Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Celecoxib-ratiopharm / Celecoxib AbZ 100/200 mg Hartkapseln (Celecoxib) DE/H/3057-3058/001-002/DC Applicant: ratiopharm GmbH / Teva Pharma B.V. Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/8 Public AR
TABLE OF CONTENTS I. INTRODUCTION... 4 II. EXECUTIVE SUMMARY... 4 II.1 Problem statement... 4 II.2 About the product... 4 II.3 General comments on the submitted dossier... 4 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles..5 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 5 III.1 Quality aspects... 5 III.2 Nonclinical aspects... 6 III.3 Clinical aspects... 6 IV. BENEFIT RISK ASSESSMENT... 8 2/8 Public AR
ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS INN (or common name) of the active substance(s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) Celecoxib-ratiopharm / Celecoxib AbZ 100/200 mg Hartkapseln Celecoxib M01AH01, Non-steroidal anti-inflammatory and antirheumatic drugs, NSAIDs, Coxibs Capsule, hard ; 100 / 200 mg DE/H/3057-3058/001-002/DC DE AT, BE, BG, CY, EL, ES, FR, HU, IS, IT, LU, NL, NO, PT, RO, SE, SK DE/H/3057/001-002/DC: ratiopharm GmbH Graf-Arco-Str. 3, D-89079 Ulm, Germany DE/H/3058/001-002/DC: Teva Pharma B.V. Computerweg 10, NL-3542DR Utrecht, The Netherlands 3/8 Public AR
I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Celecoxibratiopharm / Celecoxib AbZ 100/200 mg Hartkapseln in the treatment of Symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis, is approved. II. EXECUTIVE SUMMARY II.1 Problem statement N/A II.2 About the product Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is a selective inhibitor of cyclooxygenase-2 (COX-2). Celecoxib capsules of 100 and 200 mg strength are approved for achieving symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis if the individual patient's overall risks are outweighed by the benefit of treatment with a selective COX-2 inhibitor. Celecoxib received approval in the European Union in December 1999 following a mutual recognition procedure with Sweden serving as the reference member state. Celecoxib was approved by the US FDA in December 1998 under priority review to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis. Celecoxib is indicated for the symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. The decision to prescribe a selective COX-2 inhibitor should be based on an assessment of the individual patient's overall risks. Osteoarthritis The usual recommended daily dose is 200 mg taken once daily or in two divided doses. In some patients, with insufficient relief from symptoms, an increased dose of 200 mg twice daily may increase efficacy. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered. Rheumatoid arthritis The initial recommended daily dose is 200 mg taken in two divided doses. The dose may, if needed, later be increased to 200 mg twice daily. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered. Ankylosing spondylitis The recommended daily dose is 200 mg taken once daily or in two divided doses. In a few patients, with insufficient relief from symptoms, an increased dose of 400 mg once daily or in two divided doses may increase efficacy. In the absence of an increase in therapeutic benefit after two weeks, other therapeutic options should be considered. The maximum recommended daily dose is 400 mg for all indications. II.3 General comments on the submitted dossier The applications for Celecoxib-ratiopharm / Celecoxib AbZ 100/200 mg Hartkapseln are generic applications made according to Article 10(1) of Directive 2001/83/EC. The applicants, ratiopharm GmbH (DE/H/3057/001-002/DC ) and Teva Pharma B.V. (DE/H/3058/001-002/DC), apply through the Decentralised Procedure with Germany acting as reference member state (RMS) and AT, BE, BG, CY, EL, ES, FR, HU, IS, IT, LU, NL, NO, PT, RO, SE and SK as concerned member states (CMS). The reference medicinal product chosen for the purposes of establishing the expiry of the data protection period is Celebra 100 mg and 200 mg capsule, hard authorised in Sweden since 3 December 1999, with Pfizer AB as marketing authorisation holder. 4/8 Public AR
The active substance is not considered a new active substance. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. GMP The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product. For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. Additionally GMP certificates issued by the competent authorities for the manufacturers of the finished drug product following inspections have been provided. For the active substance Celecoxib a certificate of GMP compliance of a manufacturer, issued by the competent authority of Australia, following an inspection, dated on 09-10 October 2010 is presented. Updated QP statements covering all mentioned manufacturing sites for the drug substance itself and for the two intermediates used for the manufacture of Celecoxib have been provided. For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, issued by the inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those non- Community sites. GCP The applicant declares that the submitted bioequivalence studies (DEV2407-5CEL09 and DEV2407-6CEL09) have been performed in accordance with GCP. III. III.1 SCIENTIFIC OVERVIEW AND DISCUSSION Quality aspects Drug substance The chemical-pharmaceutical documentation and Expert Report in relation to Celecoxib-ratiopharm / Celecoxib AbZ 100/200 mg Hartkapseln are of sufficient quality in view of the present European regulatory requirements. The drug substance of the present generic product is Celecoxib, which is described in the European Pharmacopoeia. In the meantime a monograph for Celecoxib has been included in the European Pharmacopoeia 7.5 Supplement, which will be officially implemented on 1 st of July 2012. Because of the adaptation to the new Ph. Eur. Monograph for Celecoxib the ASM. updated the ASMF and the applicant updated the relevant parts of Module 3. Details on characteristics, manufacturing process, impurity profile, specifications, analytical procedures and validations of drug substances are presented in an Active Substance Master File. The drug substance manufacturer has submitted the complete ASMF (open part and restricted part) in its current version / amendment to the regulatory authority along with a letter of access to allow the applicant to refer to their ASMF. The control tests and specifications for drug substance are adequately drawn up. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of 5 years is justified. 5/8 Public AR
Drug Product The development of the products Celecoxib-ratiopharm / Celecoxib AbZ 100/200 mg Hartkapseln has been described, the choice of excipients is justified and their functions explained. Dissolution profiles of the two strengths (two capsules of 100 mg compared with one capsule of 200 mg) at different ph values (ph 1.2, ph 4.5, ph 6.8 and ph 12) under conditions of the validated testing method described in the quality part have been provided. The similarity of the dissolution profiles of both strengths could be shown under these conditions. The biowaiver for the 100 mg strength is accepted. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on 6 production batches (3 batches for the 100 mg capsules and 3 batches for the 200 mg capsules). The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. The shelf-life of 36 months with no storage restrictions is accepted for Celecoxib-ratiopharm / Celecoxib AbZ 100/200 mg Hartkapseln, stored in Alu-Alu blisters and HDPE bottles. The shelf-life of 36 months with the storage condition Do not store above 30 C is accepted for Celecoxibratiopharm / Celecoxib AbZ 100/200 mg Hartkapseln, stored in PVC-PVdC -Alu blisters. III.2 Nonclinical aspects Pharmacodynamics, Pharmacokinetics, Toxicology Nonclinical pharmacodynamic, pharmacokinetic and toxicological properties of celecoxib are well known. As celecoxib is a widely used, well-known active substance, no further nonclinical studies are required and the applicant provides none. Overview based on literature review is, thus, appropriate. The submitted nonclinical overview on the nonclinical pharmacology, pharmacokinetics and toxicology of celecoxib is adequate. From a nonclinical point of view, marketing authorization is recommended. Environmental Risk Assessment A specific environmenta risk assessment was not provided. The applicant states that, based on the assumption that this generic product is intended to substitute for other identical products on the market, the approval of the referred product should not result in an increase of the total quantity of celecoxib released into the environment. The applicant concludes that, therefore it should not result in increase of risk to the environment during storage, distribution, use and disposal. Taking into account that celecoxib will be used as a prescription-only medicinal product, this conclusion is accepted. III.3 Clinical aspects Bioequivalence studies As these are medicinal products with a systemic effect, there is the need of appropriate bioequivalence studies to justify efficacy. In order to demonstrate bioequivalence between the Applicant s formulation and the reference product, Celebrex, the applicant has submitted as report one pilot (study no DEV2407-5CEL09) and and one pivotal bioequivalence study (DEV2407-6CEL09) for the CELECOXIB 200 mg HARD CAPSULES. Based on the results of the pilot bioequivalence study (DEV2407-5CEL09), the applicant has provided the rationale for selecting a test product as a suitable formulation for use in the pivotal bioequivalence study versus the reference product. 6/8 Public AR
Based on the presented pivotal bioequivalence study (DEV2407-6CEL09), the CELECOXIB 200 mg HARD CAPSULES are considered bioequivalent with the reference product Celebrex 200 mg hard capsules, since the estimated 90% confidence intervalls for AUC and Cmax are within the preset acceptance range of 80% - 125%. Table Test vs reference product comparison in study DEV2407-6CEL09 The safety profile of the CELECOXIB 200 mg HARD CAPSULES, as observed in the pivotal bioequivalence study, was acceptable, no unexpected safety issues were identified. Biowaiver for the 100 mg strength The applicant has provided justification for a biowaiver for the 100 mg strength in accordance with the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1/Corr), stating that the CELECOXIB HARD CAPSULES, 100 and 200 mg are manufactured by the same manufacturer and process; the drug input has been shown to be linear over the therapeutic dose range; the qualitative composition of the different strengths is the same; the composition of the strengths are quantitatively proportional, i.e. the ratio between the amount of each excipient to the amount of active substance(s) is the same for all strengths; the dissolution profiles are similar under identical conditions for the additional strengths and the strength of the batch used in the bioequivalence study. Dissolution profiles of the two strengths (100 mg and 200 mg) at different ph values (ph 1.2, ph 4.5, ph 6.8 and ph 12) under conditions of the validated testing method described in the quality part have been provided. The similarity of the dissolution profiles of both strengths could be shown under these conditions. The addition of the surfactant in the chosen amount for the dissolution method has been also justified. Therefore the biowaiver for the 100 mg strength is accepted. Pharmacodynamics The pharmacodynamic profile of celecoxib is established and sufficiently characterized in literature. Literature references are reviewed in the clinical overview. No new data are requested. Clinical efficacy and safety No clinical efficacy or safety study reports are provided. Literature references to support clinical efficacy and safety of celecoxib in respective indications are reviewed in the clinical overview. The clinical data for the claimed indications are sufficiently discussed by the applicant within the clinical overview. The efficacy and safety of celecoxib is well established. The efficacy and safety characteristics of the innovator have been reassessed repeatedly after the first marketing authorisation and at last within a variation procedure in 2010 (SE/H/C/198/59). The efficacy and safety are adequately reflected in the currently approved innovator SmPC. No new safety concern was detected in this review. Overview based on literature review is appropriate. 7/8 Public AR
User testing Overall, the test methodology follows the guidelines of the European Commission (Guideline on the readability of the label and package leaflet of medicinal products for human use, Revision January 2009; Update of Directive 2001/83/EC as amended by Directive 2004/27/EC / Guidance concerning consultations with target patient groups for the packet leaflet, May 2006). Both the first and the second test round met the success criteria of 90% of the participants are able to find the requested information in the PIL, and of those, 90% being able to give the correct answer, to indicate that they can understand and properly interpret the information. The general impression of the PL (Content, language and layout) was mostly positive. In conclusion, the user test is considered acceptable. Description of Pharmacovigilance System Details have been provided of the Teva pharmacovigilance system (Version 10 dated January 2011). A statement signed by the applicant and the qualified person for pharmacovigilance, indicating that the applicant has the services of a qualified person responsible for pharmacovigilance and the necessary means for the notification of any adverse reaction occurring either in the Community or in a third country has been provided. The Pharmacovigilance system as described by the applicant fulfils the requirements as described in Volume 9A of the Rules Governing Medicinal Products in the European Union and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. Risk Management Plan The applicant has presented an application for waiver of EU Risk Management Plan dated 15 June 2010. The applicant states that an RMP is not required for this generic application as no safety concerns requiring additional risk minimisation activities have been identified with the active substance celecoxib. IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published nonclinical and clinical data. With regard to the efficacy and safety analysis, the characteristics of the innovator have been reassessed repeatedly after the first marketing authorisation and at last actualised within a finalised variation procedure in 2010 (SE/H/C/198/59). No new safety concern was detected in this review. Based on the submitted pivotal bioequivalence study, the CELECOXIB 200 mg HARD CAPSULES are considered bioequivalent with the reference product Celebrex 200 mg hard capsules. Also, the biowaiver claimed for the 100 mg strength is accepted. The application is approved. 8/8 Public AR