DE/H/3669/001/DC Applicant

Decentralised Procedure

Public Assessment Report

Moxifloxacin Sanovel 400 mg (film-coated tablets) DE/H/3669/001/DC Applicant: Sanovel GmbH Wall 39 42103 Wuppertal Germany

Reference Member State

DE

The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health

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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

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ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS

Moxifloxacin Sanovel 400 mg

Name of the drug substance (INN name):

Moxifloxacin hydrochloride

Pharmaco-therapeutic group (ATC Code):

J01MA14

Pharmaceutical form(s) and strength(s):

Film-coated tablet, 400mg

Reference Number(s) for the Decentralised Procedure

DE/H/3669/001/DC

Reference Member State:

DE

Concerned Member States:

LU

Applicant (name and address)

Sanovel GmbH Wall 39 42103 Wuppertal Germany

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I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the application for Moxifloxacin Sanovel 400 mg, in 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 ATCCode 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 seeked 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 is in line with the originator, i.e. the respiratory tract infections are restricted to second line and the indication pelvic inflammatory disease is specified for resistance in Neisseria gonorrhoeae. The daily dose is 400 mg and the treatment duration is 5 to 14 days depending on the indication. This 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 has been adequately demonstrated. According to the applicant, the bioequivalence study adhered to the CHMP guidelines “Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) and have 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 Moxifloxacin Hydrochloride is supplied from the manufacturer. Information on the active substance is provided in form of a CEP (R0-CEP 2008-113-Rev 01). The drug substance specification is in compliance with the Ph. Eur. monograph Moxifloxacin Hydrochloride and includes the specification mentioned in the CEP and additional applicant’s specifications. Stability studies have been performed and an expiry period of 5 years has been established.

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Drug Product The drug product is a pink colored, oblong film-coated tablet debossed (on one side) with MX400. The excipients are well known: Microcrystalline cellulose, Croscarmellose Sodium, Magnesium stearate, Opadry II Pink 85F24435 (Polyvinyl alcohol, Titanium dioxide, Polyethylene glycol 3000, Talc, Talc/ Iron oxide red ratio 3/1) The drug product is manufactured by a wet granulation process. A shelf-life of 24 months is accepted.

III.2 Non-clinical aspects There are no objections to approval of Moxifloxacin Sanovel 400 mg film-coated tablets from a nonclinical point of view.

III.3 Clinical aspects This application is based on the originator “Avalox”. Avalox is approved in all EU Member States with different names in same MS. Thus, the following is based on the knowledge about the originator. 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 study was conducted as a single center, open, randomized, single-dose, two-period, twotreatment, two-sequence, crossover trial in healthy volunteers. Plasma concentrations of moxifloxacin were determined and the pharmacokinetic parameters C max, tmax, AUC0-last , AUC0-inf, residual area and t1/2 were calculated. Bioequivalence was assessed for moxifloxacin parameters using ANOVA and 90%-confidence interval statistical analysis. Test and reference products Test product: Moxin 400 mg film-coated tablet Dose: One 400 mg moxifloxacin film-coated tablet Mode of Administration: Oral admioistration with 200 ml of water Batch Number: 03 Batch size: 100.000 Reference product: Avalox 400 mg film-coated tablets (Bayer Vital GmbH, Germany) Dose: One 400 mg moxifloxacin film-coated tablet Mode of Administration: Oral administration with 200 ml of water Batch Number: BXBBLSl Population studied 24 healthy, Caucasian volunteers of both sexes (females non-pregnant, non-breast-feeding) were between 18 and 55 years of age, with body-mass index of 19 to 27 kg/m', non-smokers or mild smokers smoking not more than 10 cigarettes (or 2 cigars or 2 pipes) per day. 24 volunteers completed the study 24 volunteers were included in the bioequivalence assessment

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Results Table 1.

Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax median, range)

Treatment

AUC0-t

AUC0-∞

Cmax µg/L

h

Test

28387.5

29281.4

2691.7

1,33

Reference

31742.1

32741.1

2847,7

1,50

0.8943 (0.8420-0.9499)

0.8943 (0.8444-0.9472)

0.9452 (0.8624-1.0361)

-0.0950

-1 µg·L ·h

*Ratio (90% CI) AUC 0-t AUC 0-∞ C max t max

-1 µg·L ·h

tmax

Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-72h can be reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0-72h is reported instead of AUC0-t Maximum plasma concentration T ime until Cmax is reached

*ln-transformed values Safety As reported twenty-one adverse events probably or possibly related to the study medication (eight cases of headache and nausea, and five cases of dizziness) occurred in 12 subjects. No adverse event was assessed as a serious adverse event, an unexpected adverse drug reaction or other clinically significant adverse event. Pharmacokinetic conclusion Based on the submitted bioequivalence study Sanovel Moxifloxacin 400 mg is considered bioequivalent with Avalox 400 mg film-coated tablets. 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 is reflected in section 5.1 of the SmPC. According to the table in this section, the majority of the most important pathogens for the indications sought are still susceptible to moxifloxacin. Clinical efficacy No new studies were conducted by the applicant. Thus, the clinical efficacy is based on data from the originator Avelox. As the indications in the SmPC of the originator were subject to an article 107 referral procedure, the current indications of the originator are considered to be appropriate for this generic as well. The current indications of the originator are:

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Avelox 400 mg film-coated tablets are indicated for the treatment of the following bacterial infections in patients of 18 years and older caused by bacteria susceptible to moxifloxacin (see sections 4.4, 4.8 and 5.1). Moxifloxacin should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections or when these have failed: - Acute bacterial sinusitis (adequately diagnosed) - Acute exacerbations of chronic bronchitis (adequately diagnosed) - Community acquired pneumonia, except severe cases - Mild to moderate pelvic inflammatory disease (i.e. infections of female upper genital tract, including salpingitis and endometritis), without an associated tubo-ovarian or pelvic abscess. Avelox 400 mg film-coated tablets are not recommended for use in monotherapy of mild to moderate pelvic inflammatory disease but should be given in combination with another appropriate antibacterial agent (e.g. a cephalosporin) due to increasing moxifloxacin resistance of Neisseria gonorrhoeae unless moxifloxacin-resistant Neisseria gonorrhoeae can be excluded (see sections 4.4 and 5.1). Avelox 400 mg film-coated tablets may also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous moxifloxacin for the following indications: - Community-acquired pneumonia - Complicated skin and skin structure infections Avelox 400 mg film-coated tablets should not be used to initiate therapy for any type of skin and skin structure infection or in severe community-acquired pneumonia. Consideration should be given to official guidance on the appropriate use of antibacterial agents. The indications as proposed by the applicant are in line with the indications of the originator. Clinical safety The clinical safety of moxifloxacin is well known and was subject of discussion in several variations and referrals of the originator. The most prominent risk of moxifloxacin is due to its QTc-prolonging properties resulting in the risk of Torsades des pointes. Most of the other risks are known classeffects of fluoroquinolones. The risks are adequately reflected in sections 4.3, 4.4, 4.5, and 4.8 of the SmPC. Assessment of User Testing The applicant submitted a User Testing. The results of this test indicate that the PIL 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). The User testing as proposed by the applicant is acceptable. Pharmacovigilance system (DDPS) Description of Pharmacovigilance System Details have been provided of the Sanovel pharmacovigilance system (Version 3 dated 24 December 2010). 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. Provided that a copy of the EudraVigilance registration of the QPPV is submitted, 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.

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Risk Management Plan The applicant has submitted an RMP addressing the following risks and pharmacovigilance measures in line with the RMP of the originator medicinal product. Additional risk minimisation measures are currently not considered necessary.

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The submitted revised RMP, signed 16 April 2013, is considered acceptable. The provided follow-up questionnaires for hypersensitivity/anaphylaxis, cardiac arrhythmias, hepatotoxicity, and antibiotic associated diarrhoea are considered mainly acceptable. In case of publication of standardised followup questionnaires on the CMD(h) or EMA Websites in line with GVP module V, the MAH committed (letter dated 27 May 2013) to amend its questionnaires accordingly. Periodic Safety Update Report (PSUR) The active substance moxifloxacin takes part in the PSUR Worksharing. The submission of further PSURs should follow the provisions as laid down in the EURD list when coming into effect. The MAH has committed to comply with any outcome of the PSUR Worksharing procedure for moxifloxacin and confirmed that additional safety information contained in the agreed core safety profile (CSP) and not included in the product information will be added to the product information via variation procedure. In future PSURs the applicant will closely monitor the risks as outlined in the clinical and nonclinical AR.

IV

BENEFIT RISK ASSESSMENT

The application contains an adequate review of published clinical data and the bioequivalence has been shown. The SmPC/PL as proposed by the applicant is in line with the SmPC/PL of the originator. The applicant has submitted an RMP aligned to the safety concerns included in the originator RMP. The application is approved. For intermediate amendments see current product information.

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