Public Assessment Report
Scientific discussion
Bicalutamide Farmaprojects 150 mg
Bicasil (Morenomide) 150
Bicalutamide Nycomed 150 mg
Apo-Bicalutamid (Apo-Bical) 150
Bicalutamide
This module reflects the scientific discussion for the approval of Bicalutamide Farmaprojects
150mg, Bicasil (Morenomide) 150, Bicalutamide Nycomed 150mg and Apo-Bicalutamid (ApoBical) 150. The procedure was finalised 18 November 2008. However this procedure was further
referred to CMD, and the referral was finalised on 27 January 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/140/02/DC, Farmaprojects S.A., Barcelona, Spain is applying for marketing authorization for
Bicalutamide Farmaprojects 150 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/141/02/DC, Farmaprojects S.A., Barcelona, Spain is applying for marketing authorization for
Bicasil 150 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/143/02/DC, Nycomed AB, Stockholm, Sweden is applying for marketing authorization for
Bicalutamide Nycomed 150 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/144/02/DC, , Leiden, The Netherlands is applying for marketing authorization for ApoBicalutamid 150 according to Article 10(1) so called “generic application”, also in following
Concerned Member States: Poland and United Kingdom.
II.
QUALITY ASPECTS
II.1
Introduction
Bicalutamide 150 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 150 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 150 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
CZ/H/0140/002/IB/005
IB/7c
Addition of a manufacturing site for Approved
(+7a+7b1+8b2) all other manufacturing operation 30.12.2009
except batch release – Excella
GmbH, Feucht, Germany
IB/33
Minor change in the manufacture of Approved
CZ/H/0140/002/IB/006
Nature of change
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Status/date
the finished product - due to the
addition of Excella GmbH as
manufacturing site
Addition of secondary packaging
site for all types of pharmaceutical
forms – alternative manufacturer:
Specifar SA (only applicable for
Greece)
Inclusion of a new Bioequivalence
study, it performed as per the
commitment acquired during the
referral procedure
4.11.2009
Nature of change
Status/date
CZ/H/0140/002/IA/009
IA/7a
CZ/H/0140/002/II/010
II C.Iz
No.
No. of
change
CZ/H/0141/002/IB/002
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
Approved
23.12.2009
No.
No. of
change
Status/date
CZ/H/0143/002/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
Approved
17.2.2010
No.
No. of
change
Status/date
CZ/H/0144/002/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
II/C.Iz
Submission of a new Bioequivalence
study
CZ/H/0141/002/IB/003
CZ/H/0143/002/IB/002
CZ/H/0144/002/IB/002
CZ/H/0144/002/II/003
II.4
Nature of change
Nature of change
Discussion on chemical, pharmaceutical and biological aspects
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Positive
11.1.2010
Approved
6.8.2010
Approved
23.12.2009
Approved
17.2.2010
Approved
18.12.2009
Approved
30.10.2009
Approved
6.8.2010
III.
NON-CLINICAL ASPECTS
III.1
Introduction
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
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
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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 at the moment. The time
of exclusion of the 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.
The applicant has provided a justification for a biowaiver of BE study with 150 mg strength in a
response to MO raised by the RMS in the PrAR. This MO has been endorsed by a number of CMS
involved in the procedure at day 100 of the procedure.
Further arguments supporting the justification have been provided by the Applicant on Day 190: The
dossier fulfils criteria for BE required by the section 4.1.6 of the guideline on investigation of
bioequivalence. The study was performed with the 50mg, the highest acceptable dose in volunteers.
The CI for both AUC and Cmax of both (r)-and (s)- enantiomers are within the 90-111% interval.
At day 195, all MS involved in the procedure, except the UK, accepted the Applicant´s justification
and response to the initial major objection.
IV.3
Pharmacodynamics
N/A
IV.4
Clinical efficacy
N/A
IV.5
Clinical safety
Pharmacovigilance issues
The MAH has provided description of its pharmacovigilance system and Statement on EU-RMP. The
MAH convinced that routine pharmacovigilance activities are sufficient and therefore, according to
the MAH, there is no need for EU-RMP.
IV.6
Discussion on the clinical aspects
N/A
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V.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Bioequivalence for this procedure has been shown for 50mg strength. The applicant has provided a
justification for a biowaiver of BE study with 150 mg strength in a response to MO raised by the RMS
in the PrAR. This MO has been endorsed by a number of CMS involved in the procedure at day 100 of
the procedure.
At day 195, all MS involved in the procedure, except the UK, accepted the Applicant´s justification
and response to the initial major objection. The procedure was therefore referred to CMD.
Following the discussion in CMD(h) concerning the above mentioned referral, the RMS regarded the
raised questions on PSRPH as solved and proposed to finish the CMD(h)-Referral with a final positive
conclusion.
With regard to the commitments given by the applicants and as discussed in the CMD(h), the RMS
proposed to add the following commitment and to list it in the ‘End of procedure letter’:
“The applicant commits to perform a single-dose bioequivalence study with the 150 mg strength in
healthy volunteers. The applicant commits to submit the results of this bioequivalence study by means
of a type II variation prior to the launch of Bicalutamide 150 mg, film-coating tablets in United
Kingdom.”
Reason: The possibility of extrapolating the results of bioequivalence study with 50mg strength has
been questioned due to insufficiently shown linearity of bicaluamide pharmacokinetics. The additional
study will provide formal proof of bioequivalence for 150mg tablets.
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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