Download III. Non-clinical aspects

Public Assessment Report
Scientific discussion
Bicalutamide Farmaprojects 50 mg
Bicasil (Morenomide) 50
Bicalutamide Nycomed 50 mg
Apo-Bicalutamid (Apo-Bical) 50
Bicalutamide
This module reflects the scientific discussion for the approval of Bicalutamide Farmaprojects
50mg, Bicasil (Morenomide) 50, Bicalutamide Nycomed 50mg and Apo-Bicalutamid (Apo-Bical)
50. The procedure was finalised at 23 April 2008. For information on changes after this date
please refer to the module ‘Update’.
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I.
INTRODUCTION
This is an abridged application according to Article 10(1) so called “generic application”,
Essential similarity is claimed for the generic formulation of Bicalutamide 50mg film-coated tablets to
the European brand leader marketed by AstraZeneca UK Ltd, Casodex.
With the Czech Republic as the Reference Member State in the Decentralised Procedure
CZ/H/140/01/DC, Farmaprojects S.A., Barcelona, Spain is applying for marketing authorization for
Bicalutamide Farmaprojects 50 mg according to Article 10(1) so called “generic application”, also in
following Concerned Member States: Spain, Germany, Italy, Greece, United Kingdom and Ireland.
With the Czech Republic as the Reference Member State in the Decentralised Procedure
CZ/H/141/01/DC, Farmaprojects S.A., Barcelona, Spain is applying for marketing authorization for
Bicasil 50 according to Article 10(1) so called “generic application”, also in following Concerned
Member States: Italy and Greece.
With the Czech Republic as the Reference Member State in the Decentralised Procedure
CZ/H/143/01/DC, Nycomed AB, Stockholm, Sweden is applying for marketing authorization for
Bicalutamide Nycomed 50 mg according to Article 10(1) so called “generic application”, also in
following Concerned Member States: Sweden, Denmark and Norway.
With the Czech Republic as the Reference Member State in the Decentralised Procedure
CZ/H/144/01/DC, Apotex Europe BV, Leiden, The Netherlands is applying for marketing
authorization for Apo-Bicalutamid 50 according to Article 10(1) so called “generic application”, also
in following Concerned Member States: The Netherlands, Poland and United Kingdom.
II.
QUALITY ASPECTS
II.1
Introduction
Bicalutamide 50 mg tablets are white, round, biconvex, film-coated tablets.
The product is packed into PVC/aluminium blisters. Blisters are inserted, together with a package
leaflet into a paper folding box.
II.2
2.2
Drug Substance
Bicalutamide (ATC classification L02BB03, CAS number 90357-06-5) is a pure non-steroidal
antiandrogen lacking any other endocrine activity. Specifically, it acts as a competitive inhibitor for
binding of dihydrotestosterone and testosterone to cytosolic receptors in target cells. The compound
has shown efficacy in the treatment of advanced prostate cancer.
The active substance is Bicalutamide, chemical name N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4fluorophenyl)sulphonyl]-2-hydroxy-2-methylpropanamide. No monograph of Bicalutamide has been
published in the Ph.Eur. Detailed information relating to the drug substance was submitted by EDMF
(European Drug Master File) procedure. The Letter of Access was presented including the
confirmation from the manufacturer of the active substance.
The chemical structure was sufficiently characterized. Bicalutamide exhibits polymorphism. The
combination of analytical studies confirms the structure of Bicalutamide –Form HI. Manufacture has
been described in detail.
The control of the quality was described sufficiently. All of the analytical tests used have been
satisfactorily described. Certificates of analysis have been provided. Results comply with the proposed
specification and confirm the consistency of the process.
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Packaging materials conform to the European standards, compliance certificates of EC guidelines are
provided.
The stability data are in line with ICH guideline and support the proposed re-test period of 3 years
without specific storage conditions.
II.3
Medicinal Product
Bicalutamide 50 mg exists as film-coated tablets. The qualitative and quantitative composition is
detailed for the core and the film-coating.
All excipients are common pharmaceutical grade products covered by Ph.Eur. monography.
Satisfactory Certificates of Analysis of all excipients have been provided. For the excipients that have
not been manufactured using material of animal origin, statements by the manufacturers confirming
that during the manufacturing process no materials of animal origin were use and thus these
compounds are free from TSE related problems, has been given.
The only material of animal origin is lactose monohydrate and it is manufactured in compliance with
CPMP guideline.
The development of the medicinal product has been sufficiently described; the essential similarity,
based on comparison of dissolution profiles, impurity profiles and bioequivalence with brand leader
Casodex, has been documented.
The manufacturing process can be considered as standard. The manufacture and in-process controls
are fully described in the dossier. Results of process validation have been submitted. It may be
concluded that the manufacturing process has been shown to be reliable and capable of consistently
producing a product that complies with pre-established quality and specifications.
The proposed specification is acceptable. Satisfactory control tests are applied at time of release and
during the shelf-life. Release and shelf life limits for the assay of Bicalutamide are in line with batch
and stability data. Limits for related substances comply with ICH guidelines.
Analytical methods have been satisfactorily described and validated in accordance with regulatory
requirements.
Results of analysis for three pilot batches of Bicalutamide 50 mg have been given in documentation.
All results complied with the specifications and demonstrate consistent manufacture.
The immediate packaging material is a PVC/aluminium blister. Satisfactory specifications for blister
and certificates of analysis have been provided. The packaging material complies with Ph.Eur. and EU
directives.
Stability trials were performed on the drug product according to the stability protocols and ICH
guidelines. Based on the data shelf-life of 3 years with no special conditions of storage can be granted.
The chemical-pharmaceutical documentation is well-arranged and of sufficient quality. Based on the
assessment, the product is approvable from the quality point.
Update: List of approved variations:
No.
No. of
change
Nature of change
Status/date
CZ/H/0140/001/IB/001
IB/2
Approved
28.8.2009
CZ/H/0140/001/IA/002
IA/7a
Change in the name of the medicinal
product in Spain from Bicalutamida
Farmaprojects
50
mg
to
Bicalutamida APOTEX 50 mg
Addition of secondary packaging
site for all types of pharmaceutical
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Positive
17.8.2009
CZ/H/0140/001/IB/003
CZ/H/0140/001/IB/004
CZ/H/0140/001/IB/005
CZ/H/0140/001/IB/006
CZ/H/0140/001/IA/007
CZ/H/0140/001/IA/008
forms – alternative manufacturer:
Specifar SA, Athens, Greece (only
applicable for Greece)
IB/2
Change in the name of the medicinal
product in Germany
IB/41/a2
Change in pack size of the finished
product from 28 and 30 tablets to 28,
30 and 90 tablets
IB/7c
Addition of a manufacturing site for
(+7a+7b1+8b2) all other manufacturing operation
except batch release – Excella
GmbH, Feucht, Germany
IB/33
Minor change in the manufacture of
the finished product - due to the
addition of Excella GmbH as
manufacturing site
IA/32a
Change in batch size of the finished
product – up to 10-fold compared to
the original batch size approved at
the grant of the MA
IA/7a
Addition of secondary packaging
site for all types of pharmaceutical
forms – alternative manufacturer:
Lisapharm S.p.A. (only applicable
for Italy)
No.
No. of
change
CZ/H/0141/001/IB/001
IB/2
Nature of change
Approved
17.9.2009
Approved
17.9.2009
Approved
30.12.2009
Approved
4.11.2009
Positive
19.10.2009
Positive
11.1.2010
Status/date
Change in the name of the medicinal
product in Italy from Bicalutamide
VantagePharma to Lutamid
IB/7c
Addition of a manufacturing site for
(+7a+7b1+8b2) all other manufacturing operation
except batch release – Excella
GmbH, Feucht, Germany
IB/33
Minor change in the manufacture of
the finished product due to the
addition of Excella GmbH as
manufacturing site
IA/32a
Change in batch size of the finished
product – up to 10-fold compared to
the original batch size approved at
the grant of the MA- due to the new
manufacturing site Excella GmbH
Approved
5.1.2009
No.
No. of
change
Status/date
CZ/H/0143/001/IB/001
IB/7c
Addition of a manufacturing site for
(+7a+7b1+8b2) all other manufacturing operation
except batch release – Excella
GmbH, Feucht, Germany
IB/33
Minor change in the manufacture of
the finished product due to the
addition of Excella GmbH as
manufacturing site
IA/32a
Change in batch size of the finished
CZ/H/0141/001/IB/002
CZ/H/0141/001/IB/003
CZ/H/0141/001/IA/004
CZ/H/0143/001/IB/002
CZ/H/0143/001/IA/003
Nature of change
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Approved
23.12.2009
Approved
23.12.2009
Positive
7.12.2009
Approved
17.2.2010
17.2.2010
Positive
product – up to 10-fold compared to 01.02.2010
the original batch size approved at
the grant of the MA- due to the new
manufacturing site Excella GmbH
No.
No. of
change
CZ/H/0144/001/IA/001
IA/2
CZ/H/0144/001/IB/002
CZ/H/0144/001/IB/003
CZ/H/0144/001/IB/004
CZ/H/0144/001/IB/005
CZ/H/0144/001/IA/006
Nature of change
Change in the adress of MAH for
PL, UK, CZ from Archimedesweg 2,
Leiden, NL to proposed Darwinweg
20, Leiden, NL
IB/2
Change in the name of the medicinal
product in Poland from Bicamid to
Bicalutamide Apotex
IB/2
Change in the name of the medicinal
product in the Netherlands from
Bicalutamide 50 mg Katwijk to
Bicalutamide Apotex
IB/7c
Addition of a manufacturing site for
(+7a+7b1+8b2) all other manufacturing operation
except batch release – Excella
GmbH, Feucht, Germany
IB/33
Minor change in the manufacture of
the finished product - due to the
addition of Excella GmbH as
manufacturing site
IA/32a
Change in batch size of the finished
product – up to 10-fold compared to
the original batch size approved at
the grant of the MA- due to the new
manufacturing site Excella GmbH
II.4
Discussion on chemical, pharmaceutical and biological aspects
III.
NON-CLINICAL ASPECTS
III.1
Introduction
Status/date
Positive
30.9.2008
Approved
16.10.2008
Approved
5.6.2009
Approved
18.12.2009
Approved
30.10.2009
Positive
14.10.2009
Pharmacodynamic and pharmacokinetic properties of bicalutamide are well known. As it is a widely
used, well-known active substance, no further studies are required and the applicant provides none.
Overview based on literature review is, thus, appropriate.
The non-clinical overview on the pre-clinical pharmacology and toxicology is adequate.
III.2
Pharmacology
N/A
III.3
Pharmacokinetics
N/A
III.4
Toxicology
N/A
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III.5
Ecotoxicity/environmental risk assessment
N/A
III.6
Discussion on the non-clinical aspects
No objections to the approval of bicalutamide film-coated tablets were raised by the RMS or CMS
from a non-clinical point of view.
IV.
CLINICAL ASPECTS
IV.1
Introduction
No new preclinical studies and no clinical studies were conducted, which is acceptable given that the
applications were based on essential similarity to a product that has been licensed for more than 10
years. The application contains an adequate review of published clinical data.
IV.2
Pharmacokinetics
Pharmacokinetic properties of bicalutamide:
Absorption
Bicalutamide is well absorbed after oral administration, although the absolute bioavailability is still
unknown. Co-administration of bicalutamide with food has no clinically significant effects on the rate
and extent of absorption.
Distribution
The drug is highly bound to plasma proteins (96%).
Metabolism and Elimination
Stereoselective metabolism is described for bicalutamide. The S isomer (inactive) is metabolized by
glucuronidation. The R isomer (active) undergoes mainly oxidation to inactive metabolite, which is
further glucuronized. Minor pathway of R isomer is direct glucoronidation. The S- isomer is rapidly
cleared relative to R isomer, with R enantiomer accounting for approximately 99% of total steady state
plasma levels. Both the parent compound and metabolites are excreted in urine and feces.
To support this abridged application, so called “generic application”, the applicant has submitted 2
bioequivalence studies, one of which did not demonstrate bioequivalence. Insufficiently justified
exclusions of subjects (study BCD-P5.010) based on PK data strongly suggest, that the truth results
lie even more far away from the bioequivalence range than the data presented. The time of exclusion
of subjects and the mechanism by which the subjects have been excluded also show improper way of
conducting the study and analysing the data.
The other study (60227) has been conducted at different study site with cross-over design and the
overall conduct seems to be more reliable, as well. Therefore the results of this study can be
considered reliable, while the results of BCD-P5.010 reflect low standardization and thus lower
sensitivity to describe the PK differences between products. The rationale for exclusion of study
subjects in BCD-P5.010 was later given, however in the assessors opinion is not of much importance
since the BE conclusion is unequivocally demonstrated by study No. 60227. Both studies were
conducted with 50mg strength of reference product Casodex.
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IV.3
Pharmacodynamics
N/A
IV.4
Clinical efficacy
N/A
IV.5
Clinical safety
Pharmacovigilance issues
Based on the available information, it is concluded that there is no important new safety information.
The proposed wording of SPC reflects up to date knowledge and recommendations.
The MAH has submitted the RMP. According to this MAH´s RMP, no safety concerns requiring
additional risk minimization activities have been identified. The MAH is convinced that routine
pharmacovigilance activities are completely sufficient for identified safety concerns and do not
consider additional risk minimisations activities necessary for this product.
IV.6
Discussion on the clinical aspects
N/A
V.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
User consultation
The user consultation was done by interview with potential consumers. The population characteristic
was in compliance with characteristics of the population possibly using this product. Each question
was answered and interpreted by 20 users. Correct answers represented more than the requested
minimum of 80%. The Package leaflet for bicalutamide coated tablets has been shown to provide the
tested consumer with all required information in a clear and comprehensive form and the Readability
testing was performed according to the guidelines.
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