypertension

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.

Angina

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

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 Eucardic. If such symptoms occur, diuretics should be increased and the Eucardic dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the Eucardic dose or in rare cases temporarily discontinue it. Such episodes do not preclude subsequent successful titration of Eucardic.

Eucardic 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 Eucardic 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. The following warnings will be included on the outer packaging and leaflet:

Packaging

Do not take this medicine if you have a history of wheezing due to asthma or other lung diseases.

Leaflet

Do not take Eucardic if you have ever had wheezing due to asthma or other lung diseases. If you are not sure, talk to your doctor or pharmacist before taking Eucardic.

Diabetes: Care should be taken in the administration of Eucardic 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 of Eucardic may be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when Eucardic is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly.

Peripheral vascular disease: Eucardic 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: Eucardic, 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: Eucardic may induce bradycardia. If the patient's pulse rate decreases to less than 55 beats per minute, the dosage of Eucardic should be reduced.

Hypersensitivity: Care should be taken in administering Eucardic 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 Eucardic 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 Eucardic 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 Eucardic in these patients, although the alpha-blocking activity of Eucardic may prevent such symptoms. However, caution should be taken in the administration of Eucardic 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

Carvedilol is a substrate as well as an inhibitor of P-glycoprotein. Therefore the bioavailability of drugs transported by P-glycoprotein may be increased with concomitant administration of carvedilol. In addition, the bioavailability of carvedilol can be modified by inducers or inhibitors of P-glycoprotein.

Inhibitors as well as inducers of CYP2D6 and CYP2C9 can modify the systemic and/or presystemic metabolism of carvedilol stereoselectively, leading to increased or decreased plasma concentrations of R and S-carvedilol. Some examples observed in patients or in healthy subjects are listed below but the list is not exhaustive.

Digoxin: Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol.

Ciclosporin: Two studies in renal and cardiac transplant patients receiving oral ciclosporin have shown an increase in ciclosporin plasma concentration following the initiation of carvedilol. It appears that carvedilol increases the absorption of ciclosporin po through inhibition of P-glycoprotein activity in the intestine. In an attempt to maintain therapeutic ciclosporin levels, an average 10-20% reduction of the ciclosporin dose was necessary. Therefore, due to wide interindividual variability of ciclosporin levels, it is recommended that ciclosporin concentrations are monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate. In case of iv administration of ciclosporin, no interaction with carvedilol is expected.

Rifampicin: In a study in 12 healthy subjects, rifampicin administration decreased the carvedilol plasma levels most likely by induction of P-glycoprotein leading to a decrease of the intestinal absorption of carvedilol and a decrease of the antihypertensive effect.

Amiodarone: In patients with heart failure, amiodarone decreased the clearance of Scarvedilol likely by inhibition of CYP2C9. The mean R-carvedilol plasma concentration was not altered. Consequently, there is a potential risk of increased beta-blockade caused by a raised of the plasma S-carvedilol concentration.

Fluoxetine: In a randomized, cross-over study in 10 patients with heart failure, coadministration of fluoxetine, a strong inhibitor of CYP2D6, resulted in stereoselective inhibition of carvedilol metabolism with a 77% increase in mean R(+) enantiomer AUC. However, no difference in adverse events, blood pressure or heart rate were noted between treatment groups.

Pharmacodynamic interactions

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.

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.

Verapamil, diltiazem, amiodarone or other antiarryhthmics: In combination with Eucardic can increase the risk of AV conduction 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 Eucardic 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.

Antihypertensives: As with other agents with beta-blocking activity, Eucardic 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.

Anaesthetic agents: Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic negative inotropic and hypertensive effects of carvedilol and anaesthetic drugs.

NSAIDs: The concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) and betaadrenergic blockers may result in an increase in blood pressure and lower blood pressure control.

Beta-agonist bronchodilatators: Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators.

Infections and infestations

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

(c) Description of selected adverse reactions

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.

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.

Roche Products Limited

(POM)

14 February 2012