Solifenacin HEC Pharm 5 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Solifenacin HEC Pharm 5 mg Filmtabletten
Name of the drug substance (INN name):	SOLIFENACIN SUCCINATE
Pharmaco-therapeutic group (ATC Code):	G04BD08
Pharmaceutical form(s) and strength(s):	Film-coated tablet
Reference Number(s) for the Decentralised Procedure	DE/H/6402/002/DC
Reference Member State:	DE
Concerned Member States:	ES, FR
Legal basis of application:	Generic Art 10.1 and 10.2 Dir 2001/83/EC
Marketing Authorisation Holder (name and address)	HEC Pharm GmbH Gabriele-Tergit-Promenade 17 10963 Berlin
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305b, D-14167 Berlin, Germany

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

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome.

is approved.

A need for expert involvement or for inspection has not been identified.

• II. EXECUTIVE SUMMARY

  • II.1 Problem statement

N/A

• II.2 About the product

Solifenacin is a competitive, selective muscarinic receptor antagonist. The urinary bladder is innervated by parasympathetic cholinergic nerves. Acetylcholine (Ach) contracts the detrusor smooth muscle via M3 muscarinic receptors. In vitro and in vivo pharmacological studies indicate that solifenacin is a competitive antagonist of the M3 muscarinic receptor.

Solifenacin has a high affinity for the M3 receptor subtype mediating urinary bladder contraction. By preventing ACh binding, Solifenacin reduces smooth muscle tone in the bladder, allowing the bladder to retain larger volumes of urine and reducing the number of micturition, urgency and incontinence episodes. Because of a long elimination half-life, a once-a-day dose can offer 24 hour control of the urinary bladder smooth muscle tone.

The claimed indication is:

Symptomatic treatment of urge incontinence and/or increased urinary frequency and urgency as may occur in patients with overactive bladder syndrome, which is in line with the originator product.

However, only one strength is proposed to be licensed, contrary to the originator product, for which both, a 5 mg as well as a 10 mg strength has been licensed.

• II.3 General comments on the submitted dossier

This decentralised application concerns a generic version of Vesicare (solifenacin succinate), under the trade name Solifenacin HEC Pharm 10 mg Filmtabletten (and others).

The originator product is Vesicare 5 and 10 mg tablets by Astellas Pharma Europe, registered since 16 December 2003. The pivotal bioequivalence trials have been conducted comparing the proposed generic product with the originator product licensed in Germany, which is Vesikur 10 mg of Astellas GmbH.

With Germany as the Reference Member State in this Decentralized Procedure, HEC Pharm GmbH applied for the Marketing Authorisation for Solifenacin HEC Pharm 5 mg Filmtabletten in FR, and ES as a line extension to the product Solifenacin HEC 10 mg Filmtabletten which has been the subject of the procedure DE/H/6402/001/DC and which has successfully been concluded in 2020.

According to the regulatory requirements, CPMP/EWP/QWP/1401/98 Rev 1 Guideline on the Investigation of Bioequivalence for the immediate release product claiming essential similarity to the reference product a bioequivalence study is required to support the application.

The applicant has submitted one bioequivalence study in the fasted state, which is considered to be appropriate in general for the substance under consideration and the fact that the product is not

composed proportionally according to the excipients. The applicant has furthermore submitted adequate argumentation and documentation to apply for a biowaiver for the additional strength.

• 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.

GLP

The applicant has not provided additional non-clinical studies. Principles of GLP do not apply for this application.

GCP:

A statement on the application of appropriate GCP standards in the submitted study has been provided in the dossier IEC approvals of the protocol, ICF, and CRFs are provided, and dated 19th September 2019.

Information on (previous) inspections of the company which has conducted the bioequivalence trials has been provided and been updated on request in the previous procedure DE/6402/001/DC. A GCP inspection appears not to be warranted according to the currently available data.

Orphan similarity:

The applicant does not present information’s re­lating to orphan market exclusivity – similarity.

However, for the indication proposed, a licensed orphan medicinal product cannot be identified.

Therefore, a report addressing the possible similarity with the authorised orphan medicinal product and concluding on similarity or “non” similarity is deemed not necessary. This is acceptable.

• III. SCIENTIFIC OVERVIEW AND DISCUSSION

  • III.1 Quality aspects

The chemical-pharmaceutical documentation and Quality Overall Summary in relation to Solifenacin Succinate 5 mg and 10 mg film-coated tablets are of sufficient quality in view of the present European regulatory requirements.

Drug substance

Current EDQM certificate of suitability (CEP) has been provided for the drug substance, clarifying that the drug substance can be controlled sufficiently by the respective monograph of Ph. Eur. Furthermore some additional tests are submitted to complement the methods of Ph. Eur.

The analytical procedures are described sufficiently.

The verification / validation of analytical procedures are provided.

The control tests and specifications for the drug substance are drawn up adequately.

Batch results provided are according to specification.

Information on container closure system is submitted and included in the CEP. No further details are necessary.

The proposed retest period of 60 month when stored in double polyethylene bags placed in a polyethylene drum is justified according to the CEP.

Drug Product

The drug product Solifenacin HEC Pharm 5 mg Filmtabletten is a generic version of the Reference Medicinal Product (RMP), Vesikur® Solifenacin Glenmark 5 mg Filmtabletten, marketed by Astellas Pharma GmbH. It has been developed as line extension of Solifenacin HEC Pharm 10 mg Filmtabletten.

The development of the product has been described, the choice of excipients is justified and their functions explained. The 5 mg formulation is dose proportional to the authorized 10 mg formulation for all excipients.

The bioequivalence of Solifenacin HEC Pharm 10 mg Filmtabletten to the reference product, Vesikur® 10 mg Filmtabletten, has been demonstrated in an appropriate bioavailability study. A biowaiver is requested for the 5 mg strength and justified based on dose proportionality, similar manufacturer and manufacturing process, similar pharmacokinetics, and similar dissolution profiles. Dissolution profiles of three test batches of 5 mg in comparison to the biobatch (10 mg) have been provided. Since more than 85% of the drug is dissolved within 15 minutes, dissolution profiles are accepted as similar without further mathematical evaluation.

The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on three batches. The batch analysis results show that the finished products meet the specifications proposed.

The dissolution method has been developed sufficiently and discriminatory power has been shown. Dissolution profiles of the reference 10 mg biobatch and the test 10 mg test product are provided.

All excipients used are well known and of pharmacopoeial quality.

No novel excipients are used in the manufacture of this proposed generic product.

The excipient lactose, anhydrous is derived from animal sources, therefore the statement on Transmissible Spongiform Encephalopathy/Bo­vine Spongiform Encephalopathy (TSE/BSE) form the supplier for lactose, anhydrous are provided in the dossier.

Reference standards have been provided and have been re-standardized, where applicable.

The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. In addition, a Photostability study was conducted on the drug product.

The proposed shelf-life of 24 months with the storage condition: Do not require any special storage conditions for the drug product is considered acceptable. 24 months long-term stability data for the 10 mg strength and 12 months long-term stability data for the 5 mg strength have been provided. No significant changes have been observed, the product was found stable for the proposed shelf-life and extrapolation is applicable for the 5 mg strengths.

• III.2 Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of solifenacin are well known. As solifenacin is a widely used, well-known active substance, the Applicant has not provided additional studies and further studies are not required. An overview based on literature review is, thus, appropriate.

The non-clinical overview is dated October 2020. The report refers to 21 publications up to year 2020.

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

Environmental Risk Assessment (ERA)

Since Solifenacin HEC Pharm 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 1 bioequivalen­ce study.

Dissolution profiles of the proposed product (strength of 5 mg) compared to the 10 mg strength are also presented. The dissolution testing shows that the test preparation is a fast dissolving preparation across the full range of pH conditions tested for both strengths tested. Adequate justification has also been provided for the bioequivalence waiver for the additional strength fulfilling all conditions as of the bioequivalence guideline

One bioequivalence study is presented with a standard, open label, balanced, randomized, single-oral dose, two-treatment, two-sequence, two-period, crossover design, comparing 10 mg of HEC Pharma GmbH with Vesikur 10 mg Filmtabletten of Astellas Pharma GmbH, Germany under fasted conditions. The study was conducted between February 2019 and March 2019.

Healthy male subjects of 18–45 years of age were treated with a single dose of the test and reference compounds after an overnight fast.

During the study, 3 subjects were withdrawn, with one subject not reporting back to the second period, and 2 subjects being withdrawn due to an adverse event after dosing in period 2. These exclusions are considered acceptable.

Solifenacin concentration were measured in K3EDTA human plasma using a sufficiently validated and documented method based on Liquid Liquid Extraction with LC-ESI-MS/MS. Analysis of samples is sufficiently documented including ISR and long-term stability of samples.

The main PK parameters were Cmax and AUC0–72, with tmax serving as secondary efficacy parameter.

The statistical methods and used for evaluation, which can be considered standard methods, as well as the sample size calculation and are considered fully acceptable.

The following results were achieved for the PK evaluation:

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	577.321	N/A	13.923	6.0 (3.0 – 12.0)
Reference	587.512	N/A	14.310	5.5 (3.0 – 10.0)
*Ratio (90% CI)	96.04 91.88–100.39	N/A	97.26 91.88–100.39
AUC 0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0–72h can be 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

No period, sequence or formulation effects were found in the analysis. There were no measurable predose concentrations, and there was no subject with Cmax being the first time-point.

The safety evaluation was unremarkable.

Bioequivalence has been adequately demonstrated for the test product against the reference.

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 applicant submits a complete EU Risk Management Plan. The RMP is submitted 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.

The MAH has confirmed (both in the preceding procedure DE/6402/01, as well as in response to the validation requests, 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 MAH 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 NCA websites.

Safety specification

According to the Applicant the safety specification is in accordance with the current safety specification agreed and published for a similar product 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.

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.
• 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 October 2026.

Legal Status

Medicinal product subject to medical prescription.

User Testing

The proposed package leaflet complies with the requirements of Directive 2001/83.

• IV. BENEFIT RISK ASSESSMENT