Finasterid Ascend 5 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

PUBLIC ASSESSMENT REPORT

Decentralised Procedure

Finasterid Ascend 5 mg Filmtabletten

Procedure-Number: DE/H/7045/001/DC

Active Substance:

Finasteride

Dosage Form:

Film-coated tablet

Applicant:

Ascend GmbH

Publication:

14.09.2022

This module reflects the scientific discussion for the approval of Finasterid Ascend 5 mg Filmtabletten. The procedure was finalised on 23.08.2022.

TABLE OF CONTENTS

I INTRODUCTION­.............­.............­.............­....... FEHLER! TEXTMARKE NICHT DEFINIERT.

• II.4 G eneral comments on compliance with GMP, GLP, GCP and agreed ethical

• III.1 Q uality aspects.........

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• III.2 N on clinical aspects

• III.3 C linical aspects........

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Finasterid Ascend 5 mg Filmtabletten
Name of the drug substance (INN name):	Finasteride
Pharmaco-therapeutic group (ATC Code):	G04CB01
Pharmaceutical form(s) and strength(s):	Film coated tablet
Reference Number(s) for the Decentralised Procedure	DE/H/7045/001/DC
Reference Member State:	DE
Concerned Member States:	MT
Legal basis of application:	Generic Art 10.1 Dir 2001/83/EC
Applicant (name and address)	Ascend GmbH Sebastian-Kneipp-Strasse 41 60439 Frankfurt Am Main Germany
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	Interpharma Services Ltd. 43A Cherni Vrach Blvd, Sofia, 1407 Bulgaria

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Finasterid Ascend 5 mg Filmtabletten, in the treatment of

“For the treatment of benign prostatic hyperplasia (BPH).

For reducing the risk of acute urinary retention and BPH-related surgical procedures in patients with moderate to severe symptoms of BPH (see section 5.1).

Finasterid Ascend 5 mg tablet should be used in patients with an enlarged prostate (prostate volume of approximately 40 cm3 or more).”

is approved.

There is currently no need for a GCP inspection.

II EXECUTIVE SUMMARY

• II.1 Problem statement

N/A

• II.2 About the product

Finasteride is a competitive inhibitor of human 5 α-reductase, an intracellular enzyme which metabolises testosterone into the more potent androgen, dihydrotestosterone (DHT). In benign prostatic hyperplasia (BPH), enlargement of the prostate gland is dependent upon the conversion of testosterone to DHT within the prostate. Finasteride is highly effective in reducing circulating and intraprostatic DHT. Finasteride has no affinity for the androgen receptor.

The claimed indication has been revised as follows:

“For the treatment of benign prostatic hyperplasia (BPH).

For reducing the risk of acute urinary retention and BPH-related surgical procedures in patients with moderate to severe symptoms of BPH (see section 5.1).

Finasterid Ascend 5 mg tablet should be used in patients with an enlarged prostate (prostate volume of approximately 40 cm3 or more).”

Finasteride is given as 5 mg tablet daily with or without concomitant food administration. There is no restriction of the treatment duration which is determined by the treating physician.

While there is no data on administration of the compound in patients with liver impairment, no dose adjustment is needed for patients with renal impairment.

The compound is contraindicated in children, which is the consequence of the use in BPH only.

• II.3 General comments on the submitted dossier

This mutual recognition/de­centralised application concerns a generic version of Proscar 5 mg (Finasteride 5 mg), under the trade name Finasterid Ascend 5 mg Filmtabletten. In this Assessment Report, the name Finasteride is used.

The originator product is PROSCAR 5 mg Filmtabletten (film-coated tablet) German Reg-Nr.: 42859.00.00 by Organon Healthcare GmbH, Munich, Germany (previously registered for the MAH MSD), registered since 1999–07–30.

With DE as the Reference Member State in this Decentralized Procedure Ascend GmbH, applied for the Marketing Authorisations for Finasterid Ascend 5 mg Filmtabletten in the CMS MT.

As a consequence of the product being a “generic” the active compound is not considered to be a new active substance. No similarity report is included in the dossier, which is considered acceptable. No orphan product is registered for the indication sought.

The information for Generic, Hybrid or Bio-similar Applications in the dossier is usually expected to contain a document summarizing the grounds and evidence used for demonstrating that the medicinal product is essentially similar to an authorised medicinal product. However, no such statement is included in in the dossier. Nevertheless, essential similarity – by proof of bioequivalence – is provided by the Applicant.

The Applicant has presented one bioequivalence trial with single-dose administration in the fasted state, which is considered appropriate for the type of product.

• II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles

GMP

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, 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 nonCommunity 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

The Applicant has submitted a statement according to Article 8 (ib) of Directive 2001/83/EC, stating that the bioequivalence study presented, carried out outside the European Union, meets the ethical requirements of Directive 2001/83/EC.

The Applicant has also submitted the results of previous inspections carried out by EU and US authorities during the last 6 years, which did not reveal findings of concern.

However, the status of the study and the study centre with regard to the new Indian legislation as of 2019 has been clarified.

GLP

In line with the type of Application the Applicant does not submit non-clinical studies.

III SCIENTIFIC OVERVIEW AND DISCUSSION

• III.1 Quality aspects

Drug substance

The Applicant uses the active substance from two manufacturers. Both manufacturers submit a valid CEP for the active substance. A Ph.Eur monograph exists for the drug substance.

The specifications submitted by both the active substance and the product manufacturer correspond to this monograph.

Drug Product

The drug product contains 5 mg of active substance and is an immediate release tablet. The manufacturing process is a standard one and wet granulation is used.

The Applicant provides a detailed description of the pharmaceutical development of this product. Proposed dissolution method complies with the USP and OGD specifications.

Drug product release and shelf life specifications are adequate. The dissolution limit chosen is acceptable.

Analytical procedures of the drug product are described suitably and validated.

Both active substance manufacturers and the product manufacturer have sufficiently and adequately assessed the nitrosamine issue. There is no probability of nitrosamine impurities or any source for generation of nitrosamine impurities involves during manufacturing of the drug substance, the finished product Finasterid Ascend tablet 5 mg and in the manufacture and use of the packaging material.

The blister packaging material is described adequately.

Based on suitable long term and accelerated stability studies, the shelf life of the medicinal product is fixed to 24 months and no special precautions for storage are necessary.

• III.2 Non clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of finasteride are well known. As finasteride 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.

The non-clinical overview is dated July 13th, 2022. Report refers 26 publications up to year 2022. This actualised non-clinical overview is considered adequate.

Environmental Risk Assessment (ERA)

Since Finasterid Ascend 5 mg Filmtabletten is a generic product, it will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.

• III.3 Clinical aspects

To support the application, the Applicant has submitted as report one bioequivalence study with singledose drug administration in the fasted state which is considered appropriate for the type of pharmaceutical formulation and the substance under evaluation.

No (strength) biowaiver request is submitted due to the formulation presented as single strength only.

Finasterid Ascend 5 mg Filmtabletten

DE/H/7045/01/DC Public Assessment Report Page 6/9

The presented Study was an open label, laboratory blind, randomized, two period, two treatment, two sequence, single dose, two way, cross-over bioequivalence study of Finasteride Tablets USP 5 mg with Proscar® 5 mg film – coated tablets (Finasteride) Marketing Authorisation Holder Merck Sharp & Dohme limited Hoddesdon, Hertfordshire, UK in healthy adult male human subjects under fasting condition.

The study with the clinical, analytical, as well as statistical parts was conducted between October and December 2020.

The study included 30 healthy male volunteers aged between 22 and 48 years, of which 27 could be evaluated. 3 subjects were excluded based on positive drug/alcohol screens (according to the protocol). Adequate standardised housing conditions, fluid intake and food administration were provided on the day of study drug administration.

Blood sampling was conducted with 20 sampling time-points up to 48 hours after study drug administration. The schedule of blood sampling was considered adequate, similar to the wash-out period of 9 days representing a multitude of the elimination half-life of the compound.

The test product was – as mentioned – finasteride tablets 5 mg and the reference product used was Proscar from the UK market. This reference product was deemd acceptable due to the fact that the study was finalised shortly before the final exit of the UK from the EU took place.

The Applicant has undertaken appropriate efforts on the validation of the analytical methods, and the reports submitted are considered overall acceptable. Analysis was based on an LC-MS/MS method using finasteride D9 as internal standard. The concentration range was 0.2 ng/ml to 80 ng/ml. The method used appears to be sufficiently sensitive, complying with the requirements (LoQ of 1/20 of Cmax) considering that Cmax values were a mean of 60 ng/ml with no subject below 40 ng/ml. Longterm stability adequately covers the storage period. The number of ISR samples (10% of 1000 plus 5% of those exceeding 1000=107) as well as the re-analysis itself are complying with the requirements.

The primary PK parameters were determined as Cmax and AUC-0-t, while the AUC extrapolated to infinity, Tmax, Kel, t ½, as well as the extrapolated AUC were considered secondary.

Adequate statistical methods were applied for the sample size estimation as well as for the evaluation of the study. The log-transformed pharmacokinetic parameters (Cmax and AUCo-t) were analysed using an ANOVA model which included sequence, subject nested within sequence, period and treatment as factors. Two one sided tests procedure at 5 % level of significance was used to compare the average values of pharmacokinetic parameters determined after administration of test and reference products.

The following results were achieved:

Table 4. 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	569.4800 (148.6)	590.0618 (161.2)	59.4987 (13.26)	1.519 (1.00–5.00)
Reference	591.1141 (165.99)	570.0096 (171.25)	60.259 (12.62)	2.019 (0.5–4.00)
*Ratio (90% CI)	101.00 (95.51–106.81)		98.64 (90.98–106.93)
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

According to the results achieved, Finasterid Ascend 5 mg tablets is considered bioequivalent the Proscar 5 mg tablets.

The safety evaluation of the study was unremarkable.

The Applicant has submitted additional dissolution data with adequate methods, comparing the reference medicinal product used in the study with the test product, and it could be shown that both have a similarly fast dissolution. The submission of a respective comparison to the reference medicinal product from the German market has confirmed these results.

Summary Pharmacovigilance system

The 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 considers the Summary acceptable.

Risk Management Plan

The 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 date

The common renewal date is 23 August 2027.

Legal Status

Medicinal product subject to medical prescription.

User Testing

The user test adequately demonstrates that the PL complies with the legal requirements as of Art 59/63 of Directive 2001/83

• IV BENEFIT RISK ASSESSMENT