Tadalafil HEC Pharm 2,5 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Tadalafil HEC Pharm 2,5 mg; Filmtabletten Tadalafil HEC Pharm 5mg Filmtabletten Tadalafil HEC Pharm 10mg Filmtabletten Tadalafil HEC Pharm 20mg Filmtabletten
Name of the drug substance (INN name):	Tadalafil
Pharmaco-therapeutic group (ATC Code):	G04BE08
Pharmaceutical form(s) and strength(s):	Film coated tablet, 2,5 mg; 5mg; 10mg; 20mg
Reference Number(s) for the Decentralised Procedure	DE/H/5634/001–004/DC
Reference Member State:	DE
Concerned Member States:	No CMS
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 Germany
Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA	Formula Pharmazeutische und chemische Entwicklungs GmbH Goerzallee 305 b 14167 Berlin Germany

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for Tadalafil HEC Pharm 2.5, 5, 10 and 20 mg film-coated tablets, in the treatment of erectile dysfunction in adult males and the treatment of the signs and symptoms of benign prostatic hyperplasia in adult males (5 mg strength only),

is approved.

• II. EXECUTIVE SUMMARY

  • II.1 Problem statement

N/A

• II.2 About the product

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the absence of sexual stimulation.

Therapeutic indications (as claimed by the applicant):

• Treatment of erectile dysfunction in adult males.

In order for tadalafil to be effective for the treatment of erectile dysfunction, sexual stimulation is required.

• Treatment of the signs and symptoms of benign prostatic hyperplasia in adult males (5 mg strength only).
• Tadalafil is not indicated for use by women.

The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.

Special populations

Elderly men

Dose adjustments are not required in elderly patients.

Men with renal impairment

Dose adjustments are not required in patients with mild to moderate renal impairment. For patients with severe renal impairment 10 mg is the maximum recommended dose. Once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment.

Men with hepatic impairment

The recommended dose of [Invented name] is 10 mg taken prior to anticipated sexual activity and with or without food. There is limited clinical data on the safety of [Invented name] in patients with severe hepatic impairment (Child-Pugh Class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment.

Once-a-day dosing has not been evaluated in patients with hepatic impairment; therefore, if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician.

Men with diabetes

Dose adjustments are not required in diabetic patients.

Paediatric population

There is no relevant use of [Invented name] in the paediatric population with regard to the treatment of erectile dysfunction.

• II.3 General comments on the submitted dossier

The Application is submitted in accordance with Article 10 (1) Directive 2001/83/EC (generic application) as amended. The submitted documentation in relation to the proposed product is of sufficient quality and is consistent with the current EU regulatory requirements from a non-clinical and clinical point of view.

To support the application, the applicant has submitted two bioequivalence studies (under fasting and fed conditions) showing bioequivalence of the test product Tadalafil 20mg film-coated tablets (the highest strength) with the originator product Cialis® 20mg film-coated tablets.

• 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.

A copy of a valid QP declaration has been provided.

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/GLP

According to the Applicant the bioequivalence study and the validation of the methods were conducted in accordance to the principles of GCP and GLP.

GLP

In line with the generic type of application, the Applicant has not performed non-clinical studies.

• III. SCIENTIFIC OVERVIEW AND DISCUSSION

  • III.1 Quality aspects

Drug substance

Tadalafil is described in Ph.Eur. The active substance is practically insoluble in water. Tadalafil shows polymorphism, the form used in the drug product is crystalline form –1.

The sources of the drug substance are coverd by two valide European Certificates of Suitability.

The manufacturing process of tadalafil is coverd by the CEPs.

The submitted drug substance specification is in line with the Ph. Eur. taladafil monograph and additional requirments of the CEP.

The limits for the single identified and unidentified impurities fully comply with the requirements of the general Ph. Eur. monograph Substances for Pharmaceutical Use and relevant ICH guidelines.

Additional documents have been presented by the drug product manufacturer

All aspects of the manufacture, in-process controls, control of materials, Control of critical steps are covered by two certificate of suitability for the active substance manufacturer.

The proposed retest periods are acceptable as being specified on the CEPs.

The control test and specification for drug substance product are adequately drawn up.

Drug Product

Tadalafil HEC Pharm 2.5 / 5 / 10 / 20 mg Filmtabletten are packaged in PVC/PVDC aluminium blister package system. All strengths are pink round film-coated tablets with different debossing.

The development of the product has been described, the choice of excipients is justified and their functions explained.

The proposed specification for the finished product is in line with ICH Q6A, where relevant, and is considered acceptable.

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 finished product specification is satisfactory. The methods have been described and have been adequately validated as appropriate.

The conditions used in the stability studies are according to the ICH stability guideline.

The tested parameters appearance, microbiological quality, assay, dissolution, impurities A, B, C, related substances and crystal form (for information only) are described.

The methods used during the stability studies are the same as presented for release.

Additionally, for stability studies the packaging material as proposed for marketing was used and is described. All tested parameters remained within the acceptance limits. Hence, the proposed shelflife of 24 months is accepted.

The applicant has complemented the quality document with further data. The quality documentation is adequate sufficient.

• III.2 Non-clinical aspects

Pharmacodynamic, pharmacokinetic and toxicological properties of tadalafil are well known. As tadalafil 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 April 2018. The report refers to 13 publications up to year 2014.

Upon request, the Applicant has introduced an assessment of the excipients used in the medicinal product under review in the non-clinical overview. The updated non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate.

Environmental Risk Assessment (ERA)

Since Tadalafil HEC Pharm 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

Pharmacokinetics

This application concerns 4 strengths, i.e. 2.5, 5, 10 and 20 mg film-coated tablets.

In order to show essential similarity with the original product Cialis® 20 mg Tablets (Eli Lilly Nederland B.V., The Netherlands), HEC Pharm GmbH conducted 2 bioavailability studies under fasting and fed conditions (17-VIN-0168 and 17-VIN-0169) with the test product Tadalafil 20 mg Tablets and the reference product Cialis® 20 mg Tablets (Eli Lilly Nederland B.V., The Netherlands). Both studies were performed in healthy volunteers. The GCP/GLP aspects of the clinical phases of the studies are sufficiently documented. Quality assurance documents were provided. The study center has been recently inspected by European Authorities.

Analytical methods

The analytical part of the study was conducted between 4 October 2017 and 13 October 2017.

Plasma concentrations of tadalafil were determined using an automated liquid-liquid extraction procedure and LC-MS/MS method with Tadalafil‐D3 used as internal standard.

The calibration curve for tadalafil ranged from 2.00 ng/mL to 800.00 ng/mL. Tadalafil calibration curves were obtained by using weighted (1/X2) least square linear regression analysis of the peak area ratio (analyte) versus the nominal concentration of the calibration standards. Intra-assay and inter-assay accuracy and precision were tested on tadalafil QC sample concentrations of about 2.00, 6.00, 45.00, 300.00, 600.00 and 3600.00 ng/ml during validation.

Design, conduct and statistical analyses of the study were found to be adequate and in line with respective EMA guidelines. The method used to analyse tadalafil in human plasma was found to be sufficiently validated and suitable for its intended purpose

Biowaiver

The dissolution data for Tadalafil 2.5 mg/5 mg/10 mg vs 20 mg film-coated tablets in 0.5% SLS, 0.1 M HCl, pH 4.5, and pH 6.8, respectively demonstrate an excellent dissolution in 0.5% SLS but a poor dissolution in 0.1 M HCl, pH 4.5, and pH 6.8 for both the test and the reference formulation.

The dissolution data showed that the 2.5, 5, 10 and 20 mg (biobatch) formulations have comparable dissolutions at the tested pH values. Considering that the formulations are dose proportional, are manufactured by the same manufacturing process and the linear pharmacokinetics, the requirements for the biowaiver for additional strengths have been fulfilled.

Results

Bioequivalence evaluation of tadalafil in 17-VIN-0168 (fasting condition)

Parameters (Units)	Geometrie Least Squares Means and it’s ratio (N = 30)			ISCV (%)	90% Confidence Interval	Power (%)
	Test Product cn	Reference Product CR)	(T/R)%
c (ng/mL)	335.773	376.728	89.13	13.68	83.95%- 94.62%	100.00
AUC0.t (hr*ng/mL)	9876.334	10363.950	95.30	16.38	88.72% – 102.36%	99.94
AUC0^ (hr*ng/mL)	12556.313	13600.737	92.32	19.38	84.86% – 100.44%	99.54

Bioequivalence evaluation of tadalafil in 17-VIN-0169 (fed condition)

PK Parameters (Unit)	Geometrie Least Square Means and It’s Ratio			LSCV (%)	90% CI	Power (%)
	Test Product (T)	Reference Product ®	iTR; (%)
'-max (ng/mL)	419.553	397.329	105.59	12.46	99.54% – 112.02%	100.00
AUCo.t (hr*ng/mL)	11063.4 66	10382.474	106.56	19.49	97.20% – 116.82%	98.88
AUCkirf (lir*ng'mL)	13340.1 99	13666.702	97.61	23.50	87.41%- 109.00%	95.34

Based on the submitted bioequivalence studies under both fasting and fed conditions the Tadalafil HEC Pharm 20 mg film-coated tablet is considered bioequivalent with the Cialis® 20 mg film coated tablet. The results obtained for the 20 mg tablet can be extrapolated to the 2.5, 5 and 10 mg tablets as the criteria for waiving additional strengths were fulfilled.

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 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 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 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 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

Common renewal date is 18.02.2024.

Legal status

Medicinal product subject to medical prescription.

User Test

• 24 male subjects between 18 and 65 years and above participated on the User Test. A pilot was performed with 4 participants followed by 2 rounds of testing with 10 participants.

100% of the test participants are able to find the information requested within the package leaflet of which 100% can show that they understand it.

The Package Leaflet has not been amended after conduction of the user test.

The User Test is acceptable.

• IV. BENEFIT RISK ASSESSMENT