Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete - Sildenafil HEC 50 mg Filmtabletten
TABLE OF CONTENTS
ADMINISTRATIVE INFORMATION
| Proposed name of the medicinal product(s) in the RMS | Sildenafil HEC Pharm 25 mg; 50 mg; 100 mg Filmtabletten |
| Name of the drug substance (INN name): | Sildenafil |
| Pharmaco-therapeutic group (ATC Code): | G04BE03 |
| Pharmaceutical form(s) and strength(s): | Film-coated tablet |
| Reference Number(s) for the Decentralised Procedure | DE/H/6008/001–003/DC |
| Reference Member State: | DE |
| Member States concerned: | ES, FR, IT, UK |
| Legal basis of application: | Generic Art 10.1 Dir 2001/83/EC |
| Marketing Authorisation Holder (name and address) | HEC Pharm GmbH Gabriele-Tergit-Promenade 17 D-10963 Berlin |
| Names and addresses of all manufacturer(s) responsible for batch release in the EEA | Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305 b D-14167 Berlin |
I.
Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Sildenafil HEC Pharm 25 mg, 50 mg and 100 mg, in the treatment of erectile dysfunction in adult men,
is approved.
II. EXECUTIVE SUMMARY
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II.1 Problem statement
N/A
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II.2 About the product
Sildenafil is an oral therapy for erectile dysfunction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.
Sildenafil citrate is a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5), the predominant isoenzyme metabolising cGMP in the corpus cavernosum. The inhibition of cGMP metabolism mediates the elevation of cGMP level after sexual stimulation, leading to corpus cavernosum smooth muscle relaxation, an increase in the penile blood flow and an increase in the intracavernosal pressure. All these effects result in an improvement in the erectile function.
The ATC-code is G04BE03.
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II.3 General comments on the submitted dossier
The current application for a Marketing Authorisation for Sildenafil HEC Pharm 25 mg, 50 mg and 100 mg Filmtabletten submitted by HEC Pharm GmbH, Germany concerns a generic application submitted in RMS DE and CMSs ES, FR, IT and UK under Article 10(1) of Directive 2001/83/EC, as amended.
Essential similarity to the centrally authorised reference medicinal product Viagra® is claimed. Viagra®, 25 mg, 50 mg and 100 mg film-coated tablets have been authorised since 1998–09–14 in EU, with Pfizer Limited as marketing authorisation holder (MA# EU/1/98/077/).
In support of this application a bioequivalence study has been performed. The reference product used in the bioequivalence study is Viagra® 100 mg film-coated tablet from the UK market.
The applicant has submitted one single dose bioequivalence study (fasting) with the 100 mg strength
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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
The applicant declared that the submitted BE-study was conducted in compliance with Good Clinical Practice [GCP].
GLP
In line with the type of application procedure the Applicant has not submitted non-clinical studies.
III. SCIENTIFIC OVERVIEW AND DISCUSSION
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III.1 Quality aspects
Drug substance
Drug substance
Sildenafil citrate is well known and described in the Ph.Eur. Two API suppliers are foreseen; both updated during procedure) and LoAs have been provided.
In addition to the information provided in the CEP, general information is provided from the FPM for both API sources including characterisation, impurities and control of the API. The FPM has performed method transfer for both suppliers and verification reports are provided for the quantitative methods.
Currently a re-test period of 60 months without any special storage conditions in the intended container closure system has defined for API.
Drug Product
The development of the product has been described, the choice of excipients is justified and their functions explained.
The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on five batches of each strength. The batch analysis results show that the finished products meet the specifications proposed. 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.
The proposed shelf-life of 24 months without any special storage conditions for the drug product is justified.
Issues raised during assessment have been resolved. No risk for nitrosamines was identified from the risk evaluation provided during the procedure.
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III.2 Non-clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of sildenafil are well known. As sildenafil 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.
In response to a request the Applicant updated the Non-clinical Overview in the dossier ) and the excipients and impurities of the medicinal product under review were assessed. No concerns were identified.
The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.
Environmental Risk Assessment (ERA)
Since Sildenafil HEC Pharm xx 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.
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III.3 Clinical aspects
Pharmacokinetics
To support the application, the applicant carried out 1 single dose bioequivalence study with the 100 mg tablet.
The GCP/GLP aspects of the clinical phases of the study are sufficient documented. Quality assurance documents have been provided. The study centres have been inspected by European Authorities.
Based on the submitted bioequivalence study the Sildenafil 100 mg Filmtabletten by Sunshine Lake Pharma Co., Ltd., China can be considered bioequivalent with the Viagra 100 mg film-coated tablet by Pfizer Ltd. from the UK market.
Table 1 shows the pharmacokinetic and statistical results of the bioequivalence study.
Table 1. Pharmacokinetic and statistical results of Sildenafil of study 17-VIN-0583
| Pharmacokinetic parameter | Arithmetic Mean ± SD (N = 41) | |
| Test product (T) | Reference Product ® | |
| AVC^m, (hr.ng mL) | 2639.987 ± 1212.3955 | 2602.421 ± 1186.6379 |
| AUC^j (hr.ng mL) | 2708.273 ± 1243.7818 | 2669.922 ±1221.8490 |
| C max (ng mL) | 807.590 ±334.3455 | 754.577 ± 296.9878 |
| 0.750 (0.25 – 3.00) | 1.000 (0.25 –2.50) | |
1 Median (Min – Max)
| Pharmacokinetic parameter | Geometric Mean Ratio Test Ref | Confidence Intervals | CVH1 |
| AUC2(o-t) | 101 90 | 97 15% – 106 88% | 12.87 |
| ^ max | 107 34 | 99 19% – 116.17% | 21.47 |
' Estimated from the Residual Mean Squares. For replicate design studies report the within-subject CV% using only the reference product data.
– In some cases AUC(0–72h)
Bioequivalence between Sildenafil 100 mg tablets (Sunshine Lake Pharma Co., Ltd., China) and Viagra® 100 mg tablets from UK (Pfizer Limited, UK) has been demonstrated.
Biowaiver
This application concerns 3 strengths, i.e. 25, 50 and 100 mg Filmtabletten. Bioequivalence is proven for the 100 mg strength. The results obtained for the 100 mg tablets can be extrapolated to the 25 mg and 50 mg film-coated tablets.
The following accounts: dose-proportional formulations, manufactured by the same manufacturer and manufacturing process, sildenafil shows linear pharmacokinetics over the therapeutic dose range of 25 – 100 mg and comparable dissolution data (see additional information in the quality assessment report).
The biowaiver for the Sildenafil 25 mg and 50 mg Filmtabletten is therefore acceptable.
Analytical Methods
The analytical part of the study was conducted at Veeda Clinical Research Pvt. Ltd. in Ahmedabad, India. Plasma concentrations of the parent compound sildenafil has been determined. Plasma samples were analysed for sildenafil using LC-MS/MS method by liquid phase extraction. The method was validated and a validation report was provided. The calibration curve for sildenafil ranged from 5.000 ng/mL to 2000.000 ng/mL.
To estimate the concentrations of sildenafil in human plasma, liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods were developed and validated according to applicable GLP requirements. For evaluation of accuracy and precision of the analytical method, nominal concentrations of quality control samples and the data obtained in the course of this study were compared.
Pharmacodynamics / Clinical efficacy / Clinical safety
The Clinical Overview on the rationale, clinical pharmacology, efficacy and safety is considered sufficient in view of the indications presently sought.
No new studies on pharmacodynamics, clinical efficacy or clinical safety have been submitted, which is appropriate for a generic application under Article 10(1).
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 MAH 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 Sildenafil HEC Pharm 25mg, 50mg, 100 mg.
The Risk management plan has been updated according to the Rapporteur´s questions. The current RMP is now version 0.2, data lock point 19th January 2020; date of final sign off 20 January 2020.
On 27th January, during the ongoing procedure, after finalisation of the Day 120 assessment report, the Applicant has submitted an unsolicited additional RMP with the date of final sign off being then 19 January 2020. The reason was to add information concerning the additional risk minimisation for safety concern related to PPHN and neonatal death associated with off-label use (early-onset IUGR, intrauterine growth restriction).
This measure was related to the STRIDER clinical study which was prematurely discontinued due a higher incidence of PPHN and overall neonatal death in the sildenafil arm. Although sildenafil is not
licensed for this indication, this information should be included in all RMPs for all Sildenafil containing products.
The Applicant was asked to submit a new version of the RMP with the Day 160 responses, e.g.
No.0.3 if changes to the RMP were considered necessary.
The RMP, version 0.3 with the data lock point 30.1.2020 and date of final sign off 31.1.2020 submitted with the Day 160 Responses is now acceptable.
Safety specification
Table SVIII.1: Summary of safety concerns
| Summary of safety concerns | |
| Important identified risks |
CYP3A4 inducers#) # Drugs which may increase sildenafil clearance
|
| Important potential risks |
(NAION; interruption of the blood supply to the main nerve of the eye)
patients
inhibitors and alpha blockers
(early-onset IUGR) |
| Missing information |
|
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Risk minimisation measures
As additional risk minimisation measure (RMP Part V.2) the DHPC concerning persistent pulmonary hypertension of the newborn (PPHN) and neonatal death associated with off label use of sildenafil for the treatment of early onset intrauterine growth restriction (IUGR) was added. The inclusion of this additional risk minimization measure was requested as it refers to all products containing sildenafil.
This risk has been added also to the summary of safety concerns as important potential risk.
Summary of the RMP
The Applicant has submitted a revised RMP version 0.2 signed 20th January 2020. The submitted Risk Management Plan, is considered acceptable.
On 27th January, during the ongoing procedure, after finalisation of the Day 120 assessment report, the Applicant has submitted an unsolicited additional RMP with the date of final sign off being then 19 January 2020.
The Applicant was asked to submit a new version of the RMP with the Day 160 responses, e.g. No.0.3 if changes to the RMP were considered necessary.
The RMP, version 0.3 with some minor changes compared to Version 0.2 (data lock point 30.1.2020 and date of final sign off 31.1.2020) submitted with the Day 160 Responses is now acceptable.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
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– At the request of the RMS;
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– 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)
Use the below statement in case a substance is listed in the published EURD list.
With regard to PSUR submission, the MAH should take the following into account:
- 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.
Common renewal date:
The common renewal date is 03.06.2025.
Legal status
Medicinal product subject to medical prescription.
User Test
Clinical
The proposed PL is in line with the PL of the originator.
Non-clinical
The proposed PL is in line with the PL of the originator.
IV. BENEFIT RISK ASSESSMENT
Clinical
The application contains an adequate review of published clinical data and bioequivalence has been shown between the test product Sildenafil 100 mg film-coated tablet by Sunshine Lake Pharma Co., Ltd., China and the reference product Viagra® 100 mg film-coated tablets by Pfizer Ltd. from the UK market. The results of study 17-VIN-0583 with 100 mg formulation can be extrapolated to the 25
mg and 50 mg strengths, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.
All clinical issues have been sufficiently solved by the applicant. Sildenafil HEC Pharm 25 mg, 50mg, 100mg Filmtabletten is approvable from a clinical point of view.
The RMP, version 0.3 (data lock point 30.1.2020 and date of final sign off 31.1.2020) submitted with the Day 160 Responses is now acceptable.
Non-clinical
From non-clinical point of view there are no objections against granting of marketing authorisation.
Quality
From a quality perspective there are no objections.
The application is approved. For intermediate amendments see current product information.
V.
PROPOSED CONDITIONS FOR MARKETING
Prescription only.
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V. 1 (Draft) final list of recommendations not falling under Article 21a/22 of