Document: spc-doc_PL 36390-0124 change

• spc-doc_PL 00142-0599
• spc-doc_PL 00289-0548
• spc-doc_PL 00289-0552
• spc-doc_PL 17907-0099
• spc-doc_PL 20417-0015
• spc-doc_PL 36390-0124

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Carvedilol 12.5 mg Tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 12.5 mg of Carvedilol Excipients with known effects:

Each tablet contains 62.94 mg of lactose For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Carvedilol Tablets are cream coloured, circular, biconvex tablets, 8.30 mm-8.70 mm in diameter, marked ‘C12’ on one face and plain on the reverse face.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adjunctive treatment of moderate to severe stable chronic heart failure (CHF) Essential hypertension Chronic stable angina pectoris

4.2 Posology and method of administration

Posology

Heart failure

Carvedilol is given in moderate to severe heart failure in addition to conventional basic therapy with diuretics, ACE inhibitors, digitalis, and/or vasodilators. The patient should be clinically stable (no change in NYHA-class, no hospitalisation due to heart failure) and the basic therapy must be stabilised for at least 4 weeks prior to treatment. Additionally the patient should have a reduced left ventricular ejection fraction and heart rate should be > 50 bpm and systolic blood pressure > 85 mm Hg (see section 4.3).

The initial dose is 3.125 mg twice a day for two weeks. If this dose is tolerated, the dose may be increased slowly with intervals of not less than two weeks up to 6.25 mg twice a day, then up to 12.5 mg twice a day and finally up to 25 mg twice a day. The dosage should be increased to the highest tolerable level.

The recommended maximum dosage is 25 mg twice a day for patients with body weight less than 85 kg and 50 mg twice a day for patients with a body weight above 85 kg, provided that the heart failure is not severe. A dose increase to 50 mg twice daily should be performed carefully under close medical supervision of the patient.

Transient worsening of symptoms of heart failure may occur at the beginning of treatment or due to dose increase, especially in patients with severe heart failure and/or under high dose diuretics treatment. This does usually not call for discontinuation of treatment, but dose should not be increased. The patient should be monitored by a physician/cardiologist for two hours after starting treatment or increasing the dose. Before each dose increase, an examination should be performed for potential symptoms of worsening heart failure or for symptoms of excessive vasodilatation (e.g. renal function, body weight, blood pressure, heart rate and rhythm). Worsening of heart failure or fluid retention is treated by increasing the dose of diuretic, and the dose of carvedilol should not be increased until the patient is stabilised. If bradycardia appears or in case of lengthening of AV conduction, the level of digoxin should first be monitored. Occasionally it may be necessary to reduce the carvedilol dose or temporarily discontinue treatment altogether. Even in these cases, carvedilol dose titration can often be successfully continued

Renal function, thrombocytes and glucose (in case of NIDDM and/or IDDM) should be monitored regularly during dose titration. However, after dose titration the frequency of monitoring can be reduced.

If carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg twice daily and increase gradually according to the above recommendation.

Essential Hypertension

Carvedilol may be used for the treatment of hypertension alone or in combination with other

antihypertensives, especially thiazide diuretics. Once daily dosing is recommended, however

the recommended maximum single dose is 25 mg and the recommended maximum daily dose is 50 mg.

Adults:

The recommended initial dose is 12.5 mg once a day for the first two days. Thereafter the treatment is continued at the dose 25 mg/day If necessary the dose may be further increased gradually at intervals of two weeks or more rarely.

Elderly:

The recommended initial dose in hypertension is 12.5 mg once a day which may also be sufficient for continued treatment.

However, if the therapeutic response is inadequate at this dose, the dose may be further increased gradually at intervals of two weeks or more rarely.

Children:

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

Chronic stable angina pectoris A twice-daily regimen is recommended.

Adults:

The initial dosage is 12.5 mg twice a day for the first two days. Thereafter, the treatment is continued at the dose 25 mg twice a day. If necessary, the dose may be further increased gradually at intervals of two weeks or more rarely to the recommended maximum dose of 100 mg a day divided into two doses (twice daily).

Elderly:

The recommended initial dose is 12.5 mg twice daily for two days. Thereafter, the treatment is continued at the dose 25 mg twice daily, which is the recommended maximum daily dose.

Children:

Safety and efficacy in children (under 18 years) has not been established. Moderate hepatic dysfunction Dose adjustment may be required.

Renal insufficiency

Dosage must be determined for each patient individually, but according to pharmacokinetic parameters there is no evidence that dose adjustment of carvedilol in patients with renal insufficiency is necessary.

Older people

Older patients may be more susceptible to the effects of carvedilol and should be monitored more carefully.

As with other beta blockers and especially in patients with coronary disease, the withdrawal of carvedilol should be done gradually (see section 4.4).

Method of administration:

Oral use.

The tablets should be taken with the adequate supply of fluid. The tablets do not need to be taken with a meal. However, it is recommended that heart failure patients take their carvedilol medication with food to allow the absorption to be slower and the risk of orthostatic hypotension to be reduced.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Unstable/decompensated heart failure Clinically manifest liver dysfunction,

History of bronchospasm or asthma,

2^nd and 3^rd degree AV 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 mm Hg),

Metabolic acidosis,

Concomitant intravenous treatment with verapamil or diltiazem (see section 4.5)

4.4 Special warnings and precautions for use

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, diuretic 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, as both drugs slow AV conduction (see section 4.5).

Diabetes

Care should be taken in the administration of carvedilol to patients with diabetes mellitus the early signs and symptoms of acute hypoglycaemia may be masked or attenuated. In chronic heart failure patients with diabetes, the use of carvedilol may be associated with worsening control of blood glucose (see section 4.5).

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 < 100 mm Hg), ischaemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency.

In heart failure patients with these risk factors, renal function should be monitored during dose titration of carvedilol. If significant worsening of renal function occurs, the carvedilol dose must be reduced or therapy must be discontinued.

Contact lenses

Wearers of contact lenses should bear in mind 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 two weeks).

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.

Thyrotoxicosis

Carvedilol may obscure the symptoms of thyrotoxicosis.

Bradycardia

Carvedilol may cause bradycardia. If there is a decrease in pulse rate to less than 55 beats per

minute, the carvedilol dose 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.

Raynaud's phenomenon

Carvedilol should be used with caution in patients suffering from peripheral circulatory disorder (e. g. Raynaud's phenomenon) as there may be exacerbation of symptoms.

Psoriasis

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

Pheochromocytoma

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 with its use in this condition. Cautionshould therefore 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 of carvedilol may prevent such symptoms. Caution should however, be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina.

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.

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 (see section 4.5).

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 (see section 4.5).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Antihypertensives

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.

Catecholamine-depleting agents

Patients taking both agents with P-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.

Calcium channel blockers (see section 4.4)

Isolated cases of conduction disturbance (rarely with haemodynamic compromise) have been observed when carvedilol is coadministered with diltiazem. 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.

Insulin or oral hypoglycaemics

Agents with beta-blocking properties may enhance the blood-sugar-reducing effects of insulin or oral hypoglycaemics The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycaemics, regularmonitoring of blood glucose is therefore recommended (see section 4.4).

Digoxin

The combined use of beta-blockers and digoxin may result in additive prolongation of atrioventricular (AV) conduction time.

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.

Anaesthetic agents

Careful monitoring of vital signs is recommended during anaesthesia due to the synergistic negative inotropic and hypotensive effects of carvedilol and anaesthetic drugs (see section 4.4).

Verapamil, diltiazem, aminodarone or other antiarrhythmics

In combination with carvedilol can increase the risk of AV conduction disturbances (see section 4.4).

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

Beta-agonist bronchodilators

Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended.

Dihydropyridines

The administration of dihydropyridines and carvedilol should be done under close supervision as heart failure and severe hypotension have been reported.

Nitrates

Increased hypotensive effects.

Ergotamine

Vasoconstriction increased.

Neuromuscular blocking agents Increased neuromuscular block.

Pharmacokinetic interaction

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. (see section 5.2). 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. Both digoxin and carvedilol slow AV conduction. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol (see section 4.4).

Cyclosporin

Two studies in renal and cardiac transplant patients receiving oral cyclosporin have shown an increase in cyclosporin plasma concentration following the initiation of carvedilol treatment. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On average, the dose of cyclosporine was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin be adjusted as appropriate.

Rifampicin

In a study in 12 healthy subjects, rifampicin administration decreased the carvedilol plasma levels by about 70%, most likely by induction of P-glycoprotein leading to a decrease of the intestinal absorption of carvedilol.

Amiodarone

In patients with heart failure, amiodarone decreased the clearance of S-carvedilol 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 raise 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.

Cimetidine

Cimetidine increased AUC by about 30% but caused no change in C_max. Care may be required in those patients receiving inhibitors of mixed function oxidases e.g. cimetidine, as serum levels of carvedilol 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.

4.6 Fertility, pregnancy and lactation

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 (see section 5.3). The potential risk for humans is unknown.

Carvedilol should not be used during pregnancy unless the potential benefits outweigh the potential risks.

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 (see also section 5.3).

Breast-feeding

It is unknown whether carvedilol is excreted in human breast milk. Animal studies demonstrated that carvedilol or its metabolites are excreted in breast milk. Breast feeding is therefore not recommended during the administration of carvedilol.

4.7 Effects on ability to drive and use machines

No studies have been performed on the effects of carvedilol on patient’s fitness to drive or to operate machinery.

Because of individually variable reactions (e. g. dizziness, tiredness), the ability to drive, operate machinery, or work without firm support may be impaired. This applies particularly at the start of treatment, after dose increase, on changing products, and in combination with alcohol.

4.8 Undesirable effects

Summary of the safety profile

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

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:

Very common > 1/10

Common > 1/100 and < 1/10

Rare > 1/10,000 and < 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: Leucopenia.

Immune system disorders

Very rare: Hypersensitivity (allergic reaction)

Metabolism and nutrition disorders

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

Psychiatric disorders

Common: Depression, depressed mood

Uncommon: Sleep disorders

Nervous system disorders

Very common: Dizziness, headaches

Uncommon: Presyncope, syncope, paraesthesia

Eye disorders

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

Cardiac disorders

Very common: Cardiac failure

Common: Bradycardia, oedema, hypervolaemia and fluid overload.

Uncommon: AV-block and angina pectoris Vascular disorders

Very common: Hypotension

Common: Orthostatic hypotension, disturbances of peripheral circulation (cold extremities, peripheral vascular disease, exacerbation of intermittent claudication and Raynaud's phenomenon)

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, pulmonary oedema, asthma in predisposed patients Rare: Nasal congestion Gastrointestinal disorders

Common: Nausea, diarrhoea, dyspepsia, abdominal pain and vomiting.

Hepatobiliary disorders

Very rare: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) increased

Skin and subcutaneous tissue disorders

Uncommon: Skin reaction (e. g. allergic exanthema, dermatitis, urticarial, pruritus, psoriatic and lichen planus like skin lesions), alopecia

Very rare: Severe cutaneous adverse reactions (e.g. Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis)

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

Common: Pain

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 (see section 4.4).

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

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

In addition to general supportive treatment, the vital parameters must be monitored and corrected, if necessary under intensive care conditions.

Atropine can be used for excessive bradycardia, while to support ventricular function intravenous glucagon, or sympathomimetics (dobutamine, isoprenaline) are recommended. If positive inotropic effect is required, phosphodiesterase inhibitors (PDE) should be considered. If peripheral vasodilation dominates the intoxication profile then norfenephrine or noradrenaline should be administered with continuous monitoring of the circulation. In the case of drug-resistant bradycardia, pacemaker therapy should be initiated.

For bronchospasm, beta-sympathomimetics (as aerosol or intravenous) should be given, or aminophylline 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 must be continued for a sufficiently long period, i.e. until the condition has stabilised, as a prolongation of elimination half-life and redistribution of carvedilol from deeper compartments can be expected.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha and beta blocking agents.

ATC code: C07AG02

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 ^-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.

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

• In hypertensive patients, a reduction in blood pressure is not associated with a concomitant increase in total peripheral resistance, as observed with pure beta-blocking agents. Heart rate is slightly decreased. Renal blood flow and renal function are maintained. Peripheral blood flow is maintained, therefore, cold extremities, often observed with drugs possessing beta-blocking activity, are rarely seen.

• In patients with stable angina, carvedilol has demonstrated antiischaemic and anti-anginal properties. Acute haemodynamic studies demonstrated that carvedilol reduces ventricular pre- and after-load.

• In patients with left ventricular dysfunction or chronic heart failure, carvedilol has demonstrated favourable effects on haemodynamics and improvements in left ventricular ejection fraction and dimensions.

• In a large, multi-centre, double-blind, placebo-controlled, mortality trial (COPERNICUS), 2289 patients with severe stable CHF of ischaemic or non-ischaemic origin, on standard therapy, were randomised to either carvedilol (1156 patients) or placebo (1133 patients). Patients had left ventricular systolic dysfunction with a mean ejection fraction of < 20%. All-cause mortality was reduced by 35% from 19.7% in the placebo group to 12.8% in the carvedilol group (Cox proportional hazards, p = 0.00013).

Combined secondary endpoints of mortality or hospitalisation for heart failure, mortality or cardiovascular hospitalisation and mortality or all-cause hospitalisation were all significantly lower in the carvedilol group than placebo (31%, 27% and 24% reductions, respectively, all p < 0.00004).

The incidence of serious adverse events during the study was lower in the carvedilol group (39.0% vs 45.4%). During initiation of treatment, the incidence of worsening heart failure was similar in both carvedilol and placebo groups. The incidence of serious worsening heart failure during the study was lower in the carvedilol group (14.6% vs 21.6%).

Serum lipid profile and electrolytes are not affected.

Absorption and distribution

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.

Biotransformation

The first pass effect after oral administration is approximately 60 - 75%.

Carvedilol is found to be extensively metabolised into various metabolites, which are mainly eliminated in bile. Carvedilol is metabolised in the liver mainly through aromatic ring oxidation and glucuronidation. Demethylation and hydroxylation at the phenol ring yield three active metabolites with beta-blocking activity. Compared to carvedilol, these three active metabolites have a weak vasodilatory effect. On the basis of preclinical studies, the 4’-hydroxyphenolmetabolite has a beta-blocking activity 13 times more potent than that of carvedilol. However, the metabolite concentrations in humans are approximately 10 times lower than those of carvedilol. Two of the hydroxycarbazole metabolites of carvedilol are highly potent antioxidants, with a 30-80- fold potency compared to carvedilol.

Elimination

The average elimination half-life ranges from 6 to 10 hours. Plasma clearance is approximately 590 ml/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.

Linearity/non-linearity

There is a linear correlation between the dose and plasma concentrations. In patients with slow hydroxylation of debrisoquine plasma carvedilol concentrations increased up to 2-3-fold compared to rapid debrisoquine metabolisers.

Special populations

Elderly

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.

Renal impairment

In some of the hypertensive patients with moderate (creatinine clearance 20-30 ml/min) or severe (creatinine clearance < 20 ml/min) renal insufficiency, an increase in plasma carvedilol concentrations of approximately 40-55% was seen compared to patients with normal renal function. However, there was a large variation in the results.

5.3 Preclinical safety data

Studies on rats and mice revealed no carcinogenic potential of carvedilol at doses of 75 mg/kg and 200 mg/kg (38-100 times the human maximum daily dose).

Carvedilol demonstrated no mutagenic potential in studies conducted on mammals or other animals in vitro or in vivo.

When high doses of carvedilol were administered to pregnant rats (> 200 mg/kg = > 100 times the human maximum daily dose), undesirable effects on pregnancy and fertility were observed. Physical growth and development of the foetus were delayed at doses of > 60 mg/kg (> 30 times the human maximum daily dose).

Embryotoxicity (increased mortality after implantation of the embryo) occurred, but there were no deformations in rats or rabbits at doses of 200 mg/kg and 75 mg/kg, respectively (38-100 times the human maximum daily dose).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Microcrystalline cellulose (Avicel pH 102) Low-substituted hydroxypropyl cellulose (E463) Maize starch

Yellow iron oxide (E172)

Colloidal anhydrous silica Purified talc

Magnesium stearate (E572)

10 DATE OF REVISION OF THE TEXT

20/08/2015