Public Assessment Report Decentralised Procedure ... · PAR Azithromycin 200 mg/5 ml Powder for Oral Suspension UK/H/5115/001/DC 2 Azithromycin 200 mg/5 ml Powder for Oral Suspension

PAR Azithromycin 200 mg/5 ml Powder for Oral Suspension UK/H/5115/001/DC

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Public Assessment Report

Decentralised Procedure

Azithromycin 200 mg/5 ml Powder for Oral Suspension

(Azithromycin anhydrous)

UK/H/5115/001/DC

UK Licence No: PL 29831/0479

Wockhardt UK Ltd


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PL 29831/0479

LAY SUMMARY On 10th May 2013, the Medicines and Healthcare products Regulatory Agency (MHRA) granted a Marketing Authorisation to Wockhardt UK Ltd for the medicinal product Azithromycin 200 mg/5 ml Powder for Oral Suspension (PL 29831/0479; UK/H/5115/001/DC). This medicine is only available on prescription from your doctor. Azithromycin is one of a group of antibiotic called macrolides. It is used to treat infections caused by certain bacteria and other micro-organisms, which include: • chest, throat or nasal infections (such as bronchitis , pneumonia, tonsillitis, sore throat (pharyngitis) and sinusitis) • ear infections • skin and soft tissue infections (such as an abscess or boil) • urethritis and cervicitis (sexually-transmitted diseases caused by an organism called Chlamydia) No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Azithromycin 200 mg/5 ml Powder for Oral Suspension outweigh the risks; hence a Marketing Authorisation was granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Patient Information Leaflets Page 6 Module 4: Labelling Page 7 Module 5: Scientific Discussion Page 12 1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions Module 6 Steps taken after initial procedure Page 19


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Module 1

Product Name


Type of Application

Article 10(1), Generic application

Active Substance

Azithromycin anhydrous

Form

Powder for Oral Suspension

Strength

200 mg/5 ml

MA Holder

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK

RMS

UK

CMSs

Republic of Ireland

Procedure Number

UK/H/5115/001/DC

Timetable

Day 210: 11th April 2013


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Module 2 Summary of Product Characteristics

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


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Module 3 Patient Information Leaflet

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


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Module 4

Labelling


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Module 5 Scientific discussion during initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the Reference Member State (RMS) and Concerned Member States (CMSs) consider that the application for Azithromycin 200 mg/5ml Powder for Oral Suspension for the following indications could be approved:

- acute exacerbation of chronic bronchitis - community-acquired pneumonia - acute bacterial sinusitis - pharyngitis/tonsillitis (see section 4.4 regarding streptococcal infections) - acute bacterial otitis media - skin and soft tissue infections - uncomplicated urethritis and cervicitis due to Chlamydia trachomatis.

This application was submitted according to Article 10(1) of 2001/83/EC, as amended. The reference medicinal product for this application is Zithromax 200 mg/ 5 ml Powder for Oral Suspension (PL 00057/0336), which was first authorised to Pfizer Ltd., on 4th April 1991. The reference product has been authorised in the European community for more than 10 years, so the period of data exclusivity has expired. With UK as the RMS in this Decentralised Procedure (UK/H/5115/001/DC), Wockhardt UK Ltd applied for the Marketing Authorisation for Azithromycin 200 mg/5 ml Powder for Oral Suspension in Republic of Ireland. Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is constructed by adding a nitrogen atom to the lactone ring of erythromycin A. The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis, by binding to the ribosomal 50S sub-unit and thus inhibiting the translocation of peptides. No new clinical or non-clinical studies were conducted, which is acceptable given that this is a generic application, which refers to an originator product that has been licensed for over 10 years. A bioequivalence study was carried out in accordance with Good Clinical Practice (GCP). The RMS has been assured that acceptable standards of GMP are in place for this product type 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. The RMS considers that the Pharmacovigilance System as described by the applicant fulfils the requirements 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. A suitable justification for non-submission of the risk management plan has been submitted. This is satisfactory. All member states agreed to grant a licence for the above product at the end of the procedure (Day 210 – 11th April 2013). After a subsequent national phase, the UK granted a licence for this product on 10th May 2013 (PL 29831/0479).


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State


Name(s) of the active substance(s) (USAN)

Azithromycin anhydrous

Pharmacotherapeutic classification (ATC code)

Antibacterials for systemic use

ATC code: J01FA10 Pharmaceutical form and strength(s) Powder for Oral Suspension Reference numbers for the Decentralised Procedure

UK/H/5115/001/DC

Reference Member State United Kingdom Concerned Member States

Republic of Ireland

Marketing Authorisation Number(s) PL 29831/0479 Name and address of the authorisation holder

Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS DRUG SUBSTANCE INN: Azithromycin anhydrous Chemical Names: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2,6-Dideoxy-3-Cmethyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Structure:

Molecular formula: C38H72N2O12 Molecular weight: 749 g/mol Physical form: White to off-white, amorphous powder. Solubility: Practically insoluble in water, freely soluble in anhydrous ethanol and in methylene chloride. The drug substance is the subject of a drug master file (DMF). 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. Appropriate proof-of-structure data have been supplied. All potential known impurities have been identified and characterised. An appropriate specification is provided for the active substance. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. 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. The active substance is stored in appropriate packaging. The specifications and typical analytical test reports are provided and are satisfactory. 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 the pharmaceutical excipients sucrose, hydroxypropylcellulose (E463),

trisodium phosphate anhydrous (E339), xanthan gum (E415), sucralose (E955), colloidal anhydrous


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silica (E551), cherry flavour 501027 AP0551, banana flavour 501013 AP0551, masking flavour 501482 TP0424 (contains sugar and aspartame) and banana durarome flavour 501392 TDI0991 (contains sugar and ethanol). All excipients comply with the relevant European Pharmacopoeia monographs with the exception of masking flavour 501482 TP0424 and banana durarome flavour 501392 TDI0991, cherry flavour 501027 AP0551 and banana flavour 501013 AP0551 which comply with an in-house specification and trisodium phosphate anhydrous (E339) and sucralose (E955) which are covered by national formulary. Satisfactory Certificates of Analysis have been provided for these excipients. The above excipients do not contain materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of this product. Pharmaceutical Development The objective of the pharmaceutical development programme was to obtain a stable oral suspension containing azithromycin anhydrous that could be considered a generic medicinal product of Zithromax 200 mg/ 5 ml Powder for Oral Suspension (Pfizer Limited). Suitable pharmaceutical development data have been provided for this application. Comparative dissolution and impurity profiles have been provided for the proposed and originator products. Manufacture Satisfactory batch formula has been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated and has shown satisfactory results. Process validation data on commercial batches have been provided. The results are satisfactory. Finished Product Specifications The finished product specification is satisfactory. Test methods have been described and adequately validated. Batch data have been provided and comply with the release specifications. Certificates of Analysis have been provided for any working standards used.

Container Closure System The packs of powder are contained in high density polyethylene (HDPE) bottle with a child resistant closure in a carton box. All packs contain a 10 ml oral dosing syringe with detachable adaptor. 600 mg powder (15 ml) pack (recommended for use in children up to 7 years (25 kg)) reconstitute with 9 ml of water to give 15 ml suspension. 900 mg powder (22.5 ml) pack (recommended for use in children aged from 8-11 years (26-35 kg) reconstitute with 12 ml of water to give 22.5 ml suspension. 1200 mg powder (30 ml) pack (recommended for use in children aged from 12-14 years (36-45 kg)) reconstitute with 15 ml of water to give 30 ml suspension. Specifications and Certificates of Analysis for the primary packaging material have been provided. These are satisfactory. All primary packaging is controlled to European Pharmacopoeia standards and complies with relevant guidelines. Stability Finished product stability studies have been conducted in accordance with current guidelines and in the

packaging proposed for marketing.


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Based on the results, shelf-lives of 24 months for unopened pack and 10 days once reconstituted with water have been set. This medicinal product does not require any special storage conditions. These are satisfactory. Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SPC, PIL and labelling are pharmaceutically satisfactory. A package leaflet has been submitted to the MHRA together with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet 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 the package leaflet contains. Marketing Authorisation Application (MAA) Form The MAA form is pharmaceutically satisfactory. Expert Report/Quality Overall Summary A quality overall summary has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion There are no objections to the approval of this product from a pharmaceutical point of view. III.2 NON-CLINICAL ASPECTS PHARMACODYNAMICS, PHARMACOKINETICS, TOXICOLOGY The pharmacological, pharmacokinetic and toxicological properties of azithromycin anhydrous are well-known. No new non-clinical data have been supplied with this application and none are required for applications of this type. The non-clinical expert report has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier. A suitable justification has been provided for the non-submission of the environmental risk assessment. There are no objections to the approval of this product from a non-clinical point of view. III.3 CLINICAL ASPECTS CLINICAL PHARMACOLOGY To support this application, the Marketing Authorisation Holder submitted the following bioequivalence study: An open label, balanced, randomised, two treatment, two-period, two sequence, single-dose, crossover, comparative oral bioavailability study of Azithromycin 200 mg/ 5 ml powder for oral suspension (Wockhardt Limited, India) and Zithromax Suspension 200 mg/5 ml Powder for Oral Suspension (Pfizer Italia S.r.l.,Strada Statale, Latina, Italy) in healthy subjects under fasting conditions. Blood samples were taken for plasma levels pre-dose and at 0.50, 1.00, 1.333, 1.667, 2.00, 2.333, 2.667, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 8.00, 12.00, 24.00, 36.00, 48.00 and 72.00 hours post dose in each period. The wash-out period was 21 days between the treatments.


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Results Geometric Least Squares Mean, ratios and 90% Confidence Interval for Azithromycin (n=50)

Cmax maximum plasma concentration AUC0-72 area under the plasma concentration-time curve from time zero to 72 hours CV coefficient of variation Ratios and 90% CI calculated from log-transformed data

The 90% confidence intervals for the primary variables AUC0-72 and Cmax are well within the acceptance range of 80.00% -125.00%. Bioequivalence has been demonstrated between the test formulation (Azithromycin 200 mg/ 5 ml powder for oral suspension) and the reference formulation (Zithromax Suspension 200 mg/5 ml Powder for Oral Suspension). EFFICACY No new efficacy data have been submitted and none are required for this application. SAFETY No new safety data have been submitted and none are required for this application. EXPERT REPORT The clinical overview is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The SmPC is medically satisfactory and consistent with that for the reference product. PATIENT INFORMATION LEAFLET The PIL is medically satisfactory and consistent with the SPC. LABELLING The labelling is medically satisfactory. Marketing Authorisation Application (MAA) form The MAA form is satisfactory from a clinical perspective. CONCLUSION There are no objections to the approval of this product from a clinical point of view.


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IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Azithromycin 200 mg/5 ml Powder for Oral Suspension 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. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. CLINICAL Bioequivalence has been demonstrated between the applicant’s Azithromycin 200 mg/5 ml Powder for Oral Suspension and the reference product, Zithromax Suspension 200 mg/5 ml Powder for Oral Suspension. No new or unexpected safety concerns arise from this application. The SmPC and PIL are satisfactory and consistent with those of the reference product. Satisfactory labelling has also been submitted. RISK-BENEFIT ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. Extensive clinical experience with azithromycin anhydrous is considered to have demonstrated the therapeutic value of the compound. The risk-benefit is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

Documents

Public Assessment Report Decentralised Procedure ... · PAR Azithromycin 200 mg/5 ml Powder for Oral Suspension UK/H/5115/001/DC 2 Azithromycin 200 mg/5 ml Powder for Oral Suspension