5.2       Pharmacokinetic properties

Carvedilol is a substrate of the intestinal efflux transporter P-glycoprotein which plays a major role in the bioavailability of certain drugs.  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.

In humans, carvedilol is extensively metabolized in the liver via oxidation and

conjugation into a variety of metabolites that are eliminated mainly in the bile.   The first pass effect after oral administration is approximately 60 - 75%; enterohepatic circulation of the parent substance has been shown in animals.

The oxidative metabolism of carvedilol is stereoselective. The R-enantiomer is predominantly metabolized by CYP2D6 and CYP1A2, while the S-enantiomer is mainly metabolised by CYP2C9 and to a lesser extend by CYP2D6. Other CYP450 isoenzymes involved in the metabolism of carvedilol include CYP3A4, CYP2E1 and CYP2C19. The maximal plasma concentration of R-carvedilol are approximately 2 fold higher than that S-carvedilol.

The R-enantiomer is predominantly metabolised through hydroxylation.

In slow metabolisers of CYP2D6 an increase of the plasma concentration of carvedilol, mainly the R-enantiomer may occur, leading to an increase in the alpha-blocking activity,

Carvedilol exhibits a considerable first pass effect.  The metabolite pattern reveals intensive metabolism with glucuronidation as one of the major steps.  Demethylation and hydroxylation at the phenol ring produce 3 metabolites with beta-receptor blocking activity.

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

Elderly: 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 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: Since carvedilol is primarily excreted via the faeces, significant accumulation in patients with renal impairment is unlikely.  In patients with impaired liver function, bioavailability is raised to as much as 80% due to a reduced first pass effect.

Heart failure: In a study in 24 patients with heart failure, the clearance of R-and S-carvedilol was significantly lower than previously estimated in healthy volunteers. These results suggested that the pharmacokinetics of R-and S-carvedilol is significantly altered by heart failure.

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. (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 165% 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). 

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 (see section 4.4).

Inducers and inhibitors of hepatic metabolism: Rifampicin reduced plasma concentrations of carvedilol by about 70%.  Cimetidine increased AUC by about 30% but caused no change in Cmax. Care may be required in those receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels may be increased.  However based on the relatively small effect of cimetidine on carvedilol drug levels the likelihood of any clinically important interaction is minimal.

Catecholamine-depleting agents: Patients taking both agents with beta-blocking properties and a drug that can deplete catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.

Ciclosporin: Modest increases in mean trough ciclosporin concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection.  In about 30% of patients, the dose of ciclosporin had to be reduced in order to maintain ciclosporin concentrations within the therapeutic range, while in the remainder no adjustment was needed.  On average, the dose of ciclosporin was reduced about 20% in these patients.  Due to wide interindividual variability in the dose adjustment required, it is recommended that ciclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate.

Verapamil, diltiazem, amiodarone or other antiarryhthmics: In combination with Eucardic can increase the risk of AV conduction disturbances (see section 4.4).

Pharmacodynamic interactions

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

Calcium channel blockers (see section 4.4):  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 recommendedattention must be paid during anaesthesia due to the synergistic negative inotropic and hypertensive effects of carvedilol and anaesthetic drugs (see section 4.4)..

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.

10      DATE OF REVISION OF THE TEXT

5 October 2010 20 June 2011

Underlined text has been added, text with strike through deleted:

4.3       Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Unstable/decompensated heart failure.

Eucardic is contraindicated in patients with mMarked fluid retention or overload requiring intravenous inotropic support.

Patients with oObstructive airways disease-,

Clinically manifest 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).,

sSevere bradycardia (< 50 bpm),

cCardiogenic shock,

sSick sinus syndrome (including sino-atrial block),

sSevere hypotension (systolic blood pressure < 85mmHg),

mMetabolic acidosis. and

pPhaeochromocytoma (unless adequately controlled by alpha blockade).

4.4       Special warnings and precautions for use

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.

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.

Chronic congestive heart failure: In chroniccongestive heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of Eucardic.  If such symptoms occur, the dose of diuretics should be adjustedincreased 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.

In hypertensive patients who have chronic heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, Eucardic should be used with caution in combination with digitalis glycosides since both drugsdigoxin and Eucardic may slow A-V conduction (see section 4.3).

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 this medicineEucardic 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 As with other drugs with beta-blocking activity, Eucardic may mask the early signs of acute hypoglycaemia may be masked or attenuatedin patients with diabetes mellitus.  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 (see section 4.5).

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.

Wearers of contact lenses should be advised of the possibility of reduced lacrimation.

Although angina has not been reported on stopping treatment, discontinuation should be gradual (1 - 2 weeks) particularly in patients with ischaemic heart disease, as Eucardic has beta-blocking activity.

Peripheral vascular disease: Eucardic shouldmay be used with caution in patients with peripheral vascular disease since.  Pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency.  However as Eucardic also has alpha-blocking properties this effect is largely counterbalanced.

Raynarud’s phenomenon Carvedilol should be used with caution Iin patients suffering from the 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 (see section 4.5).

Bradycardia: If Eucardic may induces bradycardia,. with a decrease in 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.

In patients suffering from the peripheral circulatory disorder Raynaud’s phenomenon, there may be exacerbation of symptoms.

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 (see section 4.5).

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, Tthere 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.

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 this medicine if you have a history of wheezing due to asthma or other lung diseases.  Consult your doctor or pharmacist first. 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.

4.5       Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

Digoxin: Digoxin concentrations are increased by about 16% when digoxin and carvedilol are administered concomitantly.  Both digoxin and carvedilol slow AV conduction.  Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol. 

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

Inducers and inhibitors of hepatic metabolism: Rifampicin reduced plasma concentrations of carvedilol by about 70%.  Cimetidine increased AUC by about 30% but caused no change in Cmax. Care may be required in those receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels may be increased.  However based on the relatively small effect of cimetidine on carvedilol drug levels the likelihood of any clinically important interaction is minimal.

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.

Catecholamine-depleting agents: Patients taking anboth agents with βbeta-blocking properties and a drug that can deplete catecholamines (e.g. reserpine and monoamine oxidase inhibitors) should be observed closely for signs of hypotension and/or severe bradycardia.

Ciclosporin: Modest increases in mean trough ciclosporin concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection.  In about 30% of patients, the dose of ciclosporin had to be reduced in order to maintain ciclosporin concentrations within the therapeutic range, while in the remainder no adjustment was needed.  On average, the dose of ciclosporin was reduced about 20% in these patients.  Due to wide interindividual variability in the dose adjustment required, it is recommended that ciclosporin concentrations be monitored closely after initiation of carvedilol therapy and that the dose of ciclosporin be adjusted as appropriate.

Verapamil, diltiazem or other antiarryhthmics: In combination with Eucardic can increase the risk of AVconduction disturbances (se section 4.4).

Isolated cases of conduction disturbance (rarely with haemodynamic disruption) have been observed when Eucardic and diltiazem were given concomitantly.  Therefore, as with other drugs with beta-blocking activity, careful monitoring of ECG and blood pressure should be undertaken when co-administering calcium channel blockers of the verapamil or diltiazem type, or class I antiarrhythmic drugs.  These types of drugs should not be co-administered intravenously in patients receiving Eucardic.

The effects of insulin or oral hypoglycaemics may be intensified.  Regular monitoring of blood glucose is therefore recommended.

Trough plasma digoxin levels may be increased by approximately 16% in hypertensive patients co-administered Eucardic and digoxin.  Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing Eucardic.  Concomitant administration of Eucardic and cardiac glycosides may prolong AV conduction time.

Pharmacodynamic interactions

Clonidine: Concomitant administration of clonidine with agents with beta-blocking properties may potentiate blood pressure and heart rate lowering effects.  When concomitant treatment with agents with beta-blocking propertiesEucardic and clonidine together is to be terminated, Eucardicthe beta-blocking agent should be discontinuedwithdrawn first,.  Clonidine therapy can then be discontinued several days later bybefore gradually decreasing the dosage of clonidine.

Care may be required in those receiving inducers of mixed function oxidases e.g. rifampicin, as serum levels of carvedilol may be reduced or inhibitors of mixed function oxidases e.g. cimetidine, as serum levels may be increased.

Calcium channel blockers (see section 4.4):  Isolated cases of conduction disturbance (rarely with haemodynamic disruptioncompromise) have been observed when Eucardic and diltiazem were given concomitantly.  Therefore, aAs with other drugsagents with beta-blocking activityproperties, careful monitoring of ECG and blood pressure should be undertaken when co-administering calcium channel blockers of the verapamil or diltiazem type, or class I antiarrhythmic drugs.  These types of drugs should not be co-administered intravenously in patients receiving Eucardic.if carvedilol is to be administered orally with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.

As with other agents with beta-blocking activity, 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.

During general anaesthesia,Careful attention shouldmust be paid during anaesthesia to the potential synergistic negative inotropic and hypertensive effects of carvedilol and anaesthetic drugs.

Modest increases in mean trough cyclosporin concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection.  In about 30% of patients, the dose of cyclosporin had to be reduced in order to maintain cyclosporin concentrations within the therapeutic range, while in the remainder no adjustment 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.

4.6       Pregnancy and lactation

Pregnancy

There areis no adequate clinical experience withdata from the use of 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.

Eucardic Carvedilol should not be used during pregnancy unless clearly necessary (i.e. unless the anticipatedpotential benefits outweighs 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)

Lactation

It is unknown whether carvedilol is excreted in human breast milk.  Animal studies demonstrated that have shown excretion of carvedilol or its metabolites are excreted in breast milk.  It is not known whether carvedilol is excreted in breast milk. Breast feeding is therefore not recommended during administration of carvedilol.A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Eucardic should be made taking into account the benefit of breast-feeding to the child and the benefit of Eucardic therapy to the woman.

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 (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 (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.

Clinical Trials

Adverse events are listed separately for CHF because of differences in the background diseases.

In chronic heart failure:

Haematological

Rare:  thrombocytopenia.

Leucopenia has been reported in isolated cases.

Metabolic

Common:  weight increase and hypercholesterolaemia.  Hyperglycaemia, hypoglycaemia and worsening control of blood glucose are also common in patients with pre-existing diabetes mellitus (see section 4.5 Interaction with other medicinal products and other forms of interaction).

Central nervous system

Very common:  dizziness, headache are usually mild and occur particularly at the start of treatment.  Asthenia (including fatigue).

Cardiovascular system

Common:  bradycardia, postural hypotension, hypotension, oedema (including generalised, peripheral, dependent and genital oedema, oedema of the legs, hypervolaemia and fluid overload).

Uncommon:  syncope (including presyncope), AV-block and cardiac failure during up-titration.

Gastro-intestinal system

Common:  nausea, diarrhoea, and vomiting.

Skin and appendages

Dermatitis, and increased sweating.

Others

Common:  vision abnormalities.

Rare:  acute renal failure and renal function abnormalities in patients with diffuse vascular disease and/or impaired renal function (see section 4.4 Special warnings and precautions for use).

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

In 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 Eucardic.

Blood chemistry and haematological

Isolated cases of changes in serum transaminases, thrombocytopenia and leucopenia have been reported.

Central nervous system

Common:  dizziness, headaches and fatigue, which are usually mild and occur particularly at the beginning of treatment.

Uncommon:  depressed mood, sleep disturbance, paraesthesia, asthenia.

Metabolic

Due to the beta-blocking properties it is also possible for latent diabetes mellitus to become manifest, manifest diabetes to be aggravated, and blood glucose counter-regulation to be inhibited.

Cardiovascular system

Common:  bradycardia, postural hypotension, especially at the beginning of treatment.

Uncommon:  syncope, hypotension, disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynauds phenomenon).  AV-block, angina pectoris (including chest pain), symptoms of heart failure and peripheral oedema.

Respiratory system

Common:  asthma and dyspnoea in predisposed patients.

Rare:  stuffy nose.  Wheezing and flu-like symptoms.

Gastro-intestinal system

Common:  gastro-intestinal upset (with symptoms such as nausea, abdominal pain, diarrhoea).

Uncommon:  constipation and vomiting.

Skin and appendages

Uncommon:  skin reactions (e.g. allergic exanthema, dermatitis, urticaria, pruritus, lichen planus-like reactions, and increased sweating).  Psoriatic skin lesions may occur or existing lesions exacerbated.

Others

Common:  pain in the extremities, reduced lacrimation.

Uncommon:  cases of sexual impotence and disturbed vision.

Rare:  dryness of the mouth and disturbances of micturition and eye irritation.

Isolated cases of allergic reactions have been reported.

Post-marketing experience

Isolated cases of urinary incontinence in women, which resolved upon discontinuation of the medication, have been reported.

4.9       Overdose

Symptoms and signs

In the event of overdose, there may be severeProfound cardiovascular effects such as hypotension, and bradycardia, would be expected after massive overdose.  H heart failure, cardiogenic shock and cardiac arrest may follow.  There may also be respiratory problems, bronchospasm, vomiting, disturbed consciousness and generalised seizures.

Treatment

Gastric lavage or induced emesis may be useful in the first few hours after ingestion.

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

Patients should be placed in the supine position.  Atropine, 0.5mg to 2mg i.v. and/or glucagon 1 to 10mg i.v. (followed by a slow i.v. infusion of 2 to 5mg/hour if necessary) may be given when bradycardia is present.  To support ventricular function intravenous glucagon or sympathomimetics (dobutamine, isoprenaline) are recommended.  If positive inotrpopic effect is required phosphodiesterase inhibitors (PDE) should be considered.  Pacemaker therapy may be necessary.  For excessive hypotension, intravenous fluids may be administered.  If peripheral vasodilation dominates the intoxication profile then addition, norepinephrine or noradrenalinemay be given, should be administered, with continuous monitoring of the circulation, either 5 to 10 micrograms i.v., repeated according to blood pressure response, or 5 micrograms per minute by infusion titrated to blood pressure. 

In the case of drug-resistant bradycardia, pacemaker therapy should be initiated. 

For Bbronchospasm, beta-sympathomimetics (as aerosol or intravenous) should be given, or may be treated using salbutamol or other beta₂-agonists given as aerosol or, if necessary, by the intravenous route.aminophylline may be administered intravenously by slow injection or infusion  In the event of seizures, slow i.v.intravenous injection of diazepam or clonazepam is recommended.

In cases of severe overdose with symptoms of shock, supportive treatment as described should be continued for a sufficiently long period of time, i.e. until the patient stabilises, since prolonged elimination half life and redistribution of carvedilol from deeper compartments can be expected.