carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg tablets pl 33410/0004-7

PAR Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets PL 33410/0004-7

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CARVEDILOL 3.125 MG, 6.25 MG, 12.5 MG AND 25 MG TABLETS PL 33410/0004-7

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Steps taken after authorisation – summary

Summary of Product Characteristics Page 13

Product Information Leaflet

Page 51

Labelling Page 53


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LAY SUMMARY

On 14 February 2011, the Medicines and Healthcare products Regulatory Agency (MHRA) granted APSLA Limited, Marketing Authorisations (licences) for the medicinal products Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets (PL 33410/0004-7). These are prescription-only medicines (POM) used for the treatment of angina, high blood pressure, and mild, moderate or severe heart failure. Carvedilol Tablets contain the active ingredient carvedilol. Carvedilol belongs to a group of medicines called beta-blockers and it dilates blood vessels. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets outweigh the risks; hence Marketing Authorisations have been granted.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk assessment Page 11


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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted APSLA Limited, Marketing Authorisations for the medicinal products Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets (PL 33410/0004-7) on 14 February 2011. The products are prescription-only medicines (POM) used in adults and the elderly for the:

• treatment of stable mild, moderate and severe chronic heart failure as adjunct to standard therapies, e.g. diuretics, digoxin, and ACE inhibitors in patients with euvolemia

• treatment of hypertension • prophylactic treatment of stable angina The applications were submitted under Article 10.1 of Directive 2001/83/EC, claiming to be generic medicinal products of Eucardic 3.125 mg, 6.25 mg, 12.5 mg and 25 mg tablets (Roche Products Limited, UK), which were first authorised in July 1994. The active ingredient 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. Carvedilol has no intrinsic sympathomimetic activity and like propranolol, it has membrane-stabilising properties. No new non-clinical data have been submitted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. A single-dose, bioequivalence study was submitted to support these applications, comparing the test product Carvedilol 25mg Tablets (APSLA Limited, UK) and the reference product Eucardic 25mg Tablets (Roche Products Limited, UK). The bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). With the exception of the bioequivalence study, no new clinical studies were performed, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been in clinical use for over 10 years. No new or unexpected safety concerns were raised during the assessment of these applications and it was, therefore, judged that the benefits of taking Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets outweigh the risks; hence Marketing Authorisations have been granted.


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PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: Carvedilol Chemical Name: (2RS)-1-(9H-Carbazol-4-yloxy)-3-[[2-(2-

methoxyphenoxy)ethyl]amino]propan-2-ol Molecular Formula: C24H26N2O4 Structure:

Molecular weight: 406.5 Appearance: A white or almost white crystalline substance, practically insoluble in

water and dilute acids, slightly soluble in alcohol. Carvedilol is the subject of a European Pharmacopoeia monograph All aspects of the manufacture and control of the active substance carvedilol, except for the proposed packaging specifications and stability data to support a suitable retest period when stored in the proposed packaging, are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. Suitable specifications have been provided for all packaging used. The primary packaging has been shown to comply with current guidelines concerning contact with foodstuff. Appropriate stability data have been generated to support a suitable retest period for the active substance when stored in the proposed packaging. MEDICINAL PRODUCT Other ingredients Other ingredients consist of the pharmaceutical excipients lactose monohydrate, microcrystalline cellulose (Avicel pH 102), low-substituted hydroxypropyl cellulose (E463), maize starch, iron oxide yellow (E172), colloidal anhydrous silica, purified talc and magnesium stearate (E572). Appropriate justifications for the inclusion of each excipient have been provided. All excipients comply with their respective European Pharmacopoeia monograph, with the exception of low-substituted hydroxypropyl cellulose and iron oxide yellow (E172). Low-substituted hydroxypropylcellulose is controlled to its National Formulary specification. Iron oxide yellow (E172) is controlled to a suitable in-house specification and is in compliance with Directive 78/25/EC (concerning use of colouring agents in foodstuff). Satisfactory Certificates of Analysis have been provided for all excipients. With the exception of lactose monohydrate and magnesium stearate, none of the excipients contain materials of animal or human origin. The supplier of lactose monohydrate has confirmed that the lactose is sourced from healthy animals under the same conditions as milk


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for human consumption and prepared without the use of other ruminant materials, except calf rennet. The supplier of magnesium stearate sourced has provided a Certificate of Suitability from the European Directorate for the Quality of Medicines (EDQM) to show that it is manufactured in-line with current European guidelines concerning the minimising of risk of transmission of Bovine Spongiform Encephalopathy/Transmissible Spongiform Encephalophathies (BSE/TSE). No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical Development The objective of the development programme was to formulate safe, efficacious, stable products that could be considered generic medicinal products of the originator products Eucardic 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets (Roche Products Limited, UK) A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro impurity and dissolution profiles have been provided for all proposed products versus their respective originator products. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of all strengths of the product, along with an appropriate account of the manufacturing process. Based on pilot-scale batches, the manufacturing process has been validated and has shown satisfactory results. The Marketing Authorisation Holder has committed to submitting validation data performed on full-scale batches as soon as they are available. Control of Finished Product The finished product specifications are satisfactory. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for all working standards used. Container Closure System All strengths of the tablets are packaged in polvinylchloride/polvinylidene chloride/ aluminium blisters (PVC/PVDC/Alu) in pack sizes of 28 and 56 tablets. In addition, the 12.5 mg and 25 mg strength tablets are available in PVC/PVDC/Alu blisters in pack sizes of 14, 30 and 100 tablets. Not all pack sizes may be marketed. However, the Marketing Authorisation Holder has committed to submitting mock-ups for approval before marketing any pack size. Satisfactory specifications and Certificates of Analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials suitable for contact with food. Stability of the Product Finished product stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for marketing. The data from


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these studies support a shelf-life of 3 years, with the storage conditions “Store in the original package in order to protect from moisture”. Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. Bioequivalence/Bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence study. Summaries of Product Characteristics (SmPCs), Patient Information Leaflet (PIL) and Labelling The SmPCs, PIL and labelling are pharmaceutically satisfactory. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. MAA Forms The MAA forms are satisfactory. Expert Report The pharmaceutical expert report is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion The grant of Marketing Authorisations is recommended.


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NON-CLINICAL ASSESSMENT PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY No new non-clinical data were submitted, which is acceptable given that the proposed products are generic medicinal products of originator products that have been licensed for over 10 years. NON-CLINICAL EXPERT REPORT The non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the non-clinical aspects of the dossier. ENVIRONMENTAL RISK ASSESSMENT A suitable justification has been provided for non-submission of an Environmental Risk Assessment. As these products are intended for generic substitution with products that are already marketed, no increase in environmental burden is anticipated. Thus, the justification for non-submission of an Environmental Risk Assessment is accepted. CONCLUSION The grant of Marketing Authorisations is recommended.


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CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY The clinical pharmacology of carvedilol acid is well-known. With the exception of data from the below bioequivalence study, no new pharmacodynamic or pharmacokinetic data are provided or required for these applications. PHARMACOKINETICS In support of these applications the Marketing Authorisation Holder has submitted the following bioequivalence study: A randomised, open-label, single-dose, two-treatment, two-sequence, two-period, crossover study comparing the pharmacokinetics of the test product Carvedilol 25 mg Tablets (APSLA Limited, UK) and the reference product Eucardic 25 mg Tablets (Roche Limited, UK) in healthy adults male subjects under fasting conditions. The subjects were given one 25 mg tablet of test or reference product with 240 ml of water after at least a 10-hour overnight fast. Blood samples were collected prior to administration and up to 48 hours after administration. The washout period between treatment arms was 7 days. The pharmacokinetic results are presented below:

Pharmacokinetic parameters (geometric mean±SD), ratio and confidence intervals [CI]) of carvedilol

Carvedilol 25 mg Tablets (Test)

Eucardic 25 mg Tablets

(Reference)

Test/Ref Ratio(%)

90% CI

Cmax (ng/ml)

90.81±40.94 92.15±33.67 98.55 81.19-119.62

AUC0-t (ng.hr/ml)

320.99±148.64 329.44±142.54 97.43 84.82-111.93

AUC0-∞, (ng.hr/ml)

353.02±156.15 372.68±170.58 94.72 82.80-108.37

AUC0-∞ area under the plasma concentration-time curve from time zero to infinity AUC0-t area under the plasma concentration-time curve from time zero to t hours Cmax maximum plasma concentration 90% geometric CI calculated from ln-transformed data SD=standard deviation

The 90% confidence intervals of the test/reference ratio of geometric means for (AUC0-t), (AUC0-∞) and (Cmax) lie within the acceptable limits of 80-125% as required by the guideline on bioequivalence (CHMP/EWP/1401/98. Rev 1) Thus, the data support the claim that the test product Carvedilol 25mg Tablets (APSLA Limited, UK) is bioequivalent to the reference product Eucardic 25mg tablets (Roche Products Limited, UK). As the 3.125 mg, 6.25 mg, 12.5mg and 25mg strength products meet all the criteria specified in the Notes for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), the results and conclusions from the bioequivalence study with the 25 mg tablet strength can be extrapolated to the 3.125 mg, 6.25 mg and 12.5mg tablet strengths. EFFICACY The efficacy of carvedilol is well-known. No new efficacy data have been submitted and none are required for applications of this type.


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SAFETY With the exception of the safety data generated during the bioequivalence study, no new safety data were submitted and none are required for applications of this type. No new or unexpected safety issues were raised by the bioequivalence data. SUMMARIES OF PRODUCT CHARACTERISTICS (SmPC), PATIENT INFORMATION LEAFLET (PIL) AND LABELS The SmPCs, PIL and labels are medically acceptable. The SmPCs are consistent with those for the originator products. CLINICAL EXPERT REPORT The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. CONCLUSION The grant of Marketing Authorisations is recommended.


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OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg Tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit-risk balance. NON-CLINICAL No new non-clinical data were submitted. As the pharmacokinetics, pharmacodynamics and toxicology of carvedilol are well-known, no additional data were required. EFFICACY With the exception of the bioequivalence study, no new data were submitted and none are required for applications of this type. Bioequivalence has been demonstrated between the applicant’s 25 mg strength tablet and the respective reference product. As the 3.125 mg, 6.25 mg, 12.5mg and 25mg strength of the product meet all the criteria specified in the Notes for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98), the results and conclusions from the bioequivalence study with the 25 mg tablet strength can be extrapolated to the 3.125 mg, 6.25 mg, 12.5mg tablet strengths. SAFETY With the exception of the safety data from the bioequivalence study, no new data were submitted and none are required for applications of this type. As the safety profile of carvedilol is well-known, no additional data were required. No new or unexpected safety concerns were raised from the bioequivalence study PRODUCT LITERATURE The SmPCs, PIL and labelling are satisfactory, and consistent with those for the reference products, where appropriate, along with current guidelines. BENEFIT-RISK ASSESSMENT The quality of the products is acceptable, and no new non-clinical or clinical safety concerns have been identified. The data provided support the claim that these products are generic medicinal products of the reference products, Eucardic 3.125mg, 6.25mg, 12.5mg and 25mg tablets (Roche Products Limited, UK). Extensive clinical experience with carvedilol is considered to have demonstrated the therapeutic value of the product. The benefit-risk is, therefore, considered to be positive.


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STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation applications on 31 October 2008

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 11 November 2008.

3 Following assessment of the applications the MHRA requested further information relating to the dossier on 31 March 2009, 06 January 2010, 06 July 2010, 12 July 2010 and 02 November 2010,

4 The applicant responded to the MHRA’s requests, providing further information on the dossier on 04 November 2009, 19 March 2010, 29 September 2010, 07 October 2010 and 31 January 2011

5 The applications were determined and 14 February 2011.


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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT Carvedilol 3.125 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 3.125 mg of Carvedilol Excipients: Each tablet contains 15.735 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, 5.30 mm-5.70 mm in diameter, marked ‘C3’ on one face and plain on the reverse face.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Symptomatic chronic heart failure (CHF) Carvedilol is indicated for the treatment of stable mild, moderate and severe chronic heart failure as adjunct to standard therapies e.g. diuretics, digoxin, and ACE inhibitors in patients with euvolemia. Hypertension Carvedilol is indicated for the treatment of hypertension. Angina Carvedilol is indicated for the prophylactic treatment of stable angina. This medicinal product is indicated in adults and the elderly.

4.2 Posology and method of administration Symptomatic chronic heart failure Initiation of therapy with carvedilol should only be under the supervision of a hospital physician, following a thorough assessment of the patient's condition. Prior to any subsequent titration of the dose, the patient must be clinically evaluated on the day of up-titration by a health-care professional experienced in the management of heart failure to ensure that the clinical status has remained stable. The dose of carvedilol should not be increased in any patient with deteriorating heart failure since last visit or with signs of decompensated or unstable chronic heart failure. The dosage must be titrated to individual requirements. For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilised prior to initiation of carvedilol treatment. Adults: The recommended dose for the initiation of therapy is 3.125 mg twice a day for two weeks. If this dose is tolerated, the dosage should be increased subsequently, at intervals of not less than two weeks, to 6.25 mg twice daily, followed by 12.5 mg twice daily and thereafter 25 mg twice daily. Dosing should be increased to the highest level tolerated by the patient. The recommended maximum daily dose is 25 mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85 kg (187 lbs). In patients with mild or moderate CHF weighing more than 85 kg, the recommended maximum dose is 50 mg twice daily.


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During up-titration of the dose in patients with systolic blood pressure < 100 mm Hg, deterioration of renal and/or cardiac functions may occur. Therefore, before each dose increase these patients should be evaluated by the physician for renal function and symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or fluid retention may be treated by adjusting doses of diuretics or ACE inhibitors or by modifying or temporarily discontinuing carvedilol treatment. Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised. If carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg twice daily and up-titrated in line with the above dosing recommendation. Elderly: As for adults. Children: Safety and efficacy in children (under 18 years) has not been established. Hypertension Once daily dosing is recommended. Adults: The recommended dose for initiation of therapy is 12.5 mg once a day for the first two days. Thereafter the recommended dosage is 25 mg once a day. Although this is an adequate dose in most patients, if necessary the dose may be titrated up to a recommended daily maximum dose of 50 mg given once a day or in divided doses. Dose titration should occur at intervals of at least two weeks. Elderly: An initial dose of 12.5 mg daily is recommended. This has provided satisfactory control in some cases. If the response is inadequate the dose may be titrated up to the recommended daily maximum dose of 50 mg given once a day or in divided doses. Children: Safety and efficacy in children (under 18 years) has not been established. Angina Adults: The recommended dose for initiation of therapy is 12.5 mg twice a day for the first two days. Thereafter, the recommended dosage is 25 mg twice a day. Elderly: The recommended maximum daily dose is 50 mg given in divided doses. Children: Safety and efficacy in children (under 18 years) has not been established. Patients with co-existing hepatic disease Carvedilol is contraindicated in patients with hepatic dysfunction (see sections 4.3 and section 5.2). Patients with co-existing renal dysfunction No dose adjustment is anticipated as long as systolic blood pressure is above 100 mm Hg (see also sections 4.4 and section 5.2). Method of administration: The tablets should be taken with fluid. For CHF patients, Carvedilol should be given with food.


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4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients. Carvedilol is contraindicated in patients with marked fluid retention or overload requiring intravenous inotropic support. Patients with obstructive airways disease, liver dysfunction. As with other beta-blocking agents: History of bronchospasm or asthma, 2nd and 3rd degree A-V heart block, (unless a permanent pacemaker is in place), severe bradycardia (< 50 bpm), cardiogenic shock, sick sinus syndrome (including sino-atrial block), severe hypotension (systolic blood pressure < 85 mm Hg), metabolic acidosis and phaeochromocytoma (unless adequately controlled by alpha blockade). Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

4.4 Special warnings and precautions for use

In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, the dose of diuretic should be adjusted and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of carvedilol. In hypertensive patients who have chronic heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, carvedilol should be used with caution since both digoxin and carvedilol may slow A-V conduction. As with other drugs with beta-blocking activity, carvedilol may mask the early signs of acute hypoglycaemia in patients with diabetes mellitus. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. In patients with diabetes, the use of carvedilol may be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when carvedilol is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly. 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 CHF patients with these risk factors, renal function should be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal failure occurs. 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 carvedilol has beta-blocking activity. Carvedilol may be used in patients with peripheral vascular disease. Pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However, as carvedilol also has an alpha-blocking property, this effect is largely counterbalanced. Carvedilol, as with other agents with beta-blocking activity, may mask the symptoms of thyrotoxicosis. If carvedilol induces bradycardia, with a decrease in pulse rate to less than 55 beats per minute, the dosage of carvedilol should be reduced. 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. In patients suffering from the peripheral circulatory disorder Raynaud's phenomenon, there may be exacerbation of symptoms.


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Patients with a history of psoriasis associated with beta-blocker therapy should be given carvedilol only after consideration of the risk-benefit ratio. In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. There is no experience of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having phaeochromocytoma. 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. However, caution should be taken in the administration of carvedilol 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.

4.5 Interaction with other medicinal products and other forms of interaction

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. Patients taking an agent with β-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. Isolated cases of conduction disturbance (rarely with haemodynamic disruption) have been observed when carvedilol 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 carvedilol. 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 carvedilol and digoxin. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol. Concomitant administration of carvedilol and cardiac glycosides may prolong AV conduction time. When treatment with carvedilol and clonidine together is to be terminated, carvedilol should be withdrawn first, several days before 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. During general anaesthesia, attention should be paid to the potential synergistic negative inotropic 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


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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 are no adequate data 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. Carvedilol should not be used during pregnancy unless clearly necessary (i.e. unless the anticipated benefits outweigh the potential risks). Lactation It is unknown whether carvedilol is excreted in human breast milk. Animal studies have shown excretion of carvedilol or its metabolites in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with carvedilol should be made taking into account the benefit of breast-feeding to the child and the benefit of carvedilol therapy to the woman.

4.7 Effects on ability to drive and use machines

No studies of the effects on ability to drive and use machines have been performed. As for other drugs which produce changes in blood pressure, patients taking carvedilol should be warned not to drive or operate machinery if they experience dizziness or related symptoms. This applies particularly when starting or changing treatment and in conjunction with alcohol.

4.8 Undesirable effects

The most commonly reported adverse reactions are dizziness, headache and asthenia (including fatigue) which are usually mild and occur at the start of the treatment. The following terminologies have been used in order to classify the occurrence of undesirable effects. VERY COMMON (≥1/10); COMMON (≥1/100 to < 1/10); UNCOMMON (≥1/1000 to <1/100); RARE (≥1/10000 to <1/1000) Adverse events are listed separately for CHF because of differences in the background diseases In chronic heart failure: Blood and lymphatic system disorders Rare: thrombocytopenia. Not known (cannot be estimated from the available data): Leucopenia. Metabolism and nutrition disorders Common: Weight increases and hypercholesterolaemia. Hyperglycaemia and hypoglycaemia are also common in patients with pre-existing diabetes mellitus (see section 4.5). Nervous system disorders Very common: dizziness, headaches are usually mild and occur particularly at the start of treatment. Asthenia (including fatigue) Eye disorders Common: vision abnormalities.


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Cardiac disorders Common: bradycardia, oedema (including generalised, peripheral, dependent and genital oedema, oedema of the legs, hypervolaemia and fluid overload). Uncommon: AV-block and cardiac failure during up-titration, syncope (including presyncope) Vascular disorders Common: postural hypotension, hypotension Gastrointestinal disorders Common: nausea, diarrhoea, and vomiting. Skin and subcutaneous tissue disorders Dermatitis and increased sweating Renal and urinary disorders Rare: acute renal failure and renal function abnormalities in patients with diffuse vascular disease and/or impaired renal function (see section 4.4). 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 carvedilol. Blood and lymphatic system disorders Not known (cannot be estimated from the available data): thrombocytopenia and leucopenia. Metabolism and nutrition disorders 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. Nervous system disorders Common: dizziness, headaches and fatigue, which are usually mild and occur particularly at the beginning of treatment. Uncommon: depressed mood, sleep disturbance, paraesthesia, asthenia. Eye disorders Common reduced lacrimation Uncommon: disturbed vision Rare: eye irritation. Cardiac disorders Common: bradycardia Uncommon: syncope, hypotension, AV-block, angina pectoris (including chest pain), symptoms of heart failure and peripheral oedema. Vascular disorders Common: postural hypotension, especially at the beginning of treatment. Uncommon: disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynauds phenomenon.


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Respiratory, thoracic and mediastinal disorders Common: asthma and dyspnoea in predisposed patients. Rare: stuffy nose, wheezing and flu-like symptoms. Gastrointestinal disorders Common: gastro-intestinal upset (with symptoms such as nausea, abdominal pain, diarrhoea). Uncommon: constipation and vomiting. Skin and subcutaneous tissue disorders 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. Renal and urinary disorders Rare: disturbances of micturition Reproductive system and breast disorders Uncommon: cases of sexual impotence General disorders and administration site conditions Common: pain in the extremities. Rare: dryness of the mouth. Not known (cannot be estimated from the available data): allergic reactions Investigations Not known (cannot be estimated from the available data): changes in serum transaminases Post-marketing experience Not known (cannot be estimated from the available data): urinary incontinence in women, which resolved upon discontinuation of the medication.

4.9 Overdose

Symptoms and signs Profound cardiovascular effects such as hypotension and bradycardia would be expected after massive overdose. 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 procedures, vital signs must be monitored and corrected, if necessary under intensive care conditions. Patients should be placed in the supine position. Atropine, 0.5 mg to 2 mg i.v. and/or glucagon 1 to 10 mg i.v. (followed by a slow i.v. infusion of 2 to 5 mg/hour if necessary) may be given when bradycardia is present. Pacemaker therapy may be necessary. For excessive hypotension, intravenous fluids may be administered. In addition, norepinephrine may be given, either 5 to 10 micrograms i.v., repeated according to blood pressure response, or 5 micrograms per minute by infusion titrated to blood pressure. Bronchospasm may be treated using salbutamol or other beta2-agonists given as aerosol or, if necessary, by the intravenous route. In the event of seizures, slow i.v. 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.


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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 α1-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 anti-ischaemic 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.

5.2 Pharmacokinetic properties

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


21

with liver cirrhosis. The first pass effect after oral administration is approximately 60 - 75%; enterohepatic circulation of the parent substance has been shown in animals. 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 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. 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. 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.

5.3 Preclinical safety data

There is no evidence from animal studies that carvedilol has any teratogenic effects. Embryotoxicity was observed only after large doses in rabbits. The relevance of these findings for humans is uncertain. Beta-blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, animal studies have shown that carvedilol crosses the placental barrier and therefore the possible consequences of alpha and beta-blockade in the human foetus and neonate should also be borne in mind. With other alpha and beta-blocking agents, effects have included perinatal and neonatal distress (bradycardia, hypotension, respiratory depression, hypoglycaemia, hypothermia). There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.

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)

6.2 Incompatibilities

Not applicable 6.3 Shelf life

3 years 6.4 Special precautions for storage

Store in the original package in order to protect from moisture 6.5 Nature and contents of container

Blister packs, PVC/PVDC Aluminium foil of 28 or 56 tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Not applicable


22

7 MARKETING AUTHORISATION HOLDER APSLA Limited Bayview House 49 North Strand Road Dublin 3 Ireland

8 MARKETING AUTHORISATION NUMBER(S)

PL 33410/0004 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 14/02/2011 10 DATE OF REVISION OF THE TEXT

14/02/2011


23


2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 6.25 mg of Carvedilol Excipients: Each tablet contains 31.47 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, 6.30 mm-6.70 mm in diameter, marked ‘C6’ on one face and plain on the reverse face.



4.2 Posology and method of administration

Symptomatic chronic heart failure Initiation of therapy with carvedilol should only be under the supervision of a hospital physician, following a thorough assessment of the patient's condition. Prior to any subsequent titration of the dose, the patient must be clinically evaluated on the day of up-titration by a health-care professional experienced in the management of heart failure to ensure that the clinical status has remained stable. The dose of carvedilol should not be increased in any patient with deteriorating heart failure since last visit or with signs of decompensated or unstable chronic heart failure. The dosage must be titrated to individual requirements. For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilised prior to initiation of carvedilol treatment. Adults: The recommended dose for the initiation of therapy is 3.125 mg twice a day for two weeks. If this dose is tolerated, the dosage should be increased subsequently, at intervals of not less than two weeks, to 6.25 mg twice daily, followed by 12.5 mg twice daily and thereafter 25 mg twice daily. Dosing should be increased to the highest level tolerated by the patient. The recommended maximum daily dose is 25 mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85 kg (187 lbs). In patients with mild or moderate CHF weighing more than 85 kg, the recommended maximum dose is 50 mg twice daily. During up-titration of the dose in patients with systolic blood pressure < 100 mm Hg, deterioration of renal and/or cardiac functions may occur. Therefore, before each dose increase these patients should be evaluated by the physician for renal function and symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or fluid retention may be treated by adjusting doses of diuretics or ACE inhibitors or by modifying or temporarily discontinuing carvedilol treatment.


24

Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised. If carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg twice daily and up-titrated in line with the above dosing recommendation. Elderly: As for adults. Children: Safety and efficacy in children (under 18 years) has not been established. Hypertension Once daily dosing is recommended. Adults: The recommended dose for initiation of therapy is 12.5 mg once a day for the first two days. Thereafter the recommended dosage is 25 mg once a day. Although this is an adequate dose in most patients, if necessary the dose may be titrated up to a recommended daily maximum dose of 50 mg given once a day or in divided doses. Dose titration should occur at intervals of at least two weeks. Elderly: An initial dose of 12.5 mg daily is recommended. This has provided satisfactory control in some cases. If the response is inadequate the dose may be titrated up to the recommended daily maximum dose of 50 mg given once a day or in divided doses. Children: Safety and efficacy in children (under 18 years) has not been established. Angina Adults: The recommended dose for initiation of therapy is 12.5 mg twice a day for the first two days. Thereafter, the recommended dosage is 25 mg twice a day. Elderly: The recommended maximum daily dose is 50 mg given in divided doses. Children: Safety and efficacy in children (under 18 years) has not been established. Patients with co-existing hepatic disease Carvedilol is contraindicated in patients with hepatic dysfunction (see sections 4.3 and section 5.2). Patients with co-existing renal dysfunction No dose adjustment is anticipated as long as systolic blood pressure is above 100 mm Hg (see also sections 4.4 and section 5.2). Method of administration: The tablets should be taken with fluid. For CHF patients, Carvedilol should be given with food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients. Carvedilol is contraindicated in patients with marked fluid retention or overload requiring intravenous inotropic support.


25

Patients with obstructive airways disease, liver dysfunction. As with other beta-blocking agents: History of bronchospasm or asthma, 2nd and 3rd degree A-V heart block, (unless a permanent pacemaker is in place), severe bradycardia (< 50 bpm), cardiogenic shock, sick sinus syndrome (including sino-atrial block), severe hypotension (systolic blood pressure < 85 mm Hg), metabolic acidosis and phaeochromocytoma (unless adequately controlled by alpha blockade). Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.


In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, the dose of diuretic should be adjusted and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of carvedilol. In hypertensive patients who have chronic heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, carvedilol should be used with caution since both digoxin and carvedilol may slow A-V conduction. As with other drugs with beta-blocking activity, carvedilol may mask the early signs of acute hypoglycaemia in patients with diabetes mellitus. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. In patients with diabetes, the use of carvedilol may be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when carvedilol is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly. 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 CHF patients with these risk factors, renal function should be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal failure occurs. 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 carvedilol has beta-blocking activity. Carvedilol may be used in patients with peripheral vascular disease. Pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However, as carvedilol also has an alpha-blocking property, this effect is largely counterbalanced. Carvedilol, as with other agents with beta-blocking activity, may mask the symptoms of thyrotoxicosis. If carvedilol induces bradycardia, with a decrease in pulse rate to less than 55 beats per minute, the dosage of carvedilol should be reduced. 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. In patients suffering from the peripheral circulatory disorder Raynaud's phenomenon, there may be exacerbation of symptoms. Patients with a history of psoriasis associated with beta-blocker therapy should be given carvedilol only after consideration of the risk-benefit ratio.


26

In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. There is no experience of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having phaeochromocytoma. 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. However, caution should be taken in the administration of carvedilol 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.


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. Patients taking an agent with β-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. Isolated cases of conduction disturbance (rarely with haemodynamic disruption) have been observed when carvedilol 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 carvedilol. 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 carvedilol and digoxin. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol. Concomitant administration of carvedilol and cardiac glycosides may prolong AV conduction time. When treatment with carvedilol and clonidine together is to be terminated, carvedilol should be withdrawn first, several days before 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. During general anaesthesia, attention should be paid to the potential synergistic negative inotropic 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


27

monitored closely after initiation of carvedilol therapy and that the dose of cyclosporin be adjusted as appropriate.


Pregnancy There are no adequate data 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. Carvedilol should not be used during pregnancy unless clearly necessary (i.e. unless the anticipated benefits outweigh the potential risks). Lactation It is unknown whether carvedilol is excreted in human breast milk. Animal studies have shown excretion of carvedilol or its metabolites in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with carvedilol should be made taking into account the benefit of breast-feeding to the child and the benefit of carvedilol therapy to the woman.




The most commonly reported adverse reactions are dizziness, headache and asthenia (including fatigue) which are usually mild and occur particularly at the start of treatment. The following terminologies have been used in order to classify the occurrence of undesirable effects. VERY COMMON (≥1/10); COMMON (≥1/100 to < 1/10); UNCOMMON (≥1/1000 to <1/100); RARE (≥1/10000 to <1/1000) Adverse events are listed separately for CHF because of differences in the background diseases In chronic heart failure: Blood and lymphatic system disorders Rare: thrombocytopenia. Not known (cannot be estimated from the available data): Leucopenia. Metabolism and nutrition disorders Common: Weight increases and hypercholesterolaemia. Hyperglycaemia and hypoglycaemia are also common in patients with pre-existing diabetes mellitus (see section 4.5). Nervous system disorders Very common: dizziness, headaches are usually mild and occur particularly at the start of treatment. Asthenia (including fatigue) Eye disorders Common: vision abnormalities. Cardiac disorders Common: bradycardia, oedema (including generalised, peripheral, dependent and genital oedema, oedema of the legs, hypervolaemia and fluid overload). Uncommon: AV-block and cardiac failure during up-titration, syncope (including presyncope)


28

Vascular disorders Common: postural hypotension, hypotension Gastrointestinal disorders Common: nausea, diarrhoea, and vomiting. Skin and subcutaneous tissue disorders Dermatitis and increased sweating. Renal and urinary disorders Rare: acute renal failure and renal function abnormalities in patients with diffuse vascular disease and/or impaired renal function (see section 4.4). 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 carvedilol. Blood and lymphatic system disorders Not known (cannot be estimated from the available data): thrombocytopenia and leucopenia. Metabolism and nutrition disorders 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. Nervous system disorders Common: dizziness, headaches and fatigue, which are usually mild and occur particularly at the beginning of treatment. Uncommon: depressed mood, sleep disturbance, paraesthesia, asthenia. Eye disorders Common: reduced lacrimation Uncommon: disturbed vision Rare: eye irritation. Cardiac disorders Common: bradycardia Uncommon: syncope, hypotension, AV-block, angina pectoris (including chest pain), symptoms of heart failure and peripheral oedema. Vascular disorders Common: postural hypotension, especially at the beginning of treatment. Uncommon: disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynauds phenomenon. Respiratory, thoracic and mediastinal disorders Common: asthma and dyspnoea in predisposed patients. Rare: stuffy nose, wheezing and flu-like symptoms. Gastrointestinal disorders Common: gastro-intestinal upset (with symptoms such as nausea, abdominal pain, diarrhoea).


29

Uncommon: constipation and vomiting. Skin and subcutaneous tissue disorders 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. Renal and urinary disorders Rare: disturbances of micturition Reproductive system and breast disorders Uncommon: cases of sexual impotence General disorders and administration site conditions Common: pain in the extremities. Rare: dryness of the mouth. Not known (cannot be estimated from the available data): allergic reactions Investigations Not known (cannot be estimated from the available data): changes in serum transaminases Post-marketing experience Not known (cannot be estimated from the available data): urinary incontinence in women, which resolved upon discontinuation of the medication.

4.9 Overdose



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.


30

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 α1-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







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. The first pass effect after oral administration is approximately 60 - 75%; enterohepatic circulation of the parent substance has been shown in animals. 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.


31

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. 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. 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.









Blister packs, PVC/PVDC Aluminium foil of 28 or 56 tablets. Not all pack sizes may be marketed.


Not applicable 7 MARKETING AUTHORISATION HOLDER

APSLA Limited Bayview House 49 North Strand Road Dublin 3 Ireland


PL 33410/0005


32

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 14/02/2011

10 DATE OF REVISION OF THE TEXT

14/02/2011


33



Each tablet contains 12.5 mg of Carvedilol Excipients: Each tablet contains 62.94 mg of lactose For a full list of excipients, see section 6.1.






Symptomatic chronic heart failure Initiation of therapy with carvedilol should only be under the supervision of a hospital physician, following a thorough assessment of the patient's condition. Prior to any subsequent titration of the dose, the patient must be clinically evaluated on the day of up-titration by a health-care professional experienced in the management of heart failure to ensure that the clinical status has remained stable. The dose of carvedilol should not be increased in any patient with deteriorating heart failure since last visit or with signs of decompensated or unstable chronic heart failure. The dosage must be titrated to individual requirements. For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilised prior to initiation of carvedilol treatment. Adults: The recommended dose for the initiation of therapy is 3.125 mg twice a day for two weeks. If this dose is tolerated, the dosage should be increased subsequently, at intervals of not less than two weeks, to 6.25 mg twice daily, followed by 12.5 mg twice daily and thereafter 25 mg twice daily. Dosing should be increased to the highest level tolerated by the patient. The recommended maximum daily dose is 25 mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85 kg (187 lbs). In patients with mild or moderate CHF weighing more than 85 kg, the recommended maximum dose is 50 mg twice daily. During up-titration of the dose in patients with systolic blood pressure < 100 mm Hg, deterioration of renal and/or cardiac functions may occur. Therefore, before each dose increase these patients should be evaluated by the physician for renal function and symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or fluid retention may be treated by adjusting doses of diuretics or ACE inhibitors or by modifying or temporarily discontinuing carvedilol treatment. Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised. If carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg twice daily and up-titrated in line with the above dosing recommendation.


34

Elderly: As for adults. Children: Safety and efficacy in children (under 18 years) has not been established. Hypertension Once daily dosing is recommended. Adults: The recommended dose for initiation of therapy is 12.5 mg once a day for the first two days. Thereafter the recommended dosage is 25 mg once a day. Although this is an adequate dose in most patients, if necessary the dose may be titrated up to a recommended daily maximum dose of 50 mg given once a day or in divided doses. Dose titration should occur at intervals of at least two weeks. Elderly: An initial dose of 12.5 mg daily is recommended. This has provided satisfactory control in some cases. If the response is inadequate the dose may be titrated up to the recommended daily maximum dose of 50 mg given once a day or in divided doses. Children: Safety and efficacy in children (under 18 years) has not been established. Angina Adults: The recommended dose for initiation of therapy is 12.5 mg twice a day for the first two days. Thereafter, the recommended dosage is 25 mg twice a day. Elderly: The recommended maximum daily dose is 50 mg given in divided doses. Children: Safety and efficacy in children (under 18 years) has not been established. Patients with co-existing hepatic disease Carvedilol is contraindicated in patients with hepatic dysfunction (see sections 4.3 and section 5.2). Patients with co-existing renal dysfunction No dose adjustment is anticipated as long as systolic blood pressure is above 100 mm Hg (see also sections 4.4 and section 5.2). Method of administration: The tablets should be taken with fluid. For CHF patients, Carvedilol should be given with food.


Hypersensitivity to the active substance or to any of the excipients. Carvedilol is contraindicated in patients with marked fluid retention or overload requiring intravenous inotropic support. Patients with obstructive airways disease, liver dysfunction. As with other beta-blocking agents: History of bronchospasm or asthma, 2nd and 3rd degree A-V heart block, (unless a permanent pacemaker is in place), severe bradycardia (< 50 bpm), cardiogenic shock, sick sinus syndrome (including sino-atrial block), severe hypotension (systolic blood pressure < 85 mm Hg), metabolic acidosis and phaeochromocytoma (unless adequately controlled by alpha blockade).


35

Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.


In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, the dose of diuretic should be adjusted and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of carvedilol. In hypertensive patients who have chronic heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, carvedilol should be used with caution since both digoxin and carvedilol may slow A-V conduction. As with other drugs with beta-blocking activity, carvedilol may mask the early signs of acute hypoglycaemia in patients with diabetes mellitus. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. In patients with diabetes, the use of carvedilol may be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when carvedilol is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly. 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 CHF patients with these risk factors, renal function should be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal failure occurs. 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 carvedilol has beta-blocking activity. Carvedilol may be used in patients with peripheral vascular disease. Pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However, as carvedilol also has an alpha-blocking property, this effect is largely counterbalanced. Carvedilol, as with other agents with beta-blocking activity, may mask the symptoms of thyrotoxicosis. If carvedilol induces bradycardia, with a decrease in pulse rate to less than 55 beats per minute, the dosage of carvedilol should be reduced. 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. In patients suffering from the peripheral circulatory disorder Raynaud's phenomenon, there may be exacerbation of symptoms. Patients with a history of psoriasis associated with beta-blocker therapy should be given carvedilol only after consideration of the risk-benefit ratio. In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. There is no experience of the use of carvedilol in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having phaeochromocytoma. 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


36

alpha-blocking activity of carvedilol may prevent such symptoms. However, caution should be taken in the administration of carvedilol 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.


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. Patients taking an agent with β-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. Isolated cases of conduction disturbance (rarely with haemodynamic disruption) have been observed when carvedilol 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 carvedilol. 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 carvedilol and digoxin. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol. Concomitant administration of carvedilol and cardiac glycosides may prolong AV conduction time. When treatment with carvedilol and clonidine together is to be terminated, carvedilol should be withdrawn first, several days before 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. During general anaesthesia, attention should be paid to the potential synergistic negative inotropic 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.


Pregnancy There are no adequate data from the use of carvedilol in pregnant women.


37

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 clearly necessary (i.e. unless the anticipated benefits outweigh the potential risks). Lactation It is unknown whether carvedilol is excreted in human breast milk. Animal studies have shown excretion of carvedilol or its metabolites in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with carvedilol should be made taking into account the benefit of breast-feeding to the child and the benefit of carvedilol therapy to the woman.




The most commonly reported adverse reactions during treatment are dizziness, headache and asthenia (including fatigue) which are usually mild and occur particularly at the start of treatment. The following terminologies have been used in order to classify the occurrence of undesirable effects. VERY COMMON (≥1/10); COMMON (≥1/100 to < 1/10); UNCOMMON (≥1/1000 to <1/100); RARE (≥1/10000 to <1/1000) Adverse events are listed separately for CHF because of differences in the background diseases In chronic heart failure: Blood and lymphatic system disorders Rare: thrombocytopenia. Not known (cannot be estimated from the available data): Leucopenia. Metabolism and nutrition disorders Common: Weight increases and hypercholesterolaemia. Hyperglycaemia and hypoglycaemia are also common in patients with pre-existing diabetes mellitus (see section 4.5). Nervous system disorders Very common: dizziness, headaches are usually mild and occur particularly at the start of treatment. Asthenia (including fatigue) Eye disorders Common: vision abnormalities. Cardiac disorders Common: bradycardia, oedema (including generalised, peripheral, dependent and genital oedema, oedema of the legs, hypervolaemia and fluid overload). Uncommon: AV-block and cardiac failure during up-titration, syncope (including presyncope) Vascular disorders Common: postural hypotension, hypotension Gastrointestinal disorders Common: nausea, diarrhoea, and vomiting. Skin and subcutaneous tissue disorders Dermatitis and increased sweating


38

Renal and urinary disorders Rare: acute renal failure and renal function abnormalities in patients with diffuse vascular disease and/or impaired renal function (see section 4.4). 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 carvedilol. Blood and lymphatic system disorders Not known (cannot be estimated from the available data): thrombocytopenia and leucopenia. Metabolism and nutrition disorders 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. Nervous system disorders Common: dizziness, headaches and fatigue, which are usually mild and occur particularly at the beginning of treatment. Uncommon: depressed mood, sleep disturbance, paraesthesia, asthenia. Eye disorders Common: reduced lacrimation Uncommon: disturbed vision Rare: eye irritation. Cardiac disorders Common: bradycardia Uncommon: syncope, hypotension, AV-block, angina pectoris (including chest pain), symptoms of heart failure and peripheral oedema. Vascular disorders Common: postural hypotension, especially at the beginning of treatment. Uncommon: disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynauds phenomenon. Respiratory, thoracic and mediastinal disorders Common: asthma and dyspnoea in predisposed patients. Rare: stuffy nose, wheezing and flu-like symptoms. Gastrointestinal disorders Common: gastro-intestinal upset (with symptoms such as nausea, abdominal pain, diarrhoea). Uncommon: constipation and vomiting. Skin and subcutaneous tissue disorders 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. Renal and urinary disorders Rare: disturbances of micturition Reproductive system and breast disorders Uncommon: cases of sexual impotence General disorders and administration site conditions Common: pain in the extremities. Rare: dryness of the mouth.


39

Not known (cannot be estimated from the available data): allergic reactions Investigations Not known (cannot be estimated from the available data): changes in serum transaminases Post-marketing experience Not known (cannot be estimated from the available data): urinary incontinence in women, which resolved upon discontinuation of the medication.

4.9 Overdose



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 α1-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


40

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.






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. The first pass effect after oral administration is approximately 60 - 75%; enterohepatic circulation of the parent substance has been shown in animals. 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 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. 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. 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.


There is no evidence from animal studies that carvedilol has any teratogenic effects. Embryotoxicity was observed only after large doses in rabbits. The relevance of these findings for humans is uncertain. Beta-blockers reduce placental perfusion which may result in intrauterine foetal death and immature and premature deliveries. In addition, animal studies have shown that carvedilol crosses the placental barrier and therefore the possible consequences of alpha and beta-blockade in the human foetus and neonate should also be borne in mind. With other alpha and beta-blocking agents, effects have included perinatal and neonatal distress (bradycardia, hypotension, respiratory depression, hypoglycaemia,


41

hypothermia). There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.






Store in the original package in order to protect from moisture

6.5 Nature and contents of container

Blister packs, PVC/PVDC Aluminium foil of 14, 28, 30, 56 or 100 tablets. Not all pack sizes may be marketed.





PL 33410/0006 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/02/2011 10 DATE OF REVISION OF THE TEXT

14/02/2011


42

1 NAME OF THE MEDICINAL PRODUCT Carvedilol 25 mg Tablets


Each tablet contains 25 mg of Carvedilol Excipients: Each tablet contains 125.88 mg of lactose For a full list of excipients, see section 6.1.






Symptomatic chronic heart failure Initiation of therapy with carvedilol should only be under the supervision of a hospital physician, following a thorough assessment of the patient's condition. Prior to any subsequent titration of the dose, the patient must be clinically evaluated on the day of up-titration by a health-care professional experienced in the management of heart failure to ensure that the clinical status has remained stable. The dose of carvedilol should not be increased in any patient with deteriorating heart failure since last visit or with signs of decompensated or unstable chronic heart failure. The dosage must be titrated to individual requirements. For those patients receiving diuretics and/or digoxin and/or ACE inhibitors, dosing of these other drugs should be stabilised prior to initiation of carvedilol treatment. Adults: The recommended dose for the initiation of therapy is 3.125 mg twice a day for two weeks. If this dose is tolerated, the dosage should be increased subsequently, at intervals of not less than two weeks, to 6.25 mg twice daily, followed by 12.5 mg twice daily and thereafter 25 mg twice daily. Dosing should be increased to the highest level tolerated by the patient. The recommended maximum daily dose is 25 mg given twice daily for all patients with severe CHF and for patients with mild to moderate CHF weighing less than 85 kg (187 lbs). In patients with mild or moderate CHF weighing more than 85 kg, the recommended maximum dose is 50 mg twice daily. During up-titration of the dose in patients with systolic blood pressure < 100 mm Hg, deterioration of renal and/or cardiac functions may occur. Therefore, before each dose increase these patients should be evaluated by the physician for renal function and symptoms of worsening heart failure or vasodilation. Transient worsening of heart failure, vasodilation or fluid retention may be treated by adjusting doses of diuretics or ACE inhibitors or by modifying or temporarily discontinuing carvedilol treatment.


43

Under these circumstances, the dose of carvedilol should not be increased until symptoms of worsening heart failure or vasodilation have been stabilised. If carvedilol is discontinued for more than two weeks, therapy should be recommenced at 3.125 mg twice daily and up-titrated in line with the above dosing recommendation. Elderly: As for adults. Children: Safety and efficacy in children (under 18 years) has not been established. Hypertension Once daily dosing is recommended. Adults: The recommended dose for initiation of therapy is 12.5 mg once a day for the first two days. Thereafter the recommended dosage is 25 mg once a day. Although this is an adequate dose in most patients, if necessary the dose may be titrated up to a recommended daily maximum dose of 50 mg given once a day or in divided doses. Dose titration should occur at intervals of at least two weeks. Elderly: An initial dose of 12.5 mg daily is recommended. This has provided satisfactory control in some cases. If the response is inadequate the dose may be titrated up to the recommended daily maximum dose of 50 mg given once a day or in divided doses. Children: Safety and efficacy in children (under 18 years) has not been established. Angina Adults: The recommended dose for initiation of therapy is 12.5 mg twice a day for the first two days. Thereafter, the recommended dosage is 25 mg twice a day. Elderly: The recommended maximum daily dose is 50 mg given in divided doses. Children: Safety and efficacy in children (under 18 years) has not been established. Patients with co-existing hepatic disease Carvedilol is contraindicated in patients with hepatic dysfunction (see sections 4.3 and section 5.2). Patients with co-existing renal dysfunction No dose adjustment is anticipated as long as systolic blood pressure is above 100 mm Hg (see also sections 4.4 and section 5.2). Method of administration: The tablets should be taken with fluid. For CHF patients, Carvedilol should be given with food.


Hypersensitivity to the active substance or to any of the excipients. Carvedilol is contraindicated in patients with marked fluid retention or overload requiring intravenous inotropic support. Patients with obstructive airways disease, liver dysfunction.


44

As with other beta-blocking agents: History of bronchospasm or asthma, 2nd and 3rd degree A-V heart block, (unless a permanent pacemaker is in place), severe bradycardia (< 50 bpm), cardiogenic shock, sick sinus syndrome (including sino-atrial block), severe hypotension (systolic blood pressure < 85 mm Hg), metabolic acidosis and phaeochromocytoma (unless adequately controlled by alpha blockade). Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.


In chronic heart failure patients, worsening cardiac failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, the dose of diuretic should be adjusted and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally it may be necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of carvedilol. In hypertensive patients who have chronic heart failure controlled with digoxin, diuretics and/or an ACE inhibitor, carvedilol should be used with caution since both digoxin and carvedilol may slow A-V conduction. As with other drugs with beta-blocking activity, carvedilol may mask the early signs of acute hypoglycaemia in patients with diabetes mellitus. Alternatives to beta-blocking agents are generally preferred in insulin-dependent patients. In patients with diabetes, the use of carvedilol may be associated with worsening control of blood glucose. Therefore, regular monitoring of blood glucose is required in diabetics when carvedilol is initiated or up-titrated and hypoglycaemic therapy adjusted accordingly. 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 CHF patients with these risk factors, renal function should be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal failure occurs. 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 carvedilol has beta-blocking activity. Carvedilol may be used in patients with peripheral vascular disease. Pure beta-blockers can precipitate or aggravate symptoms of arterial insufficiency. However, as carvedilol also has an alpha-blocking property, this effect is largely counterbalanced. Carvedilol, as with other agents with beta-blocking activity, may mask the symptoms of thyrotoxicosis. If carvedilol induces bradycardia, with a decrease in pulse rate to less than 55 beats per minute, the dosage of carvedilol should be reduced. 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. In patients suffering from the peripheral circulatory disorder Raynaud's phenomenon, there may be exacerbation of symptoms. Patients with a history of psoriasis associated with beta-blocker therapy should be given carvedilol only after consideration of the risk-benefit ratio. In patients with phaeochromocytoma, an alpha-blocking agent should be initiated prior to the use of any beta-blocking agent. There is no experience of the use of carvedilol in this condition. Therefore,


45

caution should be taken in the administration of carvedilol to patients suspected of having phaeochromocytoma. 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. However, caution should be taken in the administration of carvedilol 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.


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. Patients taking an agent with β-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. Isolated cases of conduction disturbance (rarely with haemodynamic disruption) have been observed when carvedilol 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 carvedilol. 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 carvedilol and digoxin. Increased monitoring of digoxin levels is recommended when initiating, adjusting or discontinuing carvedilol. Concomitant administration of carvedilol and cardiac glycosides may prolong AV conduction time. When treatment with carvedilol and clonidine together is to be terminated, carvedilol should be withdrawn first, several days before 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. During general anaesthesia, attention should be paid to the potential synergistic negative inotropic 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.


46

4.6 Pregnancy and lactation Pregnancy There are no adequate data 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. Carvedilol should not be used during pregnancy unless clearly necessary (i.e. unless the anticipated benefits outweigh the potential risks). Lactation It is unknown whether carvedilol is excreted in human breast milk. Animal studies have shown excretion of carvedilol or its metabolites in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with carvedilol should be made taking into account the benefit of breast-feeding to the child and the benefit of carvedilol therapy to the woman.




The most commonly reported adverse reactions during treatment are dizziness, headache and asthenia (including fatigue) which are usually mild and occur particularly at the start of treatment. The following terminologies have been used in order to classify the occurrence of undesirable effects. VERY COMMON (≥1/10); COMMON (≥1/100 to < 1/10); UNCOMMON (≥1/1000 to <1/100); RARE (≥1/10000 to <1/1000) Adverse events are listed separately for CHF because of differences in the background diseases In chronic heart failure: Blood and lymphatic system disorders Rare: thrombocytopenia. Not known (cannot be estimated from the available data): Leucopenia. Metabolism and nutrition disorders Common: Weight increases and hypercholesterolaemia. Hyperglycaemia and hypoglycaemia are also common in patients with pre-existing diabetes mellitus (see section 4.5). Nervous system disorders Very common: dizziness, headaches are usually mild and occur particularly at the start of treatment. Asthenia (including fatigue) Eye disorders Common: vision abnormalities. Cardiac disorders Common: bradycardia, oedema (including generalised, peripheral, dependent and genital oedema, oedema of the legs, hypervolaemia and fluid overload). Uncommon: AV-block and cardiac failure during up-titration, syncope (including presyncope) Vascular disorders Common: postural hypotension, hypotension Gastrointestinal disorders


47

Common: nausea, diarrhoea, and vomiting. Skin and subcutaneous tissue disorders Dermatitis and increased sweating Renal and urinary disorders Rare: acute renal failure and renal function abnormalities in patients with diffuse vascular disease and/or impaired renal function (see section 4.4). 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 carvedilol. Blood and lymphatic system disorders Not known (cannot be estimated from the available data): thrombocytopenia and leucopenia. Metabolism and nutrition disorders 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. Nervous system disorders Common: dizziness, headaches and fatigue, which are usually mild and occur particularly at the beginning of treatment. Uncommon: depressed mood, sleep disturbance, paraesthesia, asthenia. Eye disorders Common: reduced lacrimation Uncommon: disturbed vision Rare: eye irritation. Cardiac disorders Common: bradycardia Uncommon: syncope, hypotension, AV-block, angina pectoris (including chest pain), symptoms of heart failure and peripheral oedema. Vascular disorders Common: postural hypotension, especially at the beginning of treatment. Uncommon: disturbances of peripheral circulation (cold extremities, PVD, exacerbation of intermittent claudication and Raynauds phenomenon. Respiratory, thoracic and mediastinal disorders Common: asthma and dyspnoea in predisposed patients. Rare: stuffy nose, wheezing and flu-like symptoms. Gastrointestinal disorders Common: gastro-intestinal upset (with symptoms such as nausea, abdominal pain, diarrhoea). Uncommon: constipation and vomiting. Skin and subcutaneous tissue disorders 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.


48

Renal and urinary disorders Rare: disturbances of micturition Reproductive system and breast disorders Uncommon: cases of sexual impotence General disorders and administration site conditions Common: pain in the extremities. Rare: dryness of the mouth. Not known (cannot be estimated from the available data): allergic reactions Investigations Not known (cannot be estimated from the available data): changes in serum transaminases Post-marketing experience Not known (cannot be estimated from the available data): urinary incontinence in women, which resolved upon discontinuation of the medication.

4.9 Overdose



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.


49

Carvedilol is a racemate of two stereoisomers. Beta-blockade is attributed to the S(-)enantiomer; in contrast, both enantiomers exhibit the same α1-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







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. The first pass effect after oral administration is approximately 60 - 75%; enterohepatic circulation of the parent substance has been shown in animals. 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 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. 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. Since carvedilol is primarily excreted via the faeces, significant


50

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.









Blister packs, PVC/PVDC Aluminium foil of 14, 28, 30, 56 or 100 tablets. Not all pack sizes may be marketed.





PL 33410/0007 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 14/02/2011 10 DATE OF REVISION OF THE TEXT

14/02/2011


51


52


53

Labelling


54


55


56

carvedilol 3.125 mg, 6.25 mg, 12.5 mg and 25 mg tablets pl 33410/0004-7

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