CARVEDILOL 3.125 MG, 6.25 MG, 12.5 MG AND 25 …

1 PAR CARVEDILOL mg, mg, mg and 25 mg Tablets PL 33410/0004-7 1 CARVEDILOL MG, MG, 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 Page 12 Steps taken after authorisation summary Summary of Product Characteristics Page 13 Product Information Leaflet Page 51 Labelling Page 53 PAR CARVEDILOL mg, mg.

2 Mg and 25 mg Tablets PL 33410/0004-7 2 CARVEDILOL MG, MG, MG AND 25 MG TABLETS PL 33410/0004-7 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 mg, mg, 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 mg, mg, mg and 25 mg Tablets outweigh the risks; hence Marketing Authorisations have been granted.

3 PAR CARVEDILOL mg, mg, mg and 25 mg Tablets PL 33410/0004-7 3 CARVEDILOL MG, MG, MG AND 25 MG TABLETS PL 33410/0004-7 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 PAR CARVEDILOL mg, mg, mg and 25 mg Tablets PL 33410/0004-7 4 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 mg, mg, 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, diuretics, digoxin, and ACE inhibitors in patients with euvolemia treatment of hypertension prophylactic treatment of stable angina The applications were submitted under Article of Directive 2001/83/EC, claiming to be generic medicinal products of Eucardic mg, mg, mg and 25 mg tablets (Roche Products Limited, UK), which were first authorised in July 1994.

4 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).

5 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 mg, mg, mg and 25 mg Tablets outweigh the risks; hence Marketing Authorisations have been granted. PAR CARVEDILOL mg, mg, mg and 25 mg Tablets PL 33410/0004-7 5 PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE INN: CARVEDILOL Chemical Name: (2RS)-1-(9H-Carbazol-4-yloxy)-3-[[2-(2-m ethoxyphenoxy)ethyl]amino]propan-2-ol Molecular Formula: C24H26N2O4 Structure: Molecular weight: Appearance: A white or almost white crystalline substance, practically insoluble in water and dilute acids, slightly soluble in alcohol.

6 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.

7 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).

8 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 PAR CARVEDILOL mg, mg, mg and 25 mg Tablets PL 33410/0004-7 6 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).

9 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 mg, mg, 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.

10 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.