Régimen vigente

Description and Composition

Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg Film-Coated Tablets are presented as white, circular, biconvex, film-coated tablets, debossed with ‘P’ on one side and either ‘1’, ‘2’, ‘3’, ‘5’, ‘7’ or ‘10’ on the other side depending on the strength of the tablet. All the tablet strengths have a score line on one side so that the tablet can be divided into equal halves, with the exception of the 1.25 mg strength tablet which has no score-line. Full descriptions of the individual tablets and their markings may be found by referring to the SmPCs or patient information leaflet text. Other ingredients consist of pharmaceutical excipients, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, silica colloidal anhydrous, cropovidone (Type A) and magnesium stearate making up the tablet core; hypromellose 6cP (E464), titanium dioxide (E171) and macrogol 400 making up the tablet coat. All excipients used comply with their respective European Pharmacopoeial monograph. Satisfactory Certificates of Analysis have been provided for all excipients. Appropriate justification for the inclusion of each excipient has been provided. The applicant has provided a declaration confirming that there are no materials of human or animal origin contained in, or used in the manufacturing process for the proposed product. Furthermore, no genetically modified organisms are used in the manufacture of any of the excipients.

Pharmaceutical development

Details of the pharmaceutical development of the medicinal product have been supplied and are satisfactory. The objective was to develop a robust, stable generic formulation bioequivalent to the innovator product, Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated tablets, authorised to E Merck Limited (PL 00493/0179-0184).

Comparative dissolution and impurity profiles were provided for the test and reference products and were found to be similar.

Manufacture

A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies have been conducted and are accepted. The validation data demonstrated consistency of the manufacturing process. Finished Product Specification

Finished product specifications are provided for both release and shelf-life, and are satisfactory; they provide an assurance of the quality and consistency of the finished product. Acceptance limits have been justified with respect to conventional

pharmaceutical requirements and, where appropriate, safety. Test methods have been described and adequately validated, as appropriate. Satisfactory batch analysis data are provided and accepted. The data demonstrate that the batches are compliant with the proposed specifications. Certificates of Analysis have been provided for any reference standards used.

Container-Closure System

The finished products are licensed for marketing in aluminium/aluminium blister strips with pealable lidding foil or in high density polyethylene (HDPE) bottle packs, which are placed with the Patient Information Leaflet (PIL) into cardboard outer cartons. The blister strips are packaged in pack sizes of 20, 28, 30, 50, 90, 100 film- coated tablets; HDPE bottles are licensed in pack sizes of 30 or 500 film-coated tablets. The Marketing Authorisation Holder (MAH) has stated that not all pack sizes may be marketed. However, the MAH has committed to submitting the proposed packaging/labelling for any pack size before it is marketed.

Satisfactory specifications and Certificates of Analysis for all packaging components used have been provided. All primary product packaging complies with EU

legislation, Directive 2002/72/EC (as amended), and is suitable for contact with foodstuffs.

Stability

Finished product stability studies have been conducted in accordance with current guidelines and results were within the proposed specification limits. Based on the results, a shelf-life of 2 years has been approved; the exception being the in-use shelf- life for HDPE bottle pack (500 tablets) which has been approved at 6 months which is satisfactory. Storage conditions are “Store below 25oC” and “Store in original

package in order to protect from light”. Bioequivalence Studies

The applicant submitted two bioequivalence studies in support of these applications. Bioequivalence has been demonstrated between the applicant’s Bisoprolol Fumarate (2 x 1.25 mg) Film-Coated Tablets and the reference product Cardicor (2 x 1.25 mg) Film-Coated Tablets (E Merck Limited, UK) and Bisoprolol Fumarate 10 mg Film- Coated Tablets and the reference product Cardicor 10 mg Film-Coated Tablets (E Merck Limited, UK) under fasting conditions.

An evaluation of the bioequivalence studies can be found in the Clinical Aspects section of this report.

Quality Overall Summary

A satisfactory quality overview is provided and has been prepared by an

appropriately qualified expert. The curriculum vitae of the expert has been provided. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), Labels

The SmPC, PIL and labelling are pharmaceutically acceptable. Colour mock-ups of the labelling and PIL have been provided. The Marketing Authorisation Holder (MAH) has stated that not all the pack sizes may be marketed. In accordance with medicines legislation, the MAH has provided a commitment to submit mock-ups for all packaging for assessment before those pack sizes are commercially marketed. The labelling is satisfactory and fulfils the statutory requirements for Braille.

The applicant has submitted results of PIL user testing. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to understand and act upon the information that the PIL contains.

MAA Form

The MAA forms are pharmaceutically satisfactory. Conclusion

There are no objections to the approval of Bisoprolol Fumarate 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg an 10 mg Film-Coated Tablets from a pharmaceutical point of view.

III.2 NON-CLINICAL ASPECTS

The pharmacodynamic, pharmacokinetic and toxicological properties of bisoprolol fumarate are well-known. Therefore, no further studies are required and the applicant has provided none.