PUBLIC ASSESSMENT REPORT of the Medicines Evaluation Board

Public Assessment Report Of The Medicines Evaluation Board-Free PDF

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I INTRODUCTION, Based on the review of the quality safety and efficacy data the member states have granted a marketing. authorisation for Crestor 5 10 20 40 5 10 20 40 mg film coated tablets from AstraZeneca The date of. authorisation was on 6 November 2002 10 mg 20 mg 40 mg and on 20 July 2004 5 mg in the. Netherlands The product is indicated for treatment of. primary hypercholesterolaemia type IIa including heterozygous familial hypercholesterolaemia or. mixed dyslipidaemia type IIb as an adjunct to diet when response to diet and other non. pharmacological treatments e g exercise weight reduction is inadequate. homozygous familial hypercholesterolaemia as an adjunct to diet and other lipid lowering treatments. e g LDL apheresis or if such treatments are not appropriate. A comprehensive description of the indications and posology is given in the SPC. The data presented in this PAR with regard to Crestor also apply to the dossiers of Cirantan Provisacor. and Rovustatine AstraZeneca NL H 0344 0346 001 004 MR. Rosuvastatin is a selective and competitive inhibitor of HMG CoA reductase the rate limiting enzyme that. converts 3 hydroxy 3 methylglutaryl coenzyme A to mevalonate a precursor for cholesterol The primary. site of action of rosuvastatin is the liver the target organ for cholesterol lowering. Rosuvastatin increases the number of hepatic LDL receptors on the cell surface enhancing uptake and. catabolism of LDL and it inhibits the hepatic synthesis of VLDL thereby reducing the total number of. VLDL and LDL particles, This repeat use procedure concerns a so called full dossier application according to Article 8 3 of. Directive 2001 83 EC a dossier with administrative chemical pharmaceutical pre clinial and clinical data. The application is supported by a full dossier and consists of the initial dossier submitted for the first wave. that is updated with post approval safety and efficacy data from clinical and observational trials and post. marketing data Furthermore a Pharmacovigilance System and an Environmental Risk Assessment have. been added to the original dossier, The dossier has been updated with data and changes from both the first round MRP as well as post. approval variations On pages 15 19 all post approval variations are summarized The variations are. sorted into three groups variations after finalisation of the initial MRP procedure but before the repeat use. procedure 10 20 40 mg variations for 5 mg strength after MRP before repeat use procedure and. variations after finalisation of the repeat use procedure for all strengths. In addition two annexes are presented, Annex I in which type II variation NL H 343 II 033 is discussed Through this variation an indication for. a subset of the paediatric population was approved and incorporated with the adult indication Adults. adolescents and children aged 10 years or older with primary hypercholesterolaemia type IIa. including heterozygous familial hypercholersterolaemia or mixed dyslipidaemia type IIb as an. adjunct to diet when response to diet and other non pharmacological treatments e g exercise weight. reduction is inadequate, Annex II includes a discussion of type II variation NL H 343 II 035 Through this variation an additional.
indication was approved Prevention of major cardiovascular events in patients who are estimated to. have a high risk for a first cardiovascular event See Section 5 1 as an adjunct to correction of other. risk factors,The initial MRP procedures,10 20 40 mg. The original MRP procedure for the 10 mg 20 mg and 40 mg NL H 343 001 003 MR started on 7. December 2002 and ended on 7 March 2003 At day 90 7 March 2003 the marketing authorisation was. mutually recognised by AT BE DK EL FI IC IRL IT LU PT SE and UK. By day 50 of that procedure potential serious health concerns were raised by AT BE ES FR IRL IT. NO SE and UK The major issues raised by the CMS in their day 50 comments were the starting dose of. 5 mg vs 10 mg the benefit risk ratio of the 40 mg dose the use in patients with renal and liver. dysfunction and the pharmacokinetic interactions, The application for all strengths was withdrawn in Germany Norway and Spain In France the application. for 40 mg tablets was withdrawn only because of their concern with the safety of this dose level renal. The original MRP procedure for the 5 mg strength started on 8 august 2004 and ended on 19 August. 2005 At day 90 2 November 2004 there were potential serious outstanding issues and therefore the. application was referred under Article 29 to the CHMP The List of Questions that was dealt with during. the referral concerned clinical efficacy en safety. During its April 2005 meeting the CHMP in the light of the overall data submitted and the scientific. discussion within the Committee was of the opinion that the benefit risk ratio is favourable for Crestor 5. mg or Crestor 10 mg both as start dose The choice of start dose in the individual patient should take into. account aspects of efficacy and safety as detailed in the SPC Changes to SPC section 4 2 Posology. and method of administration and 4 4 Special warnings and special precautions for use arising from the. arbitration process were agreed by the CHMP and a positive opinion was adopted on 21 April 2005 The. final opinion was converted into a Decision by the European Commission on 9 August 2005. No scientific advice has been given to the MAH with respect to these products. II SCIENTIFIC OVERVIEW AND DISCUSSION,II 1 Quality aspects. Compliance with Good Manufacturing Practice, The MEB has been assured that acceptable standards of GMP see Directive 2003 94 EC are in place for. this product type at all sites responsible for the manufacturing of the active substance as well as for the. manufacturing and assembly of this product prior to granting its national authorisation. Active substance, Rosuvastatin calcium is a novel active substance The active substance is a white powder which shows.
no polymorphism Detailed information is present regarding nomenclature structural and molecular. formulas and molecular mass,Manufacture, Synthesis routes for the manufacturing of rosuvastatin calcium are presented The first steps leads from. the starting materials to the intermediate In subsequent steps the intermediates are obtained and finally. the calcium salt In 2005 the original process has been optimised by reducing the number of overall steps. Adequate descriptions of manufacturing steps control of critical steps and intermediates are present. Quality control of drug substance, Specifications for rosuvastatin calcium comprise testings on identity IR spectroscopy chiral HPLC. calcium ion assay by HPLC and calcium content related substances optical purity by HPLC residual. solvents by GC water content chloride content and particle size There are eight stereoisomers due to. two chiral centers and a double bond with four different groups by adequate analytical methods the. unwanted stereoisomers are limited The active substance is an amorphous solid without the occurrence. of polymorphs The specification is adequate to guarantee a satisfactory quality of the active substance. More than twenty possible structures related to the active substance synthesis related or degradation. products have been identified and are controlled by HPLC to assure acceptable low levels of these. impurities in the active substance,Stability of drug substance. The MAH claimed a re test period of eighteen months when stored in the proposed packaging at 2 8 C. and protected from light Stability studies have been performed using three pilot scale and three. production scale batches at 2 8 C and accelerated conditions 25 C 60 RH up to 60 C 80 RH. Photostability studies demonstrated the protective capability of the proposed packaging Eighteen months. results meeting the set specifications confirm the validity of the claimed re test period and storage. Medicinal Product,Composition, Crestor 5 5 mg are round yellow coloured film coated tablets intagliated with ZD4522 and 5 on one. side and plain on the reverse, Crestor 10 10 mg are round pink coloured film coated tablets intagliated with ZD4522 and 10 on one.
side and plain on the reverse, Crestor 20 20 mg are round pink coloured film coated tablets intagliated with ZD4522 and 20 on one. side and plain on the reverse, Crestor 40 40 mg are oval pink coloured film coated tablets intagliated with ZD4522 and 40 on one. side and plain on the reverse,The excipients are, Tablet core lactose monohydrate microcrystalline cellulose calcium phosphate crospovidone. magnesium stearate, Tablet coating lactose monohydrate hypromellose triacetin titanium dioxide E171. ferric oxide red E172 and yellow only 5 mg, The tablets are packed in an aluminium laminate aluminium foil blister packaging or an HDPE container.
with screw closure, Both 10 and 20 mg tablets are fully dose proportional In addition the 5 mg tablet is almost similar to the. 10 mg tablet except for the active substance content the 40 mg tablet is almost similar to the 20 mg tablet. except for the active substance content, The excipients and packaging are usual for this type of dosage form. Pharmaceutical development, The proposed tablet formulation has been derived by improvement and modification of the Phase III tablet. formulations in order to improve reproducibility of pharmaceutical processing Dissolution characteristics. of both Phase III tablets and the proposed tablets have been maintained constant by testing with an. established dissolution method,Excipients, In general compatibility studies between active substance and excipients have been performed The. formulations comprise well known excipients all described in pharmacopoeias and are quite usual for a. composition of film coated tablets The colourant ferric oxide red is in accordance with the applicable. European Directives 78 25 EEC and 95 45 EC this is acceptable For the coating mixtures Opadry. lactose monohydrate hypromellose glycerol triacetate titanium dioxide ferric oxide red or yellow. additional adequate specifications are given this is also acceptable In the proposed concentrations of the. excipients no safety concerns are present,Manufacturing process.
The chosen method of preparation is dry blending The manufacturing comprises well known processes. like pre blending compression and film coating The four tablet strengths are derived from two. formulation blends by variation in compression weight IPC In Process Control requirements during. compression and coating are adequate Sufficient validation data on production scale batches are. available including content uniformity testing during various stages The validation data demonstrate. satisfactory homogeneity within a batch satisfactory reproducibility between batches and sufficient. control of the manufacturing process,Container closure system. 1 Aluminum laminate aluminum foil blisters lidded with aluminium foil coated with a heat seal lacquer. The laminate consists of polyamide soft aluminium foil unplasticised PVC film. 2 In a white HDPE container with screw child resistant closure Induction sealed membranes provide. tamper evidence and a hermetic seal The packs include a desiccant canister to absorb any. atmospheric moisture within the pack,Quality control of drug substance. The main release specifications of the finished product comprise testings on identity of the active. substance HPLC IR assay HPLC identity of the colourants related substances dissolution content. uniformity water content and microbiological purity The release specifications are sufficiently adequate. Batch results are present for batches manufactured at three specific manufacturing sites Found impurity. levels are low,Stability tests on the finished product. A shelf life of 3 years is claimed if stored in the two proposed packagings alu alu blister packaging or. HDPE bottles without specific storage temperature Additional label claim for the HDPE bottle product. Keep the con tainer tightly closed The shelf life claim is well based on 3 years data of numerous. batches for each strength from the various sites In addition to assay dissolution water content hardness. and related substances also X ray analysis is applied for checking the crystalline hydrate content The. shelf life specifications for assay lower limit and related substances have been widened to some extent. the latter specifications have been qualified Considering the full dose proportionality of the 10 20 mg. tablets respectively the 40 80 mg tablets the total number of stability batches is satisfactory. Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies. Magnesium stearate a statement is present that this excipient is from vegetable origin. Lactose monohydrate a statement is present that this excipient is sourced from healthy animals in the. same condition as milk collected for human consumption Herewith the excipient is in compliance with the. NfG on Minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal. Opadry II coating systems a statement is present that the two mixtures do not contain components. belonging to category I II III or IV of the NfG mentioned above This statement is not sufficient for the. component glycerol triacetate The triacetin glycerol triacetate component of the film coating formulation. solvents by GC water content chloride content and particle size There are eight stereoisomers due to two chiral centers and a double bond with four different groups by adequate analytical methods the unwanted stereoisomers are limited The active substance is an amorphous solid without the occurrence of polymorphs The specification is

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