Decentralised Procedure Public Assessment Report Levofloxacin HEC Pharm 250 mg / 500mg Filmtabletten Levofloxacin DE/H/3929/001-002/DC Applicant: HEC Pharm GmbH Gabriele-Teregit-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... 9 DE/H/3929/001-002/DC Public AR Page 2/9
ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS 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) Levofloxacin HEC Pharm 250 mg Filmtabletten Levofloxacin HEC Pharm 500 mg Filmtabletten Levofloxacin Quinolone antibacterials, fluoroquinolones (J01MA12) Film-coated tablet; 250 mg and 500 mg DE/H/3929/001-002/DC DE LU HEC Pharm GmbH Gabriele-Teregit-Promenade 17 D-10963 Berlin Germany DE/H/3929/001-002/DC Public AR Page 3/9
I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Levofloxacin HEC 250 mg and 500 mg Filmtabletten is approved. II. EXECUTIVE SUMMARY II.1 Problem statement This is a generic application for Levofloxacin 250 mg and 500 mg film-coated tablets. II.2 About the product Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S(-) enantiomer of the racemic drug substance ofloxacin. As a fluoroquinolone antibacterial agent, levofloxacin inhibits DNA synthesis by acting on the DNA/DNA-gyrase complex and topoisomerase IV. Levofloxacin has a broad in vitro antibacterial spectrum that includes Gram-positive organisms such as Streptococcus pneumoniae regardless of resistance phenotype, methicillin-susceptible Staphylococcus aureus and Streptococci spp., fastidious Gram-negative bacteria such as Haemophilus influenzae, Moraxella catarrhalis and Enterobacteriaceae such as Escherichia coli and Klebsiella spp., and organisms responsible for atypical infection such as Legionella, Mycoplasma and Chlamydophila. Therefore, levofloxacin is active against a diverse range of common causative pathogens for sinusitis, acute exacerbation of chronic bronchitis (AECB), community-acquired pneumonia (CAP), urinary tract infections (UTIs) and skin and soft tissue infections (SSTIs). SmPC, PL and Labelling of the Originator product Tavanic has been harmonised during an Article 30 procedure in 2012 (EMEA/H/A-30/1262). II.3 General comments on the submitted dossier This is a generic application for Levofloxacin 250 mg and 500 mg film-coated tablets according to Article 10(1). Levofloxacin 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 manufacturer involved in the drug product production for the applied manufacturing operations and dosage form was adequately demonstrated by GMP certificates or manufacturing authorizations issued by a Competent Authority within the EEA. GMP compliance at the drug substance manufacturer has been adequately demonstrated by a GMP QP declaration from the QP of the manufacturer responsible for batch release. 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 levofloxacin hemihydrate. A monograph for levofloxacin hemihydrate is not included in the Ph. Eur.. No ASMF procedure is used. All the detail of the drug substance is included within the dossier provided. The drug substance is packaged in two LDPE (low density polyethylene) bags as primary packaging, and then packaged in the kraft paper drum as secondary packaging. A retest period is 2 years is accepted. DE/H/3929/001-002/DC Public AR Page 4/9
Drug Product Levofloxacin 250 mg and 500 mg Film-coated Tablets are immediate release film-coated tablets containing 250 mg and 500 mg of the drug substance Levofloxacin hemihydrate The film-coated tablets are white or off white, capsular-shaped, debossed S22 for 500 mg and S23 for 250 mg on one side and scored on both sides. The film-coated tablets are packaged into blister strips. Each tablet is sealed in an individual blister well and the number of tablets in line with relevant labelling is packaged in one blister (strip). As primary packaging intended for marketing which consists of PVdC coated PVC film and push-through aluminum foil. The blisters are packed in boxes as secondary packaging. The drug product is manufactured by a wet granulation process. The shelf-life is 24 months. III.2 Non-clinical aspects There are no objections to approval of Levofloxacin HEC 250/500 mg film-coated tablets from a non-clinical point of view. Environmental Risk Assessment (ERA) Since Levofloxacin HEC is 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 This application is based on the originator Tavanic 250 mg and 500 mg film-coated tablets by Sanofi-Aventis, registered since 1998. Tavanic is approved in all EU Member States. Thus, the following is based on the knowledge about the originator. The applicant did not conduct any clinical studies except the bioequivalence study. Biowaiver The applicant requests an extrapolation of the in vivo results (BE study for the 500 mg strength) on the lower strength (250 mg). The extrapolation is acceptable. The requirements according to the Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1/Corr**) are fulfilled: General criteria - the pharmaceutical products are manufactured by the same manufacturing process, - the qualitative composition of the different strengths is the same, - the composition of the strengths are quantitatively proportional, - appropriate in vitro dissolution data should confirm the adequacy of waiving additional in vivo bioequivalence testing. Linear pharmacokinetic The bioequivalence study has been conducted with the highest strength (500 mg). The pharmacokinetic of levofloxacin is linear in the dose range of 50 mg to 1000 mg. Pharmacokinetics To support the application, the applicant has submitted one bioequivalence study: An open label, randomized, two treatment, two period, two sequence, single dose, crossover, bioequivalence study of Levofloxacin 500 mg film-coated tablets manufactured by Sunshine Lake Pharma Co., Ltd, China and Tavanic 500 mg Filmtabletten (Levofloxacin) of Sanofi-Aventis, Deutschland GmbH, Germany in healthy human adult male subjects, under fasting conditions was performed (Project No. 2732/12). Analytical methods HPLC technique, Precipitation method Analyte: Levofloxacin Calibration curve range: 0.1012 μg/ml to 12.1852 μg/ml DE/H/3929/001-002/DC Public AR Page 5/9
Bioanalytical method validation The bioanalytical method used was validated. The applicant provided the Bioanalytical method validation report accordingly. For details, please see the Clinical Day70 AR. Pharmacokinetic Variables Primary pharmacokinetic parameters: AUC 0-t and C max Secondary pharmacokinetic parameters: AUC 0-, T max, K el, t ½, AUC ratio, NK el, TLIN and LQCT Software: WinNonlin version 5.0.1 No. of subjects included in pharmacokinetic analysis: 25 Statistical methods Software: SAS package (Version 9.2) Number of observations, arithmetic mean, standard deviation, minimum, maximum, median, percentage coefficient of variation and geometric mean were calculated for the pharmacokinetic parameters. ANOVA was performed on the log-transformed pharmacokinetic parameters-auc 0-t, AUC 0- and C max using General Linear Model (PROC GLM procedure) of SAS. 90% confidence intervals for the difference between the least square means (LSM) were calculated for the log-transformed pharmacokinetic parameters- AUC 0-t, AUC 0- and C max of Levofloxacin. Non-parametric analysis of T max was performed on untransformed data, using the Wilcoxon signed-rank test. The bioequivalence acceptance range of the 90% CI was defined as 80% to 125% for C max and AUC 0-t. Results DE/H/3929/001-002/DC Public AR Page 6/9
Safety results There were 4 AEs reported during the study of which 3 were related and 1 was unrelated to the investigational products. AEs that were reported during the study included lacerations forearm and Urticaria. All AEs were mild to moderate in intensity and treated appropriately. All AEs were followed up until resolution and resolved completely without sequelae. Pharmacokinetic conclusion Based on the submitted bioequivalence study Levofloxacin HEC 500 mg film coated tablets is considered bioequivalent with Tavanic 500 mg Filmtabletten (Sanofi-Aventis). Pharmacodynamics As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV. The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum concentration in serum (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC). Clinical efficacy No new studies were conducted by the applicant. Thus, the clinical efficacy is based on data from the originator Tavanic. As the indications in the SmPC of the originator were subject to an Article 30 procedure (EMEA/H/A-30/1262) the current indications of the originator Tavanic are considered to be appropriate for this generic as well. The indications applied for are in line with the outcome of the Article 30 procedure of Tavanic 250 mg and 500 mg film-coated tablets and are therefore acceptable: Levofloxacin HEC is indicated in adults for the treatment of the following infections (see sections 4.4 and 5.1): Acute bacterial sinusitis Acute exacerbations of chronic bronchitis Community-acquired pneumonia Complicated skin and soft tissue infections For the above-mentioned infections Levofloxacin HEC tablets should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections. Pyelonephritis and complicated urinary tract infections (see section 4.4) Chronic bacterial prostatitis Uncomplicated cystitis (see section 4.4) Inhalation Anthrax: post exposure prophylaxis and curative treatment (see section 4.4) Levofloxacin HEC tablets may also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous levofloxacin. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Clinical safety The clinical safety of levofloxacin is well known and was subject of discussion in the Articel 30 procedure of the originator. The risks are reflected in sections 4.3, 4.4, 4.5, and 4.8 of the SmPC. DE/H/3929/001-002/DC Public AR Page 7/9
User Testing Results of user testing have been provided by the applicant. The results of this test indicate that the PL is well structured and organized, easy to understand and written in a comprehensible manner. The test shows that the leaflet is readable and patients/users are able to act upon the information that it contains. This report also meets the legal requirements for Art. 59(3) of Directive 2001/83/EC (as amended). It was also confirmed that the report conforms to the study design, principles and success criteria featured in the European Commission's document Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use (Revision 1, 12 January 2009). Based on the above mentioned facts the package leaflet can be qualified as acceptable. Pharmacovigilance system (DDPS) 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. Risk Management Plan The Applicant has provided an RMP within the new format of GVP module V. The Applicant has generated a list of important safety concerns (i.e. important identified risks, potential risk and missing information) based on information provided in sections 4.3-4.6 of the SmPC with no additional risk minimisation measures and no need for additional pharmacovigilance measures. This approach without the need for additional pharmacovigilance and additional risk minimisation measures is acceptable. The submitted Risk Management Plan is approvable. The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP. DE/H/3929/001-002/DC Public AR Page 8/9
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. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. Periodic Safety Update Report (PSUR) The submission of PSURs should follow the provisions as laid down in the EURD list. The Applicant is requested to comply with any outcome of the PSUR Worksharing procedure for Levofloxacin and to confirm that additional safety information contained in the agreed core safety profile (CSP) and currently not included in the product information will be added to the product information via variation procedure. IV. BENEFIT RISK ASSESSMENT Bioequivalence with the originator has been shown. The applicant/mah is requested to comply with any outcome of upcoming PSUR Worksharing procedures for levofloxacin. The application is approved. For intermediate amendments see current product information. DE/H/3929/001-002/DC Public AR Page 9/9