Decentralised Procedure. Public Assessment Report. Metamizol Midas / Metamizol STADA / Mimetanal 500 mg Tabletten. Metamizole sodium monohydrate

Transcription

1 Decentralised Procedure Public Assessment Report Metamizol Midas / Metamizol STADA / Mimetanal 500 mg Tabletten Metamizole sodium monohydrate DE/H/ /001/DC Applicant: Midas Pharma GmbH, Germany Reference Member State DE

2 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 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 5 III.1 Quality aspects... 5 III.2 Non-clinical aspects... 5 III.3 Clinical aspects... 5 IV. BENEFIT RISK ASSESSMENT... 7 Metamizol, DE/H/ /001/DC Public AR Page 2/7

3 Proposed name of the medicinal product in the RMS ADMINISTRATIVE INFORMATION Metamizol Midas / Metamizol STADA / Mimetanal 500 mg Tabletten Name of the drug substance (INN name): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number(s) for the Decentralised Procedure Reference Member State: Concerned Member States: Applicant (name and address) Metamizole sodium monohydrate N02BB02 Tablet 500 mg DE/H/ /001/DC DE DE/H/4091/001/DC: LU DE/H/4092/001/DC: CZ, SI, SK; withdrawn: PL DE/H/4093/001/DC: RO Midas Pharma GmbH Rheinstr. 49 D Ingelheim Germany Metamizol, DE/H/ /001/DC Public AR Page 3/7

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Metamizol Midas / Metamitab / Mimetanal 500 mg Tabletten, indicated in children aged 10 years or older and adults in: - acute severe pain following trauma or surgery - painful colics - tumour pain - other acute or chronic severe pain, if other therapeutic measures are contraindicated - high fever that does not respond to other measures is approved. II. EXECUTIVE SUMMARY II.1 Problem statement For generic application this section is not applicable. II.2 About the product Metamizol is a widely used and well established non-opioid analgesic in several European countries. Metamizol is available in oral, rectal and injectable forms. It is a non-acid pyrazolone derivate with antipyretic, analgesic, spasmolytic, and anti-inflammatory effects. The mechanism of action is, as with several other analgesics, not elucidated in detail. An inhibition of prostaglandin (PG) synthesis is known, based on interaction with different cyclooxygenases (COX), resulting in changes in the arachidonic acid metabolism. Besides peripheral inhibition of PG synthesis central activities have been supposed and documented. Current indications for metamizole include acute severe pain after trauma or surgery, painful colics, tumor pain, other acute or chronic pain, if other therapeutic measures are contraindicated, and high fever, not responding to other measures. II.3 General comments on the submitted dossier With Germany as the Reference Member State in these Decentralized Procedures, Midas Pharma GmbH is applying for the Marketing Authorisations for Metamizol Midas 500 mg tablets in LU (DE/H/4091/001/DC), for Metamizol STADA 500 mg tablets in CZ, PL, SI and SK (DE/H/4092/001/DC), and for Mimetanal 500 mg tablets in RO (DE/H/4093/001/DC). However, the applicant decided to withdraw the application in PL (DE/H/4092/001/DC). The originator product is Novalgin Filmtabletten, 500 mg, film-coated tablets by Sanofi-Aventis Deutschland GmbH, registered since To support the application the applicant has submitted as report one Bioequivalence Study (EudraCT number ) to evaluate the bioequivalence of two oral preparations containing 500 mg metamizole (Metamizole 500 mg tablets vs Novalgin Film-coated tablets). The results of the study show bioequivalence of the test formulation in comparison to the reference formulation for the extent of absorption (AUC) as well as for the rate of absorption (C max). The indications proposed for the generic medicinal product are the same as authorized for the reference medicinal product. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles. 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. Regarding the statement on GMP for the active substance a statement/declaration is provided from the Metamizol, DE/H/ /001/DC Public AR Page 4/7

5 manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU. The applicant stated that the study was performed in compliance with Good Clinical Practice (GCP), the Declaration of Helsinki (with amendments) and local legal and regulatory requirements. GLP/GCP Compliance statements and Quality Assurance Unit Statements have been provided. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Metamizol Midas 500 mg Tabletten (tablets) are of sufficient quality in view of the present European regulatory requirements. The active substance metamizole sodium monohydrate is described in the European Pharmacopoeia. The quality of the drug substance is sufficiently controlled. The EDQM has been reviewed the active substance. The control tests and specifications for drug substance product 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 36 months (when the active substance is stored in the proposed polyethylene bags) is proven and justified. Drug Product The finished product is a generic formulation tablet with 500 mg metamizole sodium monohydrate. Similar products are well known. The development of the product has been described, the choice of excipients is justified and their functions explained. Dissolution studies have been carried out in detail. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods are in line with ICH requirements. Batch analysis results have been performed on three consecutive production batches. 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 the drug product are adequately drawn up. The proposed shelf-life of 36 months (with label claim: store in original package in order to protect from light) for the drug product in commercial packaging is accepted. III.2 Non-clinical aspects Pharmacology, pharmacokinetics, toxicology Pharmacodynamic, pharmacokinetic and toxicological properties of metamizole are well known. As metamizole is a widely used, well-known active substance, the applicant has not provided additional nonclinical studies and further non-clinical studies are not required. Overview based on literature review is, thus, appropriate. The submitted non-clinical overview on the non-clinical pharmacology, pharmacokinetics and toxicology of metamizole is adequate. Environmental Risk Assessment (ERA) Since the medicinal products are intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary. III.3 Clinical aspects Pharmacokinetics A bioequivalence study with the title "Evaluation of the bioequivalence of two oral preparations containing 500 mg metamizole (Metamizole 500 mg tablets (Test) vs. Novalgin Film-coated tablets (Reference)). A monocentric, open, randomized, single dose, two-period, crossover trial in healthy volunteers" (Study Code CBG14001, EudraCT number ) has been performed. Metamizol, DE/H/ /001/DC Public AR Page 5/7

6 The 90% CI calculated by means of ANOVA-log for the first primary endpoint, ratio (T/R) of AUC(0-t) of 4-methylaminoantipyrine was between 96.54% and % and thus within the acceptance range (80-125% for logtransformed values). The 90% CI calculated by means of ANOVA-log for the second primary endpoint ratio (T/R) of Cmax of 4-methylaminoantipyrine was between 94.55% and % and thus also within the acceptance limits (80-125% for log-transformed values). The point estimator of the test preparation compared with the reference drug based on the first primary endpoint AUC(0-t) was % and for the second primary endpoint Cmax it was %. In conclusion, the test preparation is bioequivalent to the reference preparation in terms of rate and extent of absorption. Pharmacodynamics The mechanism of action is, as with several other analgesics, not elucidated in detail. An inhibition of prostaglandin (PG) synthesis is known, based on interaction with different cyclooxygenases (COX), resulting in changes in the arachidonic acid metabolism. Besides peripheral inhibition of PG synthesis central activities have been supposed and documented. Clinical efficacy Metamizol is a widely used and well established non-opioid analgesic in several European countries. Metamizol is available in oral rectal and injectable forms. It is a non-acid pyrazolone derivate with antipyretic, analgesic, spasmolytic, and anti-inflammatory effects. Current indications for metamizole include acute severe pain after trauma or surgery, painful colics, tumor pain, other acute or chronic pain, if other therapeutic measures are contraindicated, and high fever, not responding to other measures. Clinical safety Metamizol is a widely used and well established non-opioid analgesic in several European countries. Because of the risk of adverse reactions (e.g. agranulocytosis) it has been banned in some other countries. Human epidemiology data have been recognized, including data from the International Agranulocytosis and Aplastic Anaemia study (IAAAS). The excess risk attributable to metamizole use was estimated to be 0.6 cases per million treated patients (2 of 8 regions) or lower. Additional data of seven human cases of agranulocytosis, which had been reported to the Swedish authority, leading to an incidence of 1 case in 1700 treated patients, had led to the suspension of metamizol in Sweden. Legal Status Subject to medical prescription User Testing The Bridging Report refers to the User Test conducted for the PL of Metamizol Midas 500 mg/ml oral drops, solution. This User Test was assessed during DE/H/3757/00/DC. Both PILs were written in English according to the QRD template. The Parent PIL follows an older QRD template and the Daughter PIL the newer version 9. Except where indicated in Section 5.1, identical sentences were used for the information presented in both PILs. The Bridging Report provides an analysis of the differences between Parent and Daughter PL and comes to the conclusion these are of minor origin and that the leaflet text and mockup format for the Daughter PIL is similar to the Parent PIL. The results of the bridging study indicate that the leaflet for Daughter PIL is well structured and organized, easy to understand and written in a comprehensible manner and therefore requires no separate user testing. Based on the above mentioned facts the package leaflet is accepted. Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable. Metamizol, DE/H/ /001/DC Public AR Page 6/7

7 Risk Management Plan Summary of safety concerns Important identified risks Agranulocytosis and other blood dyscrasias Anaphylactic/Anaphylactoid reactions (e.g. pancytopenia and thrombocytopenia) Severe skin reactions Hypotensive reactions Important potential risks Off-label-use (in particular use in patients with nonsevere pain or use as first-line therapy in patients with fever) Important missing information Use in pregnant or lactating women No additional pharmacovigilance or risk minimisation activities have been proposed. The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module of the Marketing Authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted: - At the request of the RMS; - Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account: PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list. IV. BENEFIT RISK ASSESSMENT To support the application the applicant has submitted one single-dose fasted BE Study. The results of this study show that the test formulation is bioequivalent in terms of AUC and Cmax in comparison to the reference formulation. The benefit-risk-balance for the product being subject of this procedure is positive. The application is approved. For intermediate amendments see current product information. Metamizol, DE/H/ /001/DC Public AR Page 7/7