Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete - Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung

PUBLIC ASSESSMENT REPORT

Decentralised Procedure

Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung

Procedure-Number: DE/H/7189/001/DC

Active Substance:

Tamsulosin

Dosage Form:

Modified-release hard capsule

Applicant:

Ascend GmbH

Publication: 08.12.2023

This module reflects the scientific discussion for approval of the above-mentioned procedure. The procedure was finalised on 29.06.2023.

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

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung
Name of the drug substance (INN name):	Tamsulosin
Pharmaco-therapeutic group (ATC Code):	G04CA02
Pharmaceutical form(s) and strength(s):	modified-release hard capsule
Reference Number(s) for the Decentralised Procedure	DE/H/7189/001/DC
Reference Member State:	DE
Concerned Member States:	XI
Legal basis of application:	Generic Art 10.1 and 10.2 Dir 2001/83/EC
Applicant (name and address)	Ascend GmbH Sebastian-Kneipp-Strasse 41 60439 Frankfurt Am Main
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	Interpharma Services Ltd. (BS 1) 43A, Cherni Vrach Blvd. 1407 SOFIA Bulgarien

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung. in the treatment of

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

is approved.

There is no need for a GCP inspection.

II EXECUTIVE SUMMARY

II.1 Problem statement

N/A

II.2 About the product

Tamsulosin is an alpha-adrenoceptor antagonist which binds selectively and competitively to the postsynaptic α1-adrenoceptors, in particular to subtypes α1A and α1D. It brings about relaxation of prostatic and urethral smooth muscle. Data indicate that the efficacy of tamsulosin is attributable to its blockade of α1A-adrenoceptors in the prostate gland. This blockade inhibits smooth muscle contraction and improves dynamic voiding symptoms, which leads in turn to an improvement in the maximum urinary flow rate (Qmax). The blockade of α1A- and α1D-adrenoceptors in the bladder may also contribute to the efficacy of the drug. This results in the inhibition of detrusor muscle contractions and the reduction of detrusor muscle instability and storage symptoms

Tamsulosin increases the maximum urinary flow rate. It relieves obstruction by relaxing smooth muscle in prostate and urethra thereby improving voiding symptoms. It also improves the storage symptoms in which bladder instability plays an important role. These effects on storage and voiding symptoms are maintained during long-term therapy. The need for surgery or catheterisation is significantly delayed.

Tamsulosin has an established positive benefit-risk ratio with demonstrated efficacy in the claimed indication and an acceptable tolerability profile.

This mutual recognition/decentralised application concerns a generic version of tamsulosin, under the trade name Tamsulosin Prolonged-release 0.4 mg Hartkapseln (and one other). In this Assessment Report, the name Tamsulosin is used.

The originator product is Omnic 0.4 mg capsule, hard by Astellas Pharma, BV Europe. Registered since 1995–04–11 (NL).

With DE as the Reference Member State in this Decentralized Procedure Ascend GmbH applied for the Marketing Authorisations for Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung in the UK (Northern Ireland; NI).

II.3 General comments on the submitted dossier

This is a generic application according to Art. 10 (1) Directive 2001/83. The clinical dossier consisted mainly on three bioequivalence studies (fasted, fed, both single dose, and one multiple-dose fasted), and the clinical overview and summary. The overview had only minimum extent of contents but was finally considered to be of sufficient quality.

The conduct of the mentioned three bioequivalence studies was considered appropriate.

Assessment of similarity with authorised orphan medicinal product(s) under market exclusivity According to the application form and a check of the Community Register of orphan medicinal products there is no medicinal product designated as an orphan medicinal product for a condition relating to the indication proposed in this application.

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 a GMP Certificate issued by the competent authority of Germany is provided. However, the GMP-certificate of the drug product manufacturer has expired, as it bases on an inspection conducted on 19 December 2018 and as, furthermore, the validity of the GMP-Certificate is limited to 18 months since the last day of inspection (valid until ~ 06.2020). At this time, no valid GMP certificate for the drug product manufacturer is available. However, the close out letter is expected in this week (~ 22.06.2023) and the GMP certificate by end of this month or in the first week of July 2023. With respect to “Questions and answers on regulatory expectations for medicinal products for human use during the covid-19 pandemic ”, here especially the update of section 2.2, the validity of GMP certificates for manufacturing/importing sites of active substances and/or finished products in the EEA will be extended until the end of 2023.

Thus, the response and the assurance, that the product Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung will not be placed in the market unless a valid GMP certificate is available, is acceptable.

GMP active substance

Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer responsible for batch release situated in the EU.

GCP:

A statement on the application of appropriate GCP standards in the submitted studies has been provided. Ethics committee approval letters have been submitted for all studies and GCP statements also included in the study reports.

The applicant has presented a list of previous EU authority inspections which has been extended upon request. Satisfactory responses with regard to the documentation of previous inspections were provided.

GLP:

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

III SCIENTIFIC OVERVIEW AND DISCUSSION

III.1 Quality aspects

Drug substance

The drug substance is Tamsulosin hydrochloride. A Ph. Eur. monograph “Tamsulosin hydrochloride” is available.

Characterization data are provided.

A discussion on possible impurities has been presented.

The specification includes all parameters of the Ph. Eur. monograph and additional specifications for one impurity and for residual solvents. Batch results of three production size batches showed compliance with the specification.

Long-term stability studies of overall six production size batches at 30°C±2°/65±5% RH are presented. The studies for three older batches over 5 years are finalised; the studies for three recent batches are still in progress and 36 months data are available. For the recent batches, also the results of stability studies at 40°C±2°C/75±5% RH over 6 months are provided. Long term stability results of an annual micronised batch over 60 months are also available. No trend of instability was visible in the stability batches. Re-test period of 5 years is accepted.

Conclusion on the ASMF:

All questions on the ASMF have been resolved. The ASMF is approvable.

Drug Product

The proposed drug product is a hard gelatine capsule for oral use with modified-release.

The quality of the excipients complies with the requirements of the corresponding Ph. Eur. Monograph, where applicable. The colours of the capsules and the printing ink meet the requirements of (EU) No. 231/2012.

The development of the product has been described. In order to achieve modified release, the formulation consists of drug containing core pellets, which are coated with polymeric coating and filled into capsules.

A bioequivalence study was carried out between test biobatch and the European reference product. Comparative in-vitro dissolution profiles of the clinical batches are presented. The dissolution of the test-biobatch was slower than that of the reference batch.

Discriminatory power of the dissolution test was demonstrated.

Process validation has been performed for exhibition batches and commercial batches.

The product specifications cover relevant parameters for this dosage form.

Validation results of the analytical methods have been presented.

Batch analysis results are provided for commercial batches. The acceptance criteria for the specified parameters were met.

The capsules are packed in blisters. Various package sizes are applied.

The stability data include three commercial batches stored for 36 months at long term (25 ± 2°C / 60 ± 5 % RH) and stored for 6 months at accelerated conditions (40 ± 2°C / 75 ± 5 % RH). For one additional commercial batch, 24 months long-term stability data are available. From the stability data, a shelf-life of 36 months in the proposed packaging without special storage conditions is justified.

Conclusion:

All questions have been resolved.

III.2 Non clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of tamsulosin are well known. As tamsulosin 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 not dated, but the Non-clinical expert statement is dated January 15th, 2021 and refers 13 publications up to year 2020.

The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is

adequate.

Environmental Risk Assessment (ERA)

Since Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung 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

Tamsulosin displays linear kinetics after single and multiple doses. Modified-release tamsulosin has a bioavailability of 100% under fasting conditions, with increases of 30% in the area under the curve of plasma drug concentration versus time (AUC) and 40 to 70% in the mean maximum plasma drug concentration (Cmax) relative to administration after food. The tmax is typically about 5 hr in the fasted state and about 6 hr in the fed state. Only about 1–2% is found as the unbound drug in humans. In humans, tamsulosin undergoes extensive hepatic metabolism but 8.7–15% of an oral dose is excreted in the urine in a non-metabolized form. Tamsulosin is metabolised by cytochrome P450 (CYP) enzymes, primarily CYP3A4 and CYP2D6, in the liver. In humans, 76% of the tamsulosin dose is excreted in the urine and 21% in the faeces.

Tamsulosin binds selectively and competitively to the postsynaptic α1-adrenoceptors, in particular to subtypes α1A and α1D. It brings about relaxation of prostatic and urethral smooth muscle. Data indicate that the efficacy of tamsulosin is attributable to its blockade of α1A-adrenoceptors in the prostate gland. This blockade inhibits smooth muscle contraction and improves dynamic voiding symptoms, which leads in turn to an improvement in the maximum urinary flow rate (Qmax). The blockade of α1A- and α1D-adrenoceptors in the bladder may also contribute to the efficacy of the drug. This results in the inhibition of detrusor muscle contractions and the reduction of detrusor muscle instability and storage symptoms

Safety of tamsulosin in patients with LUTS were demonstrated following chronic treatments for up to 4 years. About 5% of patients discontinued the drug because of side effects. Among these, intraoperative floppy iris syndrome and ejaculatory disorders seem related to some specific pharmacological properties of tamsulosin, rather than representing a class effect common to α1-blockers. Tamsulosin can cause some bothersome side-effects. According to the drug manufacturer, dizziness is the more common side effect, occurring in 1.3% of patients. Among uncommon sideeffects are palpitations, constipation, diarrhoea, asthenia, headache and postural hypotension.

In conclusion, tamsulosin has a positive benefit-risk ratio with demonstrated efficacy in the claimed indication and a good tolerability profile.

The applicant has submitted as report and with complete documentation the results of 3 bioequivalence studies, namely a single dose study under fasted conditions (study 1), a single dose study under fed conditions (study 2), and a multiple dose study under fasting conditions (study 3).

The study design of the studies, including its statistical planning, the analytical methods used, the conduct as well as the evaluation, have been found to be acceptable without relevant concerns. All studies included healthy male volunteers of South Asian origin. Discontinuations and drop-outs were considered acceptable based on the reasons provided. Analytical method validation has been sufficiently documented, including validation during the studies.

Study 1 (single dose fasted)

In this study, 27 of 30 subjects completed the study and were included in the final PK and statistical

evaluation. The following results were achieved:

Table. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median, range)

Treatment	AUC 0-t xg/ml/h	AUC 0-∞ xg/ml/h	C max xg/ml	t max h
Test	248.6014 ±90.55629	257.0795 ±94.11931	19.6830 ±5.35981	4.5 (3.00–10.00)
Reference	268.8770 ±86.72314	277.3994 ±91.10802	21.8948 ±5.04544	4.5 (3.50–6.00)
*Ratio (90% CI)	91.43 (87.35–96.40)	91.76 (87.35–96.40)	89.16 (82.58–96.26)
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

Study 2 (single dose fed)

Of the 30 participant included, 26 completed both periods of the study, and were used for evaluation. The following results were achieved:

Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, t max median, range)

Treatment	AUC 0-t xg/ml/h	AUC 0-∞ xg/ml/h	C max xg/ml	t max h
Test	212.5251 ±117.37795	226.4309 ±141.97978	9.9121 ±3.73833	8 (5.50–24.00)
Reference	241.6548 ±141.89272	260.3202 ±169.4138	11.3459 ±4.71666	8.0 (5.00–24.00)
*Ratio (90% CI)	89.58 (83.59–96.00)	87.96 (82.59–93.68)	88.54 (80.49–97.40)
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

The two single-dose studies documented a statistically significant formulation effect, however, the boundaries for the conclusion on bioequivalence were clearly adhered to.

Study 3 (multiple dose fasting):

In this open-label study, 32 subjects were included, of which 26 completed both periods of treatment and were included in the PK and statistical analysis. The following results were achieved.

Table 7. Pharmacokinetic parameters in steady-state (non-transformed values; arithmetic mean ± SD)

Treatment	AUC 0-τ xg/ml/h	C max,ss xg/ml	C tau,ss xg/ml	t max,ss h
Test	343.4766 ± 147.70391	28.8293 ±10.82240	6.9111 ±4.00538	149.229 ±1.01.06
Reference	345.5715 ±124.39598	30.1687 ±9.97548	6.6284 ±3.12514	149.063 ±0.6645
*Ratio (90% CI)	100.19 (92.81–108.17)	98.48 (92.03–105.39)	105.14 (92.01–120.15)
AUC 0-τ Area under the plasma concentration curve during a dosage interval at steady state C max,ss Maximum plasma concentration at steady state C min,ss Minimum plasma concentration at steady state t max,ss Time until Cmax,ss is reached

*ln-transformed values

Based on the submitted bioequivalence study/ies Tamsulosin Ascend 0,4 mg Hartkapseln mit veränderter Wirkstofffreisetzung is considered bioequivalent with Tamsu-astellas capsules 0.4 mg modified release capsules of Astellas Pharma Europe B.V. Leiden, The Netherlands.

The applicant has submitted data on comparative in-vitro dissolution under the influence of alcohol, which have revealed a similar or lesser extent of the influence of alcohol at the pH condition 0.1 N HCl as well as for pH condition 4.5. At pH 6.8, the dissolution profile was comparable between the two formulations. The risk of “dose-dumping” under the influence of alcohol has been excluded to a sufficient extent.

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/Rapporteur 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.

Upon request, the applicant has confirmed that the RMP is fully in line with the current “Guideline on good pharmacovigilance practices (GVP) Module V – Risk Management systems and the “Guidance on format of the risk management plan (RMP) in the EU”.

The MAA has further confirmed that the summary of safety concerns and all corresponding sections of the RMP, including all risk minimisation measures and pharmacovigilance measures are aligned with the RMP for the originator or similar products as adopted by CHMP (EPAR), published on: and/or CMD(h), published on: and/or NCAs, published on the respective NCA websites.

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.
In case the active substance will be removed in the future from the EURD list because the MAs have been withdrawn in all but one MS, the MAH shall contact that MS and propose DLP and frequency for further PSUR submissions together with a justification.

Common Renewal Date

The common renewal date is 29.06.2028.

Legal Status

Medicinal product subject to medical prescription.

User Testing

The proposed PIL complies with the legal requirements for Art. 59(3) of Directive 2001/83/EC (as amended).

IV BENEFIT RISK ASSESSMENT