Upload
dinhquynh
View
230
Download
0
Embed Size (px)
Citation preview
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.
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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.
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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.
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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
No new data have been submitted and none are required for this type of application. Refer to Section
III.1 Introduction, above.
III.4 Toxicology
No new data have been submitted and none are required for this type of application. Refer to Section
III.1 Introduction, above.
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.
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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:
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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.
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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.
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
12
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
13
PAR Linezolid 600 mg film-coated tablets UK/H/6727/001/DC
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)