UKPAR for Levofloxacin 250mg and 500mg film-coated tablets PL

UKPAR Levofloxacin 250mg and 500mg Film-coated Tablets PL 24668/0102-5

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LEVOFLOXACIN 250MG FILM-COATED TABLETS

PL 24668/0102 and 0104


PL 24668/0103 and 0105

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Steps taken after authorisation – summary

Page 14

Summary of Product Characteristics

Page 15

Product Information Leaflet

Page 16

Labelling Page 17 Annex 1 Page 30


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PL 24668/0102 & 0104


PL 24668/0103 & 0105

LAY SUMMARY On 8th January 2010, the MHRA granted Caduceus Pharma Limited Marketing Authorisations (licences) for the medicinal products Levofloxacin 250mg and 500mg Film-coated tablets (PL 24668/0102-5). These are prescription-only medicines. Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class. Levofloxacin is used to treat infections caused by bacteria against which the medicine is active. Infections which the tablets can be used to treat include infections of the sinuses, infection of the lungs, urinary tract infections, skin infections and infection of the prostate. No new or unexpected safety concerns arose from these applications and it was, therefore, judged that the benefits of taking Levofloxacin 250mg and 500mg Film-coated tablets outweigh the risks. Hence Marketing Authorisations have been granted. A subsequent Change of Ownership (CoA) was granted for Levofloxacin 250mg and 500mg Film-coated tablets (PL 24668/104-105) on 26 May 2012, to change the Marketing Authorisation Holder to Aptil Pharma Limited (PL 40378/0019-0020).


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PL 24668/0102 & 0104


PL 24668/0103 & 0105

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment (including statistical assessment)

Page 9

Overall conclusion and risk benefit assessment Page 12


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INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK granted Marketing Authorisations for the medicinal products Levofloxacin 250mg and 500mg Film-coated tablets (PL 24668/0102-5) on the 8th January 2010. These products are prescription-only medicines (POM). These are National abridged complex and standard applications for Levofloxacin 250 mg and 500 mg film coated tablets submitted under article 10 (1) of Directive 2001/83/EC, as amended. The application claims the products to be generic medicinal products of Tavanic 250mg and 500mg, authorised to Hoechst Marion Roussel, (PL 13402/0011-0012) in 1997. Levofloxacin is the S-(-)-isomer of the fluoroquinolone antibacterial ofloxacin. Levofloxacin is generally considered to be about twice as active as ofloxacin, the racemic substance. Usual doses range from 250 to 500 mg once or twice daily for 7 to 14 days depending on the severity and nature of the infection. Levofloxacin is indicated for the following infections: 250mg

• Acute sinusitis • Acute exacerbations of chronic bronchitis • Community-acquired pneumonia • Uncomplicated urinary tract infections • Complicated urinary tract infections including pyelonephritis • Chronic bacterial prostatitis. • Skin and soft tissue infections. 500mg

• Acute sinusitis • Acute exacerbations of chronic bronchitis • Community-acquired pneumonia • Complicated urinary tract infections including pyelonephritis • Chronic bacterial prostatitis.

• Skin and soft tissue infections. A subsequent Change of Ownership (CoA) was granted for Levofloxacin 250mg and 500mg Film-coated tablets (PL 24668/104-105) on 26 May 2012, to change the Marketing Authorisation Holder to Aptil Pharma Limited (PL 40378/0019-0020).


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PHARMACEUTICAL ASSESSMENT

DRUG SUBSTANCE Nomenclature rINN: Levofloxacin hemihydrate Chemical names: (-)-(s)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4 benzoxazine-6-carboxylic acid hemihydrate. Structure

Molecular formula: C18H20FN3O4.½H2O Molecular Mass: 370.38 Physical Description: Light yellowish-white odourless powder. Solubility: Sparingly soluble in methanol, aqueous solubility decreases with increase in pH The drug substance is the subject of a European Drug Master File (EDMF). A letter of access has been provided by the drug substance manufacturer. Synthesis of the drug substance from the designated starting material has been adequately described and appropriate in-process controls and intermediate specifications are applied. Satisfactory specifications are in place for all starting materials and reagents and these are supported by relevant Certificates of Analysis. An appropriate specification based on the European Pharmacopoeia has been provided. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. Levofloxacin hemihydrate is stored in appropriate packaging. The specifications and typical analytical test reports are provided and are satisfactory.


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Batch analysis data are provided and comply with the proposed specification. Satisfactory Certificates of Analysis have been provided for working standards used by the drug substance manufacturer and finished product manufacturer during validation studies. Appropriate stability data have been generated, supporting a suitable retest period when the drug substance is stored in the packaging proposed. DRUG PRODUCT Other ingredients Other ingredients consist of pharmaceutical excipients, namely colloidal anhydrous silicon dioxide, titanium dioxide, silicified microcrystalline cellulose, copovidone, crospovidone, lactose monohydrate, HPMC 2910 15CPS, sodium stearyl fumarate, glycerol triacetate, iron oxide red K 5609 and iron oxide yellow 17268E172. All excipients used comply with their respective European Pharmacopoeia monograph with the exception of iron oxide red K 5609 and iron oxide yellow 17268E172 which complies with national formulae. Satisfactory Certificates of Analysis have been provided for all excipients. Confirmation has been given that the sodium stearyl fumarate used in the tablets is of vegetable origin. Pharmaceutical development Suitable pharmaceutical development data have been provided for these applications. Comparable dissolution and impurity profile are provided for these products versus the originator product. Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory based on process validation data and controls on the finished product. Process validation has been carried out on batches of the product. The results appear satisfactory. Finished product specification The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used. Container Closure System Product is packaged in aluminium/PVC blister packs and HDPE container with LDPE lid. Specifications and Certificates of Analysis for all packaging types used have been provided. These are satisfactory. All primary product packaging complies with EU legislation regarding contact with food. Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 2 years is set and this is acceptable. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are pharmaceutically satisfactory. The applicant has submitted results of PIL user testing. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains.


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MAA Form The MAA form is pharmaceutically satisfactory. Expert Report The pharmaceutical expert report is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion It is recommended that Marketing Authorisations are granted for these applications.


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PRECLINICAL ASSESSMENT

The pharmacodynamic, pharmacokinetic and toxicological properties of the product are well-known. Thus, the applicant has not provided additional studies and further studies are not required. A preclinical expert report has been provided, written by an appropriately qualified person. This is satisfactory. A suitable justification has been provided for non-submission of an Environmental Risk Assessment.


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CLINICAL ASSESSMENT TOXICOLOGY No new preclinical data have been submitted and none are required for these applications. CLINICAL PHARMACOLOGY BIOEQUIVALENCE (STUDY NO.: 901/06) A randomised, single dose, randomized, 2-period, 2-way crossover study to assess the pharmacokinetics of the test product Levofloxacin 250mg Film-coated tablets versus the reference product Tavanic 250mg, in healthy fasted volunteers. 28 healthy male Indians with age range from 18 to 42 years were included in the study. Inclusion and exclusion criteria were presented. All volunteers completed both study phases. Subjects were housed in the clinical facility at the evening before drug administration until 24 hours after drug administration. Study drug was administered after an overnight fast with 240 ml water. 21 blood samples were collected at 0, 0.25, 0.5, 0.67, 0.83, 1, 1.167, 1.33, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 6, 8, 12, 16, 24 and 36 hours post dose with washout period of 7 days between study periods. One of the predose samples (period 2, Subject 7) contained levofloxacin (<5% of Cmax). One subject (Subject 12) vomited 4 hours after administration of test product.

Results All study subjects (n=28) completed both study phases and were included in statistical analysis.

Pharmacokinetic parameters for the Test product (A) and Reference product (B) are given below.

No significant differences were observed in mean Tmax values between test (1 h) and reference (1.16 h).


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Assessor's Conclusion on Bioequivalence Clinical part of the Bioequivalence study was conducted in line with EMEA current guidance. Standard single dose BE study was conducted with 250 mg tablets. BE was shown based on point estimates and 90%CI of the log-transformed PK parameters. The applicant is seeking Marketing Authorisation for 250 mg and 500 mg strengths. Biowaiver to the 500 mg strength can be granted since the pharmacokinetics of levofloxacin is linear, pharmaceutical composition of both strength is proportionally similar, both products are manufactured by the same process and dissolution profiles with 250 mg and 500 mg were similar. According to the EMEA guideline on the Investigation of BA &BE, a bioequivalence study with the highest strength should have been conducted. The bioequivalence between the two formulations of 250mg products was demonstrated with a very narrow CI. Biowaiver to the 500 mg could be considered therefore acceptable. EFFICACY No new efficacy data have been submitted and none are required for these applications. SAFETY No new safety data have been submitted and none are required for these applications. EXPERT REPORT A clinical expert report has been written by clinical consultant to the pharmaceutical industry. The report is satisfactory. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) Clinically satisfactory PATIENT INFORMATION LEAFLET This is satisfactory LABELLING These are satisfactory. MARKETING AUTHORISATION FORM These are satisfactory.


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DISCUSSION The applicant has conducted a bioequivalent study comparing the applicant’s product with the cross referred medicinal product. The study has confirmed that both products are bioequivalent and therefore would exhibit the same efficacy and safety profile. CONCLUSION The grant of Marketing Authorisations is recommended.


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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT

QUALITY The important quality characteristics of Levofloxacin 250mg and 500mg Film-coated tablets are well defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY No new data have been submitted and none are required for an application of this type. Levofloxacin 250mg and 500mg Film-coated tablets are the generic versions of Tavanic 250mg and 500mg (Hoechst Marion Roussel). The use of the reference product is well-established in the UK. Both products contain the same quantitative and qualitative composition of the active ingredients, levofloxacin hemihydrate. The 90% confidence intervals for the test/reference lie within the acceptance criteria specified in the CPMP/EWP/QWP/1401/98 Notes for Guidance on the Investigation of Bioavailability and Bioequivalence. Bioequivalence of the test product to the reference formulation has been satisfactorily demonstrated in accordance with CHMP criteria. No new safety data are supplied or required for these generic applications. Levofloxacin hemihydrate have well-established side-effect profiles and are generally well-tolerated. The SmPC, PIL and labelling are satisfactory. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicant’s product and the innovator product are interchangeable. Extensive clinical experience with Levofloxacin 250mg and 500mg Film coated tablets is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


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PL 24668/0102 and 0104


PL 24668/0103 and 0105

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the Marketing Authorisation applications on 8th August

2007

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 29th October 2007

3 Following assessment of the applications the MHRA requested further information relating to the quality dossier on 31st October 2008.

4 The applicant responded to the MHRA’s requests, providing further information to the quality section on 13th March 2009

5 The applications were determined on 8th January 2010


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PL 24668/0102 and 0104


PL 24668/0103 and 0105

STEPS TAKEN AFTER AUTHORISATION – SUMMARY

The following table lists a non-safety update to the Marketing Authorisations for Levofloxacin 250mg and 500mg Film coated tablets (PL 40378/0019-0020 previously PL 24688/0104-0105) that has been approved by the MHRA since the products were first licensed. The table includes an update that has been added as an annex to this PAR. This is not a complete list of the post-authorisation changes that have been made to these Marketing Authorisations. Date submitted

Application type

Scope Outcome

27 January 2014

Type 1B To update sections 4 (Clinical particulars) and 5 (Pharmacological properties) of the Summary of Product Characteristics (SmPC) and, consequentially, the Patient Information Leaflet (PIL) in line with the outcome of Article 30 referral.

Approved 06 March 2014


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Summary of Product Characteristics

In accordance with Directive 2010/84/EU, the Summaries of Product Characteristics (SmPCs) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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PATIENT INFORMATION LEAFLET

In accordance with Directive 2010/84/EU, the Patient Information Leaflets (PILs) for products granted Marketing Authorisations at a national level are available on the MHRA website.


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LABELLING

The following text is the approved label text. No label mock-ups have been provided. In accordance with medicines legislation, the products shall not be marketed in the UK until approval of the label mock-ups has been obtained


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Annex 1

Our Reference: PL 40378/0019, Application 12 Product: Levofloxacin 250 mg film-coated tablets Marketing Authorisation Holder: Aptil Pharma Limited Active Ingredient(s): Levofloxacin hemihydrate Type of Procedure: National Submission Type: Variation Submission Category: Type IB Submission Complexity: Standard EU Procedure Number (if applicable): Reason: To update sections 4 (Clinical particulars) and 5 (Pharmacological properties) of the Summary of Product Characteristics (SmPC) and, consequentially, the Patient Information Leaflet (PIL) in line with the outcome of Article 30 referral. Linked / Related Variation(s) or Case(s): The Assessment Report refers to the Collection ID 148625 and covers the following submissions PL40378/0020, Application 0012. Supporting Evidence Revised SmPC fragments and the PIL have been provided. Evaluation Adequate clinical information has been provided. The updated sections of the SmPC and the updated PIL are satisfactory. Conclusion The amendments to the SmPC and PIL are acceptable and there are no objections to approval. In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are available on the MHRA website. Decision – Approved 06 March 2014

UKPAR for Levofloxacin 250mg and 500mg film-coated tablets PL

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