CARVEDILOL

For oral administration. 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 patients' condition.

Prior to any subsequent titration of the dose, the patient must be clinically evaluated on the day of up - titration 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 stabilized prior to initiation of carvedilol treatment. 125 mg twice a day for two weeks. 5 mg twice daily and thereafter 25 mg twice daily.

Dosing should be increased to the highest level tolerated by the patient. The recommended maximum daily dose is 25 mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85 kg (187 lbs).

In patients with mild or moderate CHF weighing more than 85 kg, the recommended maximum dose is 50 mg 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. 125 mg 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. 5 mg once a day for the first two days. Thereafter the recommended dosage is 25 mg 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 50 mg given once a day or in divided doses. Dose titration should occur at intervals of at least two weeks.

5 mg 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 50 mg given once a day or in divided doses. Children Safety and efficacy in children (under 18 years) has not been established.

5 mg twice a day for the first two days. Thereafter, the recommended dosage is 25 mg twice a day. Elderly The recommended maximum daily dose is 50 mg 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 contra-indicated in patients with hepatic dysfunction (see sections

a) Summary of the safety profile The frequency of adverse experiences is not dose dependent, with the exception of dizziness, abnormal vision and bradycardia. b) Tabulated list of adverse reactions The risk of most adverse reactions associated with carvedilol is similar across all indications.

Exceptions are described in subsection (c).

Frequency categories are as follows:

Adverse drug reactions are listed below by system organ class and frequency.

Frequencies are defined as:

Very common ≥ 1/10; Common ≥ 1/100 and < 1/10; Uncommon ≥ 1/1,000 and < 1/100; Rare ≥ 1/10,000 and < 1/1,000; Very rare < 1/10,000. 4) Cardiac disorders Atrioventricular-block, angina pectoris Skin and subcutaneous tissue disorder Dermatitis, increased sweating, alopecia Uncommon (>1/1000, <1/100) Nervous system disorders Presyncope, syncope Rare (>1/10000, <1/1000) Blood and lymphatic system disorders Thrombocytopenia Blood and lymphatic system disorders Leucopenia Immune system disorder Hypersensitivity (Allergic reaction) Hepatobiliary disorder Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyltransferase (GGT) increased Renal and urinary disorders Urinary incontinence in women Very rare (incl.

g. 5) In patients with hypertension and angina The profile is similar to that observed in chronic heart failure although the incidence of events is generally lower in patients with hypertension or angina treated with carvedilol. Frequency System organ class Adverse events Cardiac disorders Cardiac failureVery common (> 1/10) Vascular disorders Hypotension Frequency System organ class Adverse events Infections and infestations Bronchitis, pneumonia, upper respiratory tract infection, urinary tract infection Blood and lymphatic system disorders Anaemia Psychiatric disorder Depression and depressed mood Nervous system disorders Dizziness, fatigue, headache: usually mild, occur particularly at the start of treatment Eye disorders Lacrimation decreased (dry eye), visual impairment, eye irritation Cardiac disorders Bradycardia, postural hypotension, especially at the beginning of treatment.

Vascular disorders Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Raynaud’s phenomenon) Respiratory, thoracic and mediastinal disorders Dyspnea, pulmonary oedema and asthma in predisposed patients Gastro-intestinal disorders Gastro-intestinal upset (with symptoms such as abdominal pain, dyspepsia, diarrhoea, nausea) Musculoskeletal and connective tissue disorder Pain in the extremities Renal and urinary disorders Micturition disorder Common (>1/100, <1/10) General disorder Pain Nervous system disorders Asthenia, syncope, paraesthesia Psychiatric disorder Sleep disorder Eye disorders Disturbed vision Cardiovascular system Angina pectoris (including chest pain), AV-block, symptoms of heart failure and peripheral oedema.

Gastro-intestinal Disorders Constipation, vomiting Uncommon (>1/1000, <1/100) Skin and subcutaneous tissue disorder Skin reactions (eg allergic exanthema, dermatitis, increased sweating, lichen planus-like skin lesions, pruritus, urticaria).

Psoriatic skin lesions may occur or existing lesions exacerbated. Alopecia Frequency System organ class Adverse events Reproductive system Sexual impotence, erectile dysfunction Respiratory, thoracic and mediastinal disorders Flu-like symptoms, nasal congestion, wheezing Rare (>1/10000, <1/1000) Gastro-intestinal disorders Dryness of the mouth Blood and lymphatic system disorders Changes in serum transaminases, leucopenia, Thrombocytopenia Immune system disorder Hypersensitivity (Allergic reaction) Hepatobiliary disorder Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyltransferase (GGT) increased Renal and urinary disorders Urinary incontinence in women Very rare (incl.

g. Erythema mulitforme, Stevens- Johnson syndrome, Toxic epidermal necrolysis) c) Description of selected adverse reactions Dizziness, syncope, headache and asthenia are usually mild and more likely to occur at the beginning of treatment.

4). Cardiac failure is a commonly reported […]

2 Pharmacokinetic properties). 1. • Carvedilol is contra-indicated in patients with marked fluid retention or overload requiring intravenous inotropic support. • Patients with obstructive airways disease, unstable/decompensated heart failure, clinically manifested liver dysfunction.

• As with other beta-blocking agents: 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 < 85 mmHg), metabolic acidosis and phaeochromocytoma (unless adequately controlled by alpha blockade).

• Prinzmetal's angina. • Severe peripheral arterial circulatory disturbances. 5). • Unsuitable for patients with lactase insufficiency, galactosaemia or glucose/galactose malabsorption syndrome. 4 Special warnings and precautions for use Chronic Heart Failure In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol.

If such symptoms occur, the dose of 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. 5). In hypertensive patients who have chronic heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, carvedilol should be used with caution since both digoxin and carvedilol may slow A-V conduction.

Renal function in Chronic Heart Failure Reversible deterioration of renal function has been observed with carvedilol therapy in chronic heart failure patients with low blood pressure (systolic BP < 100 mmHg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency.

In patients with these risk factors, renal function should be monitored during up-titration of Carvedilol and the drug discontinued or dosage reduced if worsening of renal failure occurs. Left ventricular dysfunction following acute myocardial infarction Before treatment with Carvedilol is initiated the patient must be clinically stable and should have received an ACE inhibitor for at least the preceding 48 hours, and the dose of the ACE inhibitor should have been stable for at least the preceding 24 hours.

Chronic obstructive pulmonary disease Carvedilol should be used with caution, in patients with chronic obstructive pulmonary disease (COPD) with a bronchospastic component who are not receiving oral or inhaled medication, and only if the potential benefit outweighs the potential risk.

In patients with a tendency to bronchospasm, respiratory distress can occur as a result of a possible increase in airway resistance. Patients should be closely monitored during initiation and up-titration of Carvedilol and the dose of carvedilol should be reduced if any evidence of bronchospasm is observed during treatment.

Diabetes Care should be taken in the administration of Carvedilol to patients with diabetes mellitus, as the early signs and symptoms 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 Carvedilol may 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 as beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However as Carvedilol also has alpha-blocking properties this effect is largely counterbalanced.

g Raynaud's phenomenon) as there may be exacerbation of symptoms. 2). Thyrotoxicosis Carvedilol may obscure the symptoms of thyrotoxicosis. Anesthesia 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 of 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 […]

2 Pharmacokinetic properties). Patients with co-existing renal dysfunction No dose adjustment is anticipated as long as systolic blood pressure is above 100 mmHg (see also sections