Zusammenfassung der Merkmale des Arzneimittels - Abirateron Polisano 250 mg Filmtabletten
Decentralised Procedure
Abirateron Polisano 250 mg Filmtabletten
Abirateron Polisano 500 mg Filmtabletten
Procedure-Number: DE/H/7465/001–002/DC
Active Substance:
Abiraterone Acetate
Dosage Form: Film-coated tablet
Applicant:
Polisano Pharmaceuticals SA
Publication:
13.09.2023
This module reflects the scientific discussion for the approval of the above-mentioned procedure. The procedure was finalised on 22.06.2023.
II.4 G eneral comments on compliance with GMP, GLP, GCP and agreed ethical
V RECOMMENDATIONS AND CONDITIONS FOR MARKETING AUTHORISATION
V.1 L ist of recommendations not falling under A rticle 21 a /22 of D irective
| Proposed name of the medicinal product in the RMS | Abirateron Polisano 250 mg Filmtabletten Abirateron Polisano 500 mg Filmtabletten |
| Name of the drug substance (INN name): | Abiraterone Acetate |
| Pharmaco-therapeutic group (ATC Code): | L02BX03 |
| Pharmaceutical form(s) and strength(s): | Film-coated tablet, 250 mg + 500 mg |
| Reference Number(s) for the Decentralised Procedure | DE/H/7465/001–002/DC |
| Reference Member State: | DE |
| Concerned Member States: | RO |
| Legal basis of application: | Generic Art 10.1 and 10.2 Dir 2001/83/EC |
| Applicant (name and address) | POLISANO PHARMACEUTICALS S.A., Șos. Alba Iulia, Nr. 156, cod 550052, Sibiu, jud. Sibiu, România |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | POLISANO PHARMACEUTICALS S.A., Șos. Alba Iulia, Nr. 156, cod 550052, Sibiu, jud. Sibiu, România |
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Abirateron Polisano 250 mg / 500 mg Filmtabletten, in combination with prednisone or prednisolone indicated for:
the treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT) (see section 5.1) the treatment of metastatic castration resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated (see section 5.1) the treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.is approved.
II.1 Problem statement
Not applicable
II.2 About the product
This decentralised application concerns a generic version of abiraterone acetate, under the trade name Abirateron Polisano 250 mg / 500 mg Filmtabletten. In this Assessment Report, the name Abiraterone Polisano is used.
The originator products are Zytiga 250 mg tablets and Zytiga 500 mg film-coated tablets by Janssen-Cilag International N.V., registered since 05/09/2011 (MA numbers: Zytiga 250 mg tablets EU/1/11/714/001; Zytiga 500 mg film-coated tablets EU/1/11/714/002–003).
With DE as the Reference Member State in this Decentralized Procedure, Polisano Pharmaceuticals S.A. applied for the Marketing Authorisations for Abiraterone Polisano 250 mg film-coated tablets and Abiraterone Polisano 500 mg film-coated tablets in RO.
Oral abiraterone acetate is a selective inhibitor of the enzyme CYP17 and thereby inhibits androgen biosynthesis, with androgen signalling crucial in the progression from primary to metastatic prostate cancer (PC) and subsequently, in the development of metastatic castration-resistant PC (mCRPC).
Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis inhibitor. Specifically, abiraterone selectively inhibits the enzyme 17α-hydroxylase/C17,20-lyase (CYP17).
This enzyme is expressed in and is required for androgen biosynthesis in testicular, adrenal and prostatic tumour tissues. CYP17 catalyses the conversion of pregnenolone and progesterone into testosterone precursors, DHEA and androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17,20 bond. CYP17 inhibition also results in increased mineralocorticoid production by the adrenals.
Androgen-sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with LHRH analogues or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumour. Treatment with abiraterone acetate decreases serum testosterone to undetectable levels (using commercial assays) when given with LHRH analogues (or orchiectomy).
The therapeutic indications are applied for in this DCP are identical with the therapeutic indications approved for the reference products Zytiga 250 mg tablets and Zytiga 500 mg film-coated tablets:
The recommended dose is 1,000 mg (four 250 mg film-coated tablets or two 500 mg film-coated tablets) as a single daily dose that must not be taken with food. Taking the tablets with food increases systemic exposure to abiraterone. For mHSPC, abiraterone acetate is used with 5 mg prednisone or prednisolone daily. For mCRPC, abiraterone acetate is used with 10 mg prednisone or prednisolone daily.
II.3 General comments on the submitted dossier
The applications are submitted under article 10 (1), generic application of Council Directive 2001/83/EC, as amended, claiming to be generics to the reference products Zytiga 250 mg tablets and Zytiga 500 mg film-coated tablets.
The following CMS are involved in this procedure: RO.
The originator producst are Zytiga 250 mg tablets and Zytiga 500 mg film-coated tablets by Janssen-Cilag International N.V., registered since 05/09/2011 (MA numbers: Zytiga 250 mg tablets EU/1/11/714/001; Zytiga 500 mg film-coated tablets EU/1/11/714/002–003).
With regard to the dossier, one pivotal bioequivalence study was submitted. The reference product used in this study was Zytiga 500 mg film-coated tablets, manufactured by Janssen-Cilag International NV., Belgium, approved within the EU via the centralised procedure.
This approach is accepted, and no further clinical data are required.
No scientific advice has been provided.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.
The RMS has been assured that acceptable standards of GMP are in place for these product types 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.
For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.
GMP active substance
Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.
GCP
GCP compliance of the submitted bioequivalence study was declared by the Sponsor and in the study reports. The study site has been inspected by competent European authorities in 2010 and 2019. During the assessment, there were no indications of GCP non-compliance. Thus, no concerns are raised with respect to GCP.
III.1 Quality aspects
An ASMF has been presented for the drug substance Abiraterone acetate
The assessment of the Active Substance Master Files (ASMFs) is provided in separate ASMF Assessment Reports with confidential annexes on the Restricted Parts.
Drug ProductThe finished product is presented as 250 mg (white) and 500 mg (purple) film-coated tablets packed in either blisters or HDPE containers. The finished product is sufficiently described including qualitative and quantitative composition and function of each ingredient. The score line of the 500 mg strength is mentioned.
The finished drug product release and shelf-life specifications have been presented for 250 mg and 500 mg film-coated tablets. The specifications cover all relevant parameters for solid, oral dosage forms and acceptable limits have been established.
Abiraterone acetate film coated tablets will be either packed in PVC/PE/PVDC aluminium foil blisters or HDPE container pack. Appropriate specifications and analytical procedures are provided.
In-use stability studies have been sufficiently conducted for the proposed HDPE container for up to 60 days.
The proposed shelf life of 24 months without special storage condition can be granted.
III.2 Non clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of abiraterone are well known. As abiraterone is a widely used, well-known active substance, the applicant has not provided additional studies and further studies are not required. Overview based on literature review is, thus, appropriate. Information about impurities are enclosed in the quality part which is acceptable.
The non-clinical overview is adequate. Further, justification for the lack of Environmental Risk Assessment Report and the CV of the non-clinical expert have been submitted.
Environmental Risk Assessment (ERA)Since Abiraterone Polisano is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
III.3 Clinical aspects
BioequivalenceTo support the application, the applicant has submitted as report one bioequivalence study. The bioequivalence study is presented in the dossier.
This was an open label, balanced, randomized, two-treatment, four-period, two-sequence, single dose, fully replicate crossover oral bioequivalence study in healthy, adult, male, human subjects, under fasting conditions.
The test product was Abiraterone Acetate 500 mg Tablets. The reference product was Zytiga®
(abiraterone acetate) 500 mg film-coated tablets from the Belgian market, (MA number: EU/1/11/714/002–003).
A total of 48 male human subjects aged in the range of 18– 45 years (both inclusive) were planned. In period I, 47 subjects were dosed, 42 subjects were dosed in periods II, and 44 subjects were dosed in period III and period IV. 46 subjects were included in pharmacokinetic and statistical analysis.
Analytical MethodsIn the bioequivalence study Abiraterone was determined by RP-HPLC-MS/MS (MRM) using deuterated Abiraterone (d4-Abiraterone) as internal standard after liquid/liquid extraction. The method is described in detail and relevant SOPs have been provided. The validation is performed according to the Guideline on bioanalytical method validation, EMEA/C HMP/EWP/192217/2009 and ICH M10 EMA/CHMP/ICH/172948/2019. LLOQ is 0.20 ng/mL and thus within an acceptable range (minimal Cmax around 26 ng/mL).
The performance of the analytical methods was successfully demonstrated in the validation reports. Long-term stability of study samples has been confirmed for the indicated storage period of 54 days. Concomitant medication has been included in method validation addendum I. Concomitant medications used in clinical studies showed no interference.
Results of incurred samples reanalysed according to ICH M10 (EMA/CHMP/ICH/-172948/2019) presented for all studies, show the suitability of the method used. From the results of the validation, it can be concluded that the method used has adequate sensitivity, precision, accuracy, and specificity to determine Abiraterone at the concentration levels expected in real samples. The clinical details are presented in the dossier.
Results
Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median, range)
| Treatment | AUC 0-t ng/ml/h | AUC 0-∞ ng/ml/h | C max ng/ml | t max h |
| Test | 525.264 ± 270.299 | 543.072 ± 275.452 | 110.99 ± 54.379 | 1.50 (0.75 – 5.00) |
| Reference | 493.531 ± 252.221 | 507.854 ± 255.616 | 104.01 ± 59.721 | 1.75 (0.50 – 6.00) |
| *Ratio (90% CI) | 107.66% (100.67%-115.15%) | 110.78% (102.14%-120.14%) | ||
| AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h canbe reported instead of AUC0-t, in studies with sampling period of 72 h, and where the concentration at 72 h is quantifiable. Only for immediate release products AUC 0-∞ Area under the plasma concentration curve extrapolated to infinite time. AUC0-∞ does not need to be reported when AUC0–72h is reported instead of AUC0-t C max Maximum plasma concentration t max Time until Cmax is reached | ||||
*ln-transformed values
The reference-scaled procedure was applied for Cmax as the reference within subject variability was more than 30%. Hence a widened BE acceptance range (78.75 – 126.98%) was employed.
Regarding Cmax, the reference intra-subject variability was above 30% and thus, the acceptance range for Cmax was 78.75 – 126.98% for 90% CI of T/R. This is agreed. The 90% confidence interval of T/R of Cmax was also within the conventional acceptance range of 80% to 125%.
With regard to AUCt, the acceptance range of 80% to 125% was also met.
Conclusion regarding bioequivalence
The application contains an adequate review of published clinical data. Bioequivalence can be concluded.
The SPC and PIL are fully in accordance with the product information of the reference product Zytiga.
Summary Pharmacovigilance systemThe Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS/Rapporteur considers the Summary acceptable.
Risk Management PlanThe MAA has submitted a risk management plan, 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 the medicinal product(s) applied for authorisation.
Safety specification
According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product/similar products which is acceptable.
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Risk minimisation measures
Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.
Summary of the RMP
The submitted Risk Management Plan is considered acceptable.
After approval the MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in the dossier of the Marketing Authorisation and any agreed subsequent updates of the RMP
An updated RMP should be submitted:
– At the request of the RMS;
– Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached.
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.
Periodic Safety Update Report (PSUR)
With regard to PSUR submission, the MAH should take the following into account:
PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c (7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.Common Renewal DateThe common renewal date is 22.06.2028.
Legal StatusMedicinal product subject to medical prescription
User TestingIn the report on the user testing, it was concluded that the PL can be qualified as acceptable.
This is agreed.
The application contains an adequate review of published clinical data. Bioequivalence can be concluded.
The biowaiver for the 250 mg tablets can be granted based on the comparative dissolution profiles provided.
From a quality point of view the B/R is positive.
The application is approved. For intermediate amendments, see the current product information.