Public Assessment Report Decentralised Procedure Linezolid ... · PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC 3 For the full list of all side effects reported with Linezolid

Public Assessment Report

Decentralised Procedure

Linezolid 600 mg film-coated tablets

(Linezolid)

Procedure No: UK/H/6727/001/DC

UK Licence No: PL 22363/0018

Kappler Pharma Consult GmbH

PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC

2

Lay Summary

Linezolid 600mg film-coated tablets

(linezolid)

This is a summary of the Public Assessment Report (PAR) for Linezolid 600 mg film-coated tablets

(PL 22363/0018; UK/H/6727/001/DC). It explains how Linezolid 600 mg film-coated tablets was

assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide

practical advice on how to use Linezolid 600 mg film-coated tablets.

For practical information about using Linezolid 600 mg film-coated tablets, patients should read the

package leaflet or contact their doctor or pharmacist.

For ease of reading, the product will be referred to as ‘Linezolid tablets’ in this lay summary.

What are Linezolid tablets and what are they used for?

Linezolid tablets is a ‘generic medicine’ that is identical to a ‘reference medicine’, already authorised in

the European Union (EU) called Zyvox 600 mg film-coated tablets (Pharmacia Ltd; PL 00032/0261).

Linezolid 600 mg film-coated tablets are used to treat pneumonia and some infections in the skin or

under the skin. The prescribing doctor will decide if this medicine is suitable to treat the infection.

How do Linezolid tablets work?

Linezolid tablets contain the active ingredient linezolid, which is an antibiotic of the oxazolidinones

group that works by stopping the growth of certain bacteria (germs) that cause infections.

How are Linezolid used?

Linezolid tablets are taken by mouth. The whole tablet should be swallowed with some water.

The patient should always take this medicine exactly as their doctor or pharmacist has told them. The

patient should check with their doctor or pharmacist if they are not sure.

For adults, the usual dose is one tablet (600 mg linezolid) twice daily (every twelve hours). A course of

treatment usually lasts 10 to 14 days but can last up to 28 days.

Linezolid Tablets are not normally used in children and adolescents under 18 years old.

This medicine can only be obtained with a prescription.

Please read Section 3 of the package leaflet for detailed information on dosing recommendations, the

route of administration and the duration of treatment.

What benefits of Linezolid tablets have been shown in studies?

Because Linezolid tablets is a generic medicine, studies in patients have been limited to tests to

determine that it is bioequivalent to the reference product, Zyvox 600 mg film-coated tablets (Pharmacia

Limited). Two medicines are bioequivalent when they produce the same levels of the active substance in

the body.

What are the possible side effects of Linezolid tablets?

As Linezolid tablets is a generic medicine of the reference medicine, Zyvox 600 mg film-coated tablets,

its possible side effects are taken as being the same as the reference medicine.

For the full list of restrictions, see the package leaflet.


3

For the full list of all side effects reported with Linezolid tablets, see section 4 of the package leaflet

available on the MHRA website.

Why was Linezolid tablets approved?

It was concluded that, in accordance with EU requirements, Linezolid tablets have been shown to have

comparable quality and to be bioequivalent to Zyvox 600 mg film-coated tablets. Therefore, the view

was that, as for Zyvox 600 mg film-coated tablets, the benefits outweigh the identified risks.

What measures are being taken to ensure the safe and effective use of Linezolid tablets?

A Risk Management Plan (RMP) has been developed to ensure that Linezolid tablets are used as safely

as possible. Based on this plan, safety information has been included in the Summary of Product

Characteristics (SmPC) and the package leaflet for this product, including the appropriate precautions to

be followed by healthcare professionals and patients.

Known side-effects are continuously monitored. Furthermore new safety signals reported by patients

and healthcare professionals will be monitored and reviewed continuously as well.

Other information about Linezolid tablets

The UK agreed to grant a Marketing Authorisation for Linezolid tablets on 26 June 2018. A Marketing

Authorisation was granted in the UK to Kappler Pharma Consult GmbH on 23 July 2018.

The full PAR for Linezolid tablets follows this summary.

For more information about treatment with Linezolid tablets, read the package leaflet or contact your

doctor or pharmacist.

This summary was last updated in September 2018


4

TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 6

III Non-clinical aspects Page 8

IV Clinical aspects Page 9

V User consultation Page 10

VI Overall conclusion, benefit/risk assessment and Page 10

recommendation

Table of content of the PAR update for MRP and DCP Page 14


5

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the UK considered that the application

for Linezolid tablets (PL 22363/0018; UK/H/6727/001/DC) could be approved. The product may be

referred to as ‘Linezolid tablets’ in this scientific discussion.

The product, Linezolid tablets, is a prescription-only medicine (legal status POM) and is indicated in

adults for the treatment of:

- community acquired pneumonia and nosocomial pneumonia when known or suspected to be

caused by susceptible Gram positive bacteria. In determining whether Linezolid is an appropriate

treatment, the results of microbiological tests or information on the prevalence of resistance to

antibacterial agents among Gram positive bacteria should be taken into consideration.

Linezolid is not active against infections caused by Gram negative pathogens. Specific therapy

against Gram negative organisms must be initiated concomitantly if a Gram negative pathogen is

documented or suspected.

- complicated skin and soft tissue infections only when microbiological testing has established that

the infection is known to be caused by susceptible Gram positive bacteria. Linezolid is not active

against infections caused by Gram negative pathogens. Linezolid should only be used in patients

with complicated skin and soft tissue infections with known or possible co-infection with Gram

negative organisms if there are no alternative treatment options available. In these circumstances

treatment against Gram negative organisms must be initiated concomitantly.

Use of Linezolid should only be initiated in a hospital environment and after consultation with a relevant

specialist such as a microbiologist or infectious diseases specialist. Consideration should be given to

official guidance on the appropriate use of antibacterial agents.

This application was submitted using the Decentralised Procedure (DCP), with the UK as Reference

Member State (RMS), and Luxembourg as Concerned Member State (CMS); subsequently,

Luxembourg was withdrawn during the procedure.

This application for Linezolid tablets was submitted under Article 10.1 of Directive 2001/83/EC, as

amended, claiming to be a generic medicinal product of the reference medicinal product Zyvox 600 mg

film-coated tablets (PL 00032/0261; Pharmacia Ltd) which was first licensed in the UK on 05 January

2001.

Linezolid tablets contain the active substance, linezolid. Linezolid is a synthetic, antibacterial agent that

belongs to a class of antimicrobials called oxazolidinones. It has in vitro activity against aerobic Gram

positive bacteria and some anaerobic micro-organisms. Linezolid selectively inhibits bacterial protein

synthesis by binding to a site on the bacterial ribosome (23S of the 50S subunit) and preventing the

formation of a functional 70S initiation complex, which is an essential component of the translation

process.

No new non-clinical data were submitted, which is acceptable given that the application was based on

being a generic medicinal product of reference product that has been in clinical use for over 10 years.

A suitable justification for a Biopharmaceutics Classification System (BCS) - based biowaiver was

provided. To further support the application, the results from a bioequivalent study with a 600 mg

strength tablet formulation was provided. With the exception of the bioequivalence study, no new

clinical data was provided to support this application; which is acceptable.


6

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in

place for these product types at all sites responsible for the manufacture, assembly and batch release 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.

For manufacturing sites outside the Community, the RMS has accepted copies of current GMP

Certificates of satisfactory inspection summary reports, as certification that acceptable standards of

GMP are in place at those non-Community sites.

The UK considered that the application could be approved at the end of procedure (Day 210) on 26 June

2018. After a subsequent national phase, a Marketing Authorisation (PL 22363/0018) was granted in the

UK to Kappler Pharma Consult GmbH on 23 July 2018.

II QUALITY ASPECTS

II.1 Introduction This application is submitted according to Article 10.1 of Directive 2001/83/EC, as amended.

The submitted documentation concerning the proposed product is of sufficient quality and meets the

current EU regulatory requirements.

The quality overall summary has been written by an appropriately qualified person and is a suitable

summary of the pharmaceutical aspects of the dossier.

The product is an oblong, biconvex, white to off-white film-coated tablet; each tablet contains 600 mg of

linezolid, as active substance. The products also contain pharmaceutical excipients in the tablet core and

coating, namely silicified microcrystalline cellulose (consisting of cellulose microcrystalline and silica

colloidal anhydrous), sodium starch glycolate (type A), cellulose, microcrystalline, povidone K90,

magnesium stearate, hypromellose, propylene glycol, titanium dioxide (E171) and talc. Appropriate

justification for the inclusion of each excipient has been provided.

All excipients used comply with their respective European Pharmacopoeia monographs with the

exception of silica colloidal anhydrous which complies to its United States Pharmacopoeia (USP)

monograph.

None of the excipients contain materials of animal or human origin.

The product does not contain or consist of genetically modified organisms (GMO).

The finished product is packaged in polyvinylchloride/polyvinyldene chloride-aluminium foil blisters, in

a pack size of 10 film-coated tablets packaged in a carton. Satisfactory specifications and Certificates of

Analysis have been provided for all packaging components. All primary packaging complies with the

current European regulations concerning materials in contact with food.

II.2 Drug Substance

INN: Linezolid

Chemical Name: N-[[(5S)-3-[3-Fluoro-4-(4-morpholinyl) phenyl]-2-oxo –5- oxazolidinyl]methyl]

acetamide


7

Structural formula:

Molecular formula: C16H20FN3O4

Mr: 337.35

Appearance: White to off-white crystalline powder or crystals.

Solubility: Linezolid is freely soluble in chloroform, sparingly soluble in methanol.

Chirality: Linezolid is a chiral compound and exhibits isomerism (optically active)

Polymorphism Linezolid exhibits polymorphism.

Linezolid is not the subject of a European Pharmacopoeia monograph.

Synthesis of the active substance from the designated starting materials has been adequately described

and appropriate in-process controls and intermediate specifications are applied. Satisfactory

specification tests are in place for all starting materials and reagents, and these are supported by relevant

Certificates of Analysis. No materials of animal or human origin are used in the production of the active

substance.

Appropriate proof-of-structure data have been supplied for the active substance. All potential impurities

have been identified and monitored appropriately.

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 all working standards.

Suitable specifications have been provided for all packaging used. The primary packaging has been

shown to comply with current guidelines concerning contact with food.

Appropriate stability data have been provided supporting a suitable retest period when stored in the

proposed packaging.

II.3 Medicinal Product

Pharmaceutical development

The objective of the development programme was to formulate safe, efficacious, film-coated tablets

containing 600 mg linezolid that are bioequivalent to the reference product Zyvox 600 mg film-coated

tablets.

Comparative dissolution and impurity profiles have been presented for the proposed and reference

products.


8

Manufacture of the product

A satisfactory batch formula has been provided for the manufacture of the product, along with an

appropriate account of the manufacturing process. Based on pilot-scale batches, the manufacturing

process has been validated and has shown satisfactory results. The Marketing Authorisation Holder has

committed to performing process validation studies on the first three full-scale production batches.

Control of Finished Product

The finished product specification is satisfactory. The test methods have been described and adequately

validated. Batch data have been provided that comply with the release specifications. Certificates of

Analysis have been provided for any working standards used.

Stability of the product

Finished product stability studies have been conducted in accordance with current guidelines and in the

packaging proposed for marketing.

Based on the results, a shelf life of 5 years with no special storage conditions, has been approved.

Bioequivalence/Bioavailability

A suitable justification and supporting data for a BCS - based biowaiver have been submitted for this

application.

II.4 Discussion on chemical, pharmaceutical and biological aspects

The grant of a Marketing Authorisation is recommended, from a quality point of view.

III NON-CLINICAL ASPECTS

III.1 Introduction The pharmacodynamic, pharmacokinetic and toxicological properties of linezolid are well known. As

linezolid is a widely used, well-known active substance, no new non-clinical data have been supplied

and none are required for this type of application.

The applicant’s non-clinical overview has been written by an appropriately qualified person and is

satisfactory, providing an appropriate review of the relevant pharmacology and toxicology.

III.2 Pharmacology

No new data have been submitted and none are required for this type of application. Refer to Section

III.1 Introduction, above.

III.3 Pharmacokinetics



III.4 Toxicology



III.5 Ecotoxicity/environmental risk assessment (ERA)

The Marketing Authorisation Holder has provided adequate justification for not submitting an

Environment Risk Assessment (ERA). Since Linezolid tablets are intended for generic substitution, this

will not lead to an increased environmental exposure. An environmental risk assessment (ERA) is

therefore not deemed necessary.

III.6 Discussion on the non-clinical aspects

There are no objections to the approval of this product, from a non-clinical point of view.


9

IV CLINICAL ASPECTS

IV.1 Introduction

The pharmacodynamic, pharmacokinetic, clinical efficacy and safety properties of linezolid are well

known. An overview based on literature review is considered appropriate.

The applicant’s clinical overview has been written by an appropriately qualified person and is

considered acceptable.

According to current regulatory requirements, a bioequivalence study should be submitted for the

immediate release product to claim essential similarity with the reference product. A BCS based

biowaiver may be acceptable for specific types of products.

A case for a BCS based biowaiver in accordance with Appendix III of EMA Guideline on the

Investigation of Bioequivalence (Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) has been

submitted, as linezolid qualifies as BCS class-I compound. Appropriate comparative data have

been provided against the reference products. The case for BCS based biowaiver is acceptable. In

addition, the applicant has made reference to the results of a bioequivalence study using a 600 mg

tablet formulation. The results from this study demonstrated bioequivalence between the 600 mg

formulation and the reference product under fasting conditions. This data was considered

supportive and will not be discussed further.

IV.2 Pharmacokinetics

The pharmacokinetic profile of linezolid is well known. No new clinical pharmacokinetic data is

provided or required for this application.

A BCS Class I biowaiver justification has been submitted along with comparative impurity and

dissolution data for the finished drug product versus the reference product. This is acceptable.

IV.3 Pharmacodynamics

The clinical pharmacodynamic profile of linezolid is well-known. No new pharmacodynamic data were

submitted and none are required for this type of application.

IV.4 Clinical efficacy

The clinical efficacy of linezolid is well-known. No new efficacy data are presented for this application

and none are required. Efficacy is adequately reviewed in the clinical overview.

IV.5 Clinical safety

No new safety data are presented for this application and none are required. The safety profile of

linezolid is well-known and has been adequately summarised in the clinical overview. No new or

unexpected safety concerns arose from this application.

IV.6 Risk Management Plan (RMP)

The Marketing Authorisation Holder (MAH) has submitted an RMP, in accordance with the

requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and

interventions designed to identify, characterise, prevent or minimise risks relating to Linezolid tablets.

A summary of safety concerns in listed in the table below:


10

Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.

IV.7 Discussion on the clinical aspects

The grant of a Marketing Authorisation is recommended for this application, from a clinical point of

view.

V USER CONSULTATION

A user consultation with target patient groups on the Patient Information Leaflet (PIL) has been

performed on the basis of a bridging report making reference to the PIL for “Linezolid STADA 600mg

film-coated tablets (DE/H/3489 and 3490/001/DC) ”. The bridging report is acceptable.

VI OVERALL CONCLUSION, BENEFIT-RISK ASSESSMENT AND

RECOMMENDATION

The quality of the product is acceptable, and no new non-clinical or clinical concerns have been

identified. A suitable justification and supporting data for a BCS – based biowaiver has been accepted.

The data provided by the applicant showed that the test product is comparable to the reference product.

Extensive clinical experience with linezolid is considered to have demonstrated the therapeutic value of

the compound.

The benefit/risk balance is, therefore, considered to be positive.

The grant of a Marketing Authorisation is recommended.


11

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling

In accordance with Directive 2010/84/EU the current version of the Summary of Product Characteristics

(SmPC) and Patient Information Leaflet (PIL) is available on the MHRA website.

The labelling text below is that agreed at the end of the Decentralised Procedures (UK/H/6727/001/DC).

The Marketing Authorisation Holder has committed to submit the labelling for review to the regulatory

authorities before marketing the product.


12


13


14

Table of content of the PAR update for MRP and DCP

Steps taken after the initial procedure with an influence on the Public Assessment Report

Scope Procedure

number

Product

information

affected

Date of

start of the

procedure

Date of end

of

procedure

Approval/

non

approval

Assessment

report

attached

Y/N

(version)

Documents

Public Assessment Report Decentralised Procedure Linezolid ... · PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC 3 For the full list of all side effects reported with Linezolid