SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Teva Carvedilol 25 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 25 mg of carvedilol.

Excipient(s) with known effect:

Each tablet also contains 86.25mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablet.

White to off-white, round flat tablet. Scored on one side, debossed on the other side with “CVL” on top and “T4” on bottom. The tablet can be divided into equal halves.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Essential hypertension Chronic stable angina pectoris

Adjunctive treatment of moderate to severe stable chronic heart failure

4.2    Posology and method of administration

Posology

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.

Older people

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.

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).

Older people

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.

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 4.3 Contraindications).

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 a body weight of 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 a dose increase, especially in patients with severe heart failure and/or under high dose diuretic 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 has been withdrawn for more than two weeks, the therapy should be reinitiated with 3.125 mg twice a day and increased gradually according to the above recommendations.

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.

Moderate hepatic dysfunction Dose adjustment may be required.

Paediatric population)

There are insufficient data on the efficacy and safety of carvedilol.

Older people

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

As with other betablockers and especially in patients with coronary disease, the withdrawal of carvedilol should be done gradually (see 4.4 Special warning and special precautions for use).

Methods 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

-Heart failure belonging to NYHA Class IV of the heart failure classification requiring intravenous inotropic treatment.

-Clinically manifest hepatic dysfunction.

-History of bronchospasm or asthma

-AV block, 2^nd or 3^rd degree (unless a permanent pacemaker is in place).

-Severe bradycardia (<50 bpm).

-Sick sinus syndrome (including sino-atrial block).

-Cardiogenic shock.

-Severe hypotension (systolic blood pressure below 85 mmHg). -Hypersensitivity to carvedilol or to any of the excipients.

-Metabolic acidosis.

-Concomitant intravenous treatment with verapamil or diltiazem (see 4.5).

4.4 Special warnings and precautions for use

Warnings to be considered in patients with congestive heart failure

In chronic heart failure patients carvedilol should be administered principally in addition to diuretics, ACE inhibitors, digitalis and/or vasodilators. Initiation of therapy should be under the supervision of a hospital physician. Therapy should only be initiated, if the patient is stabilized on conventional basic therapy for at least 4 weeks. Patients with severe heart failure, salt and volume depletion, elderly or patients with low basic blood pressure should be monitored for approximately 2 hours after the first dose or after dose increase as hypotension may occur. Hypotension due to excessive vasodilatation is initially treated by reducing the dose of the diuretic. If symptoms still persist, the dose of any ACE inhibitor may be reduced. At the start of therapy or during up-titration of Carvedilol worsening of heart failure or fluid retention may occur. In these cases, the dose of diuretic should be increased and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally, it may be necessary to reduce the carvedilol dose or withdraw it.

In patients with chronic heart failure treated with digitalis, carvedilol should be given with caution, as digitalis and carvedilol both lenghten the AV conduction time (see 4.5 Interaction with other medicinal products and other forms of interaction).

Renal function in Congestive Heart Failure

Reversible deterioration of renal function has been observed during carvedilol therapy in heart failure patients with low blood pressure (systolic < 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.

Left ventricular dysfunction following acute myocardial infarction

Before treatment with carvedilol is initiated, the patient must be clinically stable and should have received an ACEinhibitor 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

Patients with a chronic obstructive pulmonary disease (COPD) with a tendency towards bronchospasms who are not treated with oral or inhalation medicine should only be given carvedilol with caution and only if the expected improvement outweighs the possible 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 monitored closely in the initial phase, and titration of carvedilol and carvedilol dose should be reduced in case of bronchospasms.

Diabetes

Carvedilol may mask or attenuate early signs and symptoms of acute hypoglycaemia. Impaired blood glucose control may occasionally occur in patients with diabetes mellitus and heart failure in connection with the use of carvedilol. Therefore, close monitoring of diabetic patients receiving carvedilol is required by means of regular blood glucose measurements, especially during dose titration, and adjustment of antidiabetic medication as necessary (see 4.5 Interaction with other medicinal products and other forms of interaction). Blood glucose levels should also be closely monitored after a longer period of fasting.

Thyrotoxicosis

Carvedilol may mask features (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.

Concomitant use of calcium channel blockers

When carvedilol is used concomitantly with calcium channel blocking agents such as verapamil and diltiazem or with other antiarrhythmics, specifically amiodarone, the patient’s blood pressure and ECG have to be carefully monitored. Intravenous co-administration should be avoided (see 4.5 Interaction with other medicinal products and other forms of interaction).

Cimetidine should be administered only with caution concomitantly as effects of carvedilol may be increased (see 4.5 Interaction with other medicinal products and other forms of interaction).

Contact lenses

Persons wearing contact lenses should be advised of a possible reduction of the secretion of lacrimal fluid.

Hypersensitivity

Care should be taken in administrating 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

Cautions should be exercised when prescribing beta-blockers to patients with psoriasis since skin reactions may be aggravated. Such patients should take carvedilol only after consideration of the risk/benefit ratio.

Peripheral vascular disease and Raynaud's phenomenon

Carvedilol should be used with caution in patients with peripheral vascular diseases, as beta-blockers may aggravate symptoms of the disease. The same also applies to those with Raynaud’s syndrome, as there may be exacerbation or aggravation of symptoms.

Patients who are known as poor metabolizers of debrisoquine, should be closely monitored during initiation of therapy (see 5.2 Pharmacokinetic properties).

Since there is limited clinical experience, carvedilol should not be administered in patients with labile or secondary hypertension, orthostasis, acute inflammatory heart disease, haemodynamic relevant obstruction of heart valves or outflow tract, end-stage peripheral arterial disease, concomitant treatment with a₁-receptor antagonist or a₂-receptor agonist.

Pheochromocytoma

In patients with pheochromocytoma, an initial treatment with alpha blockers should be started before using any beta blocker. Although carvedilol exercises alpha and beta blockade there is not sufficient experience in this disease, therefore caution should be advised in these patients.

Because of its negative dromotropic action, carvedilol should be given with caution to patients with first degree heart block.

Prinzmetal’s variant angina

Agents with non-selective beta blocking activity may provoke chestpain 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. Caution should, however, be taken in the administration of carvedilol to patients suspected of having Prinzmetal's variant angina.

Anaesthesia and major surgery

Beta blockers reduce the risk of arrhythmias at anaesthesia, however the risk of hypotension may be increased as well. Caution should therefore be exercised in patients undergoing general surgery, because of the synergistic negative inotropic effects of carvedilol and anaesthetic drugs. Newer studies suggest however, a benefit of betablockers in preventing perioperative cardiac morbidity and reduction of the incidence of cardiovascular complications.

Withdrawal syndrome

As with other beta-blockers, carvedilol should not be discontinued abruptly. This applies in particular to patients with ischaemic heart disease. Carvedilol therapy must be discontinued gradually within two weeks, e.g. by reducing the daily dose to half every three days. If necessary, at the same time replacement therapy should be initiated to prevent exacerbation of angina pectoris.

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

4.5 Interaction with other medicinal products and other forms of interaction

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. An increase of steady state digoxin levels by approximately 15% and of digitoxin by approximately 13% has been seen in hypertensive patients in connection with the concomitant use of carvedilol and digoxin. Both digoxin and carvedilol slow AV conduction. Increased monitoring of plasma digoxin concentrations is recommended when initiating, discontinuing or adjusting treatment with carvedilol.

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.

Cyclosporin.Two studies in renal and cardiac transplant patients receiving oral cyclosporin have shown an increase in cyclosporin plasma concentrations following initiation of carvedilol treatment. In about 30% of patients, the dose of cyclosporin had to be reduced in order to maintain cyclosporin concentrations within the therapeutic range, while in the remainder no adjsutment was needed. On average, the dose of cyclosporin 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.

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 P-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 Cmax. 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.

Pharmacodynamic interactions

Catecholamine-depleting agents. Concomitant treatment with reserpine, guanethidine, methyldopa, guanfacine and monoamine oxidase inhibitors can lead to additional decrease in heart rate. Patients should be monitoredclosely for signs of hypotension and/or severe bradycardia.

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.

Other antihypertensive drugs. Carvedilol may potentiate the effects of other concomitantly administered antihypertensives (e.g. a₁-receptor antagonists) and drugs with antihypertensive side effects such as barbiturates, phenothiazines, tricyclic antidepressants, vasodilating agents and alcohol.

Clonidine. Concomitant administration of clonidine with agents with beta blocking properties may potentiate blood-pressure- and heart-rate-lowering effects. When concomitanttreatment with agents with beta blocking properties and clonidine is tobe terminated, the beta blocking agent should be discontinued first. Clonidine therapy can then be discontinued severaldays later by gradually decreasing the dosage.

Calcium channel blockers or other antiarrhytmics (see section 4.4 Special warnings and precautions for use):    Isolated cases of conduction disturbance (rarely compromised

haemodynamics) have been reported, if oral carvedilol and oral diltiazem verapamil and/or amiodarone are given concomitantly. As with other beta-blockers, ECG and blood pressure should be monitored closely when concomitantly administering calcium-channel-blockers of the verapamil and diltiazem type due to the risk of AV conduction disorder or risk of cardiac failure (synergetic effect). Close monitoring should be done in case of co-administration of carvedilol, and amiodarone therapy (oral) or class I antiarrhythmics. Bradycardia, cardiac arrest, and ventricular fibrillation have been reported shortly after initiation of beta-blocker treatment in patients receiving amiodarone. There is a risk of cardiac failure in case of class Ia or Ic antiarrhythmics concomitant intravenous therapy.

Antidiabetics including insulin. The blood sugar-lowering effect of insulin and oral diabetic drugs may be intensified. The signs of hypoglycaemia may be masked or attenuated (especially tachycardia). In patients taking insulin or oral hypoglycemics regular monitoring of blood glucose levels is necessary.

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 Special warnings and precautions for use)

NSAIDs, estrogens and corticosteroids. The antihypertensive effect of carvedilol is decreased due to water and sodium retention. The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) and beta-adrenergic blockers may result in an increase in blood pressure and lower blood pressure control.

Sympathomimetics with alpha-mimetic and beta-mimetic effects. Risk of hypertension and excessive bradycardia. Non-cardioselective beta blockers oppose the bronchodilator effects of beta-agonist bronchodilators. Careful monitoring of patients is recommended.

Ergotamine. Vasoconstriction increased.

Neuromuscular blocking agents. Increased neuromuscular block.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no adequate clinical experience with carvedilol in pregnant women.

Use of carvedilol is not recommended during pregnancy and lactation, unless the potential benefit for the mother outweighs the potential risk for the foetus/neonate.. Animal studies are insufficient with respect to effects on pregnancy, embryonal/foetal development, parturition and postnatal development (see 5.3 Preclinical safety data). The potential risk for humans is unknown .

Beta-blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia bradycardia, respiratory depression and hypothermia) 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 5.3 Preclinical safety data).

The treatment should be stopped 2-3 days before expected birth. If this is not possible the newborn has to be monitored for the first 2-3 days of life.

Breast-feeding

Carvedilol is lipophilic and according to results from studies with lactating animals, carvedilol and its metabolites are excreted in breast milk. It is not known whether carvedilol is excreted in human milk. and, therefore, breast-feeding in not recommended in mothers receiving carvedilol.

4.7 Effects on ability to drive and use machines

No studies have been performed on the effects of carvedilol on patients' fitness to drive or to operate machinery. Because ofindividually variable reactions (e.g. dizziness, tiredness) the ability to drive, operate machinery, or work without firm support may be impaired. Thie applies particularly at the start of treatmenbt, after dose increases, on changing products, and in combination with alcohol.

4.8 Undesirable effects

(a)    Summary of the safety profile

The frequency of adverse reactions 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:

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

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, 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 Gastrointestinal disorders

Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain 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, urticaria, 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

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 (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

Overdose may cause serious hypotension, bradycardia, heart failure, cardiogenic shock and cardiac arrest. There may also be respiratory problems, bronchospasm, vomiting, reduced consciousness and convulsions.

Treatment. In addition to general supportive treatment, vital parameters must be monitored and, if necessary, corrected at an intensive care unit. The following supportive measures may be taken:

Atropine: 0.5 - 2 mg intravenously (for treatment of excessive bradycardia).

To support ventricular function intravenous glucagon or symphaticomimetics are recommended.

Glucagon: initially 1 - 10 mg intravenously followed if necessary by a slow infusion of 2 -5 mg/hour (in order to maintain cardiovascular function).

Sympathomimetics according to their efficacy and the patient’s weight: dobutamine, isoprenaline or adrenaline.

If positive inotropic effect is required, phophodiesterase inhibitors (PDE) should be considered. If peripheral vasodilatation is the dominant symptom of overdose, the patient has to be given noradrenaline, norfenefrine or etilefrine. The patient’s circulation must be monitored continuously.

If the patient has bradycardia unresponsive to pharmacotherapy, pacemaker therapy should be started. For the treatment of bronchospasm, the patient must be given beta-sympathomimetics (as aerosol or intravenously, if the aerosol does not provide adequate effect) or aminophylline may be administered intravensouly by slow injection or infusion. If the patient has convulsions, diazepam or clonazepam may be administered as a slow intravenous injection.

Carvedilol is highly protein-bound. Therefore, it cannot be eliminated by dialysis.

Important! In cases of severe overdose when the patient is in shock, supportive treatment should be continued for a sufficiently long period of time, i.e. until the patients' condition has stabilised since the elimination and redistribution of carvedilol are likely to be slower than normal. Duration of the antidote treatment depends on the seriousness of the overdose; supportive treatment must be continued until the patient stabilises.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: alpha- and beta-blocking agents ATC code: C07A G02

Carvedilol is a vasodilatory non-selective beta-blocker, which reduces the peripheral vascular resistance by selective alpha₁-receptor blockade and suppresses the renin-angiotensin through non-selective beta-blockade. Plasma rennin activity is reduced and fluid retention is rare.

Carvedilol has no intrinsic sympathomimetic activity (ISA). Like propranolol, it has membrane stabilising properties.

Carvedilol is a racemate of two stereoisomers. Both enantiomers were found to have alpha-adrenergic blocking activity in animal models. Non-selective beta₁-and beta₂-adrenoceptor blockade is attributed mainly to the S(-) enantiomer.

The antioxidant 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.

In hypertensive patients, a reduction in blood pressure is not associated with a concomitant increase in peripheral resistance, as observed with pure beta-blocking agents. Heart rate is slightly decreased. Stroke volume remains unchanged. Renal blood flow and renal function remain normal, as does peripheral blood flow, therefore, cold extremities, often observed with beta-blockers, are rarely seen. In hypertensive patients carvedilol increases the plasma norepinephrine concentration.

In prolonged treatment of patients with angina, carvedilol has been seen to have an antiischaemic effect and to alleviate pain. Haemodynamic studies demonstrated that carvedilol reduces ventricular pre- and after-load. In patients with left ventricular dysfunction or congestive heart failure, carvedilol has a favourable effect on haemodynamics and left ventricular ejection fraction and dimensions.

Carvedilol has no negative effect on the serum lipid profile or electrolytes. The ratio of HDL (high-density lipoproteins) and LDL (low-density lipoproteins) remains normal.

5.2 Pharmacokinetic properties

Absorption and distribution. The absolute bioavailability of orally administered carvedilol is approximately 25 %. Plasma levels peak at approximately 1 hour after dosing. Food does not affect bioavailability although the time to reach maximum plasma concentration is delayed. Carvedilol is a highly lipophilic compound. Approximately 98% to 99% of carvedilol is bound to plasma proteins. Its volume of distribution is approximately 2 l/kg.

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 30-80fold potency compared to carvedilol.

Elimination.The average elimination half-life of carvedilol ranges from 6 to 10 hours. Plasma clearance is approximately 590 ml/min. Elimination is mainly biliary. The primary route of excretion of carvedilol is via the faeces. A minor portion is eliminated via the kidneys as 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.

Older people. The pharmacokinetics of carvedilol are affected by age; plasma levels of carvedilol are approximately 50% higher in the elderly compared to young subjects.

Hepatic impairment In a study in patients with liver cirrhosis, the bioavailability of carvedilol was four times greater and the peak plasma level five times higher and the volume of distribution three 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).

PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Povidone Crospovidone Colloidal silica anhydrous Magnesium stearate

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years

6.4    Special precautions    for    storage

Do not store above 25°C

6.5    Nature and contents of the container

White opaque PVC/PVdC aluminium blisters.

Pack sizes: 14, 28, 30, 50, 56 & 100 tablets.

Hospital packs of 50 and 100 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions    for    disposal and other handling

No special requirements.

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited Brampton Road Hampden Park Eastbourne BN22 9AG

England

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/0553

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

25/02/2009

10 DATE OF REVISION OF THE TEXT

16/06/2014