Decentralised Procedure Public Assessment Report Moxifloxacin HEC Pharm 400 mg Filmtabletten Moxifloxacin DE/H/3966/001/DC Applicant: HEC Pharm GmbH Gabriele-Tergit-Promenade 17 D-10963 Berlin Germany Reference Member State DE 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.. 4 III SCIENTIFIC OVERVIEW AND DISCUSSION ............................................................... 4 III.1 Quality aspects ............................................................................................................... 4 III.2 Non-clinical aspects ........................................................................................................ 5 III.3 Clinical aspects ............................................................................................................... 5 IV BENEFIT RISK ASSESSMENT ....................................................................................... 8 Moxifloxacin HEC Pharm 400 mg Filmtabletten, DE/H/3966/001/DC Public AR Page 2/8 ADMINISTRATIVE INFORMATION Proposed name of the medicinal Moxifloxacin HEC Pharm 400 mg Filmtabletten product in the RMS Name of the drug substance (INN Moxifloxacin name): Pharmaco-therapeutic group Quinolone antibacterials, fluoroquinolones (J01MA14) (ATC Code): Pharmaceutical form(s) and Film-coated tablet, 400mg strength(s): Reference Number(s) for the DE/H/3966/001/DC Decentralised Procedure Reference Member State: DE Concerned Member States: LU Applicant (name and address) HEC Pharm GmbH Gabriele-Tergit-Promenade 17 D-10963 Berlin Germany Moxifloxacin HEC Pharm 400 mg Filmtabletten, DE/H/3966/001/DC Public AR Page 3/8 I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Moxifloxacin HEC Pharm 400 mg Filmtabletten, indicated for the treatment of acute bacterial sinusitis, acute exacerbations of chronic bronchitis, community acquired pneumonia, and mild to moderate pelvic inflammatory disease, is approved. II EXECUTIVE SUMMARY II.1 Problem statement This is a generic application for moxifloxacin 400 mg film-coated tablets. II.2 About the product Moxifloxacin is a quinolone antibacterial and belongs to the group of fluoroquinolones. The ATC- Code is J01 MA 14. The bactericidal action of moxifloxacin is mediated by the inhibition of DNA gyrase (Topoisomerase II) and topoisomerase IV. These enzymes are essential for bacterial DNA replication, transcription, repair, and recombination. The applicant seeks for the indications acute bacterial sinusitis, acute exacerbations of chronic bronchitis, community acquired pneumonia, and mild to moderate pelvic inflammatory disease. The wording of the indications as proposed by the applicant is completely in line with the originator. II.3 General comments on the submitted dossier This is a generic application for moxifloxacin film-coated tablets according to Article 10(1). Moxifloxacin is no new substance. The company did not seek scientific advice prior to submission. II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles GMP compliance at the manufacturing sites involved in the production of the drug product is adequately demonstrated by GMP certificates and / or Manufacturing Authorisations issued by a Competent Authority of one of the Member States of the EEA. A GMP declaration (date of audit July 2014) for the Drug Substance Manufacturer complying with the new EMA QP declaration template has been provided. GCP/agreed ethical principles The bioequivalence study was conducted in accordance with ICH “Guidance on Good Clinical Practice” and has been approved by an Ethical Committee to ensure compliance with the Declaration of Helsinki. III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The drug substance is Moxifloxacin hydrochloride. A Certificate of Suitability has been provided. The drug substance is packaged in double layer low-density polyethylene (LDPE) bags as primary package, and then packaged in the kraft paper drum as secondary packaging. A re-test period of 2 years is proposed. Drug Product The drug product is an immediate release film-coated tablet containing 400 mg of Moxifloxacin as Moxifloxacin hydrochloride. The drug products are packaged into blister strips as primary packaging intended for marketing which consists of PVdC coated PVC film and push-through aluminium foil. The blisters are packed in carton as secondary packaging. The drug product is manufactured by a wet granulation process. After granulation and drying, dried granules are milled. The milled granules from two runs are compressed into tablets, followed by film-coating. The shelf-life is 2 years. Moxifloxacin HEC Pharm 400 mg Filmtabletten, DE/H/3966/001/DC Public AR Page 4/8 III.2 Non-clinical aspects The wording of SmPC’s section 4.6 and 5.3 is adequate. Environmental Risk Assessment (ERA) Evaluation of the potential environmental risk posed by the medicinal product has not been provided. As it concerns a generic product which is intended for substitution of the innovator, such an evaluation is deemed unnecessary since no additional amount of moxifloxacin will be introduced in the environment. III.3 Clinical aspects This application is based on the originator Avalox. The applicant did not conduct any clinical studies except the bioequivalence study. Pharmacokinetics To support the application, the applicant has submitted one bioequivalence study. The objective of the study was to compare the bioavailability, to characterise the pharmacokinetic profile, and to assess the bioequivalence of the test product Moxifloxacin 400 mg film-coated tablets manufactured by Sunshine Lake Pharma Co., Ltd, China with the reference product Avalox® 400 mg Filmtabletten of Bayer Schering Pharma AG, Germany in healthy adult human subjects, under fasted conditions. The study was conducted as a randomised, balanced, open-label, 2-treatment, 2-period, 2-sequence, single-dose, crossover bioequivalence study in accordance with GCP, relevant regulatory guidance, and written SOPs of the contract research organisation. The pharmacokinetic parameters included Cmax, AUC0-t, AUC0-∞, AUC-%Extrap_obs, tmax, λz and t1/2. In order to assess the relative bioavailability, 90% confidence intervals for the difference between the least square means (LSM) were calculated for the ln-transformed pharmacokinetic parameters Cmax and AUC0-t of Moxifloxacin. The bioequivalence acceptance range of the 90% CI was defined as 80% to 125% for Cmax and AUC0-t. The results were as follows: Pharmacokinetic Data Pharmacokinetic Arithmetic Means (± SD) Parameter Test Product Reference Product ξ AUC(0-t) (ng.h /mL) 45294.346 ± 5323.1663 45418.947 ± 5351.3442 ξ AUC(0-∞) (ng.h/mL) 46830.226 ± 5773.1862 46917.999 ± 5918.7784 Cmax (ng /mL) 2971.727 ± 636.5366 3035.497 ± 400.1447 1 tmax (h) 2.000 (0.500 - 5.000) 2.000 (0.750 - 3.000) 1Median (Min, Max) ξN = 24 Additional Pharmacokinetic Data Record1 Descriptor Related Information 2 2 AUC(0-t)/ AUC(0-∞) <0.8 <1004, period 1, R > Cmax is the first point None Pre-dose sample >5% Cmax None 1 Only if the last sampling of AUC(0-t) is less than 72h 2F = T for the Test formulation or F = R for the Reference formulation Moxifloxacin HEC Pharm 400 mg Filmtabletten, DE/H/3966/001/DC Public AR Page 5/8 Bioequivalence Evaluation Pharmacokinetic Geometric Mean 90% Confidence CV%1 Parameter Ratio Test/Reference Intervals (%) lnAUC(0-t) 99.7 98.25 - 101.19 3.0 lnCmax 96.8 92.01 - 101.93 10.6 1Estimated from the Residual Mean Squares. Based on the submitted bioequivalence study Moxifloxacin HEC 400 mg film-coated tablet is considered bioequivalent with Avalox® 400 mg film-coated tablets, the product of the Originator. Pharmacodynamics The bactericidal action of moxifloxacin is mediated by the inhibition of DNA gyrase (topoisomerase II) and topoisomerase IV, essential enzymes involved in bacterial DNA replication, transcription, repair and recombination. Moxifloxacin was highly active against S. pneumoniae isolates, including strains bearing DNA gyrase and topoisomerase IV mutations resistant to older quinolones, such as ciprofloxacin and levofloxacin. This was associated with the substitution at C-8. Quinolones inhibit the action of DNA gyrase and topoisomerase IV and kill bacteria by binding to these enzyme-DNA complexes, thereby disrupting DNA replication. Mutation in the genes that encode for DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE) can change the structure of one or more subunits of these enzymes, and may lead to development of a resistance. The methoxy group at the C-8 position enhances anaerobic activity, results in a lower phototoxicity, and enables moxifloxacin to bind simultaneously and equally at both DNA gyrase and topoisomerase IV enzymes. This mechanism of action renders the development of bacterial resistance unlike. The current resistance situation