Public Assessment Report

Scientific discussion

Tadalafil Hexal 2.5 mg, 5 mg, 10 mg and 20 mg,

film-coated tablets

(tadalafil)

NL/H/4396/001-004/DC

Date: 12 November 2019

This module reflects the scientific discussion for the approval of Tadalafil Hexal 2.5 mg, 5
mg, 10 mg and 20 mg, film-coated tablets. The procedure was finalised on 15 May 2019.
For information on changes after this date please refer to the ‘steps taken after
finalisation’ at the end of this PAR.
List of abbreviations
ASMF Active Substance Master File
CEP Certificate of Suitability to the monographs of the European
Pharmacopoeia
CHMP Committee for Medicinal Products for Human Use
CMD(h) Coordination group for Mutual recognition and Decentralised
procedure for human medicinal products
CMS Concerned Member State
EDMF European Drug Master File
EDQM European Directorate for the Quality of Medicines
EEA European Economic Area
ERA Environmental Risk Assessment
ICH International Conference of Harmonisation
MAH Marketing Authorisation Holder
Ph.Eur. European Pharmacopoeia
PL Package Leaflet
RH Relative Humidity
RMP Risk Management Plan
SmPC Summary of Product Characteristics
TSE Transmissible Spongiform Encephalopathy

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I. INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have
granted a marketing authorisation for Tadalafil Hexal 2.5 mg, 5 mg, 10 mg and 20 mg, film-
coated tablets from Hexal AG.

The product is indicated for:

 Treatment of erectile dysfunction in adult males. In order for tadalafil to be effective,
sexual stimulation is required.

Tadalafil Hexal is not indicated for use by women.

A comprehensive description of the indications and posology is given in the SmPC.

This decentralised procedure concerns a generic application claiming essential similarity with
the innovator products Cialis 2.5 mg, 5 mg, 10 mg and 20 mg, film-coated tablets which have
been registered in the EEA through centralised procedure EMEA/H/C/000436 by Eli Lilly
Nederland B.V. since 12 November 2002.

The concerned member state (CMS) involved in this procedure was Germany.

The marketing authorisation has been granted pursuant to Article 10(1) of Directive
2001/83/EC.

II. QUALITY ASPECTS

II.1 Introduction

Tadalafil Hexal 2.5 mg is a ochre to yellow coloured, round shaped film-coated tablets
debossed with “2.5” on one side and plain on the other side.
Tadalafil Hexal 5 mg is a ochre to yellow, oval shaped film-coated tablet debossed with “5”
on one side and plain on the other side.
Tadalafil Hexal 10 mg is a ochre to yellow, oval shaped film-coated tablet debossed with “10”
on one side and plain on the other side.
Tadalafil Hexal 20 mg is a ochre to yellow, oval shaped film-coated tablets. On one side it is
scored and debossed with “2” on the left side of the score and with “0” on the right side of
the score. The other side is plain. The tablet can be divided into equal halves.

Each film-coated tablet contains 2.5 mg, 5 mg, 10 mg or 20 mg tadalafil.

The film-coated tablets are packed in Alu-Alu(Al-OPA/Al/PVC), PVC/ACLAR/PVC-Al or

PVC/ACLAR/PVdC/PVC-Al blisters

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The excipients are:
Tablet core: lactose monohydrate, sodium laurilsulfate (E487), povidone K-12 (E1201),
crospovidone (type B; E1202) and sodium stearyl fumarate
Tablet coating: polyvinyl alcohol (E1203), macrogol 3350 (E1521), titanium dioxide (E171),
talc (E553b), yellow iron oxide (E172)

The four different tablet strengths have a fully dose proportional composition.

II.2 Drug Substance

The active substance is tadalafil, an established active substance described in the European
Pharmacopoeia (Ph.Eur.). Tadalafil is a white or almost white powder. It is practically
insoluble in water, freely soluble in dimethyl sulfoxide and slightly soluble in methylene
chloride. Tadalafil can exist in different crystalline forms and an amorphous form and
exhibits polymorphism. The manufacturer consistently produces the anhydrous form-1.

The CEP procedure is used for the active substance. Under the official Certification
Procedures of the EDQM of the Council of Europe, manufacturers or suppliers of substances
for pharmaceutical use can apply for a certificate of suitability concerning the control of the
chemical purity and microbiological quality of their substance according to the
corresponding specific monograph, or the evaluation of reduction of Transmissible
Spongiform Encephalopathy (TSE) risk, according to the general monograph, or both. This
procedure is meant to ensure that the quality of substances is guaranteed and that these
substances comply with the Ph.Eur.

Manufacturing process
A CEP has been submitted; therefore no details on the manufacturing process have been
included.

Quality control of drug substance

The active substance specification is considered adequate to control the quality. It meets the
requirements of the monograph in the Ph.Eur. and additional requirements of the CEP,
including tests for identity, heavy metals and residual solvents that have been adopted from
the specification of the supplier and additional in-house tests for particle size, bulk- and
tapped density. Batch analytical data demonstrating compliance with this specification have
been provided for two batches.

Stability of drug substance

The active substance is stable for 60 months when stored under the stated conditions.
Assessment thereof was part of granting the CEP and has been granted by the EDQM.

II.3 Medicinal Product

Pharmaceutical development
The product is an established pharmaceutical form and its development is adequately
described in accordance with the relevant European guidelines. The choice of excipients is

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justified and their functions explained. The main development studies were the
characterisation of the reference product, optimisation of the excipient levels in the
formulation and the performance of comparative dissolution studies. The choices of the
packaging and manufacturing are justified.
A bioequivalence study under fasted conditions has been performed with the 20 mg
strength. The dissolution studies showed similarity in dissolution between the test product
and the reference product. For the additional strengths a biowaiver has been requested and
has been justified based on in vitro dissolution data. The MAH has sufficiently demonstrated
that this discrepancy was due to poor dissolution of the active substance and was not drug
product related. The pharmaceutical development of the product has been adequately
performed.

Manufacturing process
The main steps of the manufacturing process are premixing, wet granulation, drying, milling,
blending, compression, coating and packaging. The manufacturing process has been
adequately validated according to relevant European guidelines. Process validation data on
the product has been presented for two pilot scaled batches of the 2.5 mg, 5 mg and 10 mg
strengths and three pilot scaled batches for the 20 mg strength. The product is
manufactured using conventional manufacturing techniques. Process validation for full
scaled batches will be performed post authorisation.

Control of excipients
All excipients comply with their Ph.Eur. monographs except Opadry film-coating material,
which is controlled according to an in-house specification. The specifications are acceptable.

Quality control of drug product

The finished product specifications are adequate to control the relevant parameters for the
dosage form. The specification includes tests for appearance, identity, dissolution,
uniformity of dosage units, assay, optical purity, related substances, microbiological quality,
loss on drying and uniformity of mass for subdivided parts (only 10 mg and 20 mg products).
Except for optical purity and related substances, the release and shelf-life requirements are
identical. Limits in the specification have been justified and are considered appropriate for
adequate quality control of the product.
Satisfactory validation data for the analytical methods have been provided. Batch analytical
data from three pilot scale batches per strength from the proposed production site have
been provided, demonstrating compliance with the specification.

Stability of drug product

Stability data on the product has been provided for two pilot scaled batches of the 2.5 mg, 5
mg and 10 mg strengths and three pilot scaled batches for the 20 mg strength stored at
25°C/60% RH (24 months) and 40°C/75% RH (6 months). The conditions used in the stability
studies are according to the ICH stability guideline. The batches were stored in the proposed
packaging. Except for a slight increase in impurities at accelerated storage conditions and
some variability in some of the test parameters, the stability data showed no clear trends or
changes at both storage conditions. Results of a formal photostability study showed that the
drug product was not sensitive to light exposure when directly exposed. Based on the

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presented stability data, the proposed shelf-life of 24 months without any special storage
requirements is justified.

Specific measures concerning the prevention of the transmission of animal spongiform

encephalo-pathies
Specific measures for the prevention of the transmission of animal spongiform
encephalopathies
Lactose monohydrate is of animal origin. Compliance with the Note for Guidance on
Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal
Products has been confirmed.

II.4 Discussion on chemical, pharmaceutical and biological aspects

Based on the submitted dossier, the member states consider that Tadalafil Hexal has a
proven chemical-pharmaceutical quality. Sufficient controls have been laid down for the
active substance and finished product.

No post-approval commitments were made.

III. NON-CLINICAL ASPECTS

III.1 Ecotoxicity/environmental risk assessment (ERA)

Since Tadalafil Hexal is intended for generic substitution, this will not lead to an increased
exposure to the environment. An environmental risk assessment is therefore not deemed
necessary.

III.2 Discussion on the non-clinical aspects

This product is a generic formulation of Cialis which is available on the European market.
Reference is made to the preclinical data obtained with the innovator product. A non-clinical
overview on the pharmacology, pharmacokinetics and toxicology has been provided, which
is based on up-to-date and adequate scientific literature. The overview justifies why there is
no need to generate additional non-clinical pharmacology, pharmacokinetics and toxicology
data. Therefore, the member states agreed that no further non-clinical studies are required.

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IV. CLINICAL ASPECTS
IV.1 Introduction

Tadalafil is a well-known active substance with established efficacy and tolerability.

A clinical overview has been provided, which is based on scientific literature. The overview
justifies why there is no need to generate additional clinical data. Therefore, the member
states agreed that no further clinical studies are required.

For this generic application, the MAH has submitted a bioequivalence study, which is
discussed below.

IV.2 Pharmacokinetics

The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test
product Tadalafil Hexal 20 mg, film-coated tablets (Hexal AG, NL ) is compared with the
pharmacokinetic profile of the reference product Cialis 20 mg, film-coated tablets (Eli Lilly
Nederland B.V., NL).

The choice of the reference product in the bioequivalence study is justified as the reference
product was authorised in the EU through a centralised procedure.
The formula and preparation of the bioequivalence batch is identical to the formula
proposed for marketing.

Biowaiver
The following criteria for extrapolation of the results obtained in the bioequivalence studies
for the 20 mg to the 5 mg and 10 mg tablets have been fulfilled:
 the formulations are dose proportional.
 the formulations are manufactured by the same manufacturer and manufacturing
process.
 tadalafil shows linear pharmacokinetics over the therapeutic dose range of 2.5 – 20 mg.
 comparable dissolution has been shown at pH 1.2, 4.5 and 6.8 using the same dose; the
f2 factor was above 50 in all cases.

Bioequivalence study: 20 mg under fasted conditions

Design
A open-label, balanced, randomised, single-dose, two-treatment, two-sequence, two-period,
crossover bioequivalence study was carried out under fasted conditions in 20 healthy male
subjects, aged 22-54 years. Each subject received a single dose (20 mg) of one of the 2
tadalafil formulations. The tablet was orally administered with 240 ml water after an
overnight fast. There were 2 dosing periods, separated by a washout period of 14 days.

Blood samples were collected pre-dose and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.5,
4, 4.5, 5, 6, 8, 12, 24, 36, 48, 60 and 72 hours after administration of the products.

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The design of the study is acceptable. Tadalafil can be taken regardless of food, according to
the SmPC.

Analytical/statistical methods
The analytical method has been adequately validated and is considered acceptable for
analysis of the plasma samples. The methods used in this study for the pharmacokinetic
calculations and statistical evaluation are considered acceptable.

Results
Two subjects withdrew consent due to personal reasons and one subject was withdrawn due
to an adverse event. Therefore, 17 subjects were eligible for pharmacokinetic analysis.

Table 1. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD,

tmax (median, range)) of 20 mg tadalafil under fasted conditions.
Treatment AUC0-72 AUC0-∞ Cmax tmax t1/2
N=25 ng.h/ml ng.h/ml ng/ml h h
Test 7706  2566 9065  3805 293  45 3.0 23  8
(1.33 – 4.5)
Reference 8649  3254 10129  4712 328  91 3.0 23  8
(0.67 – 5.0)
*Ratio (90% 0.90 -- 0.91 -- --
CI) (0.83 – 0.98) (0.84 – 0.99)

CV (%) 14.1 -- 14.3 -- --

AUC0-∞ area under the plasma concentration-time curve from time zero to
infinity
AUC0-72 area under the plasma concentration-time curve from time zero to 72
hours
Cmax maximum plasma concentration
tmax time for maximum concentration
t1/2 half-life
CV coefficient of variation
*ln-transformed values

Conclusion on bioequivalence study

The 90% confidence intervals calculated for AUC0-t and Cmax are within the bioequivalence
acceptance range of 0.80 – 1.25. Based on the submitted bioequivalence studies Tadalafil
Hexal is considered bioequivalent with Cialis.

The MEB has been assured that the bioequivalence study has been conducted in accordance
with acceptable standards of Good Clinical Practice (GCP, see Directive 2005/28/EC) and
Good Laboratory Practice (GLP, see Directives 2004/9/EC and 2004/10/EC).

The results of study 2013-3225 with the 20 mg formulation can be extrapolated to other
strengths 2.5 mg, 5 mg, and 10 mg, according to conditions in Guideline on the Investigation
of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.
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 IV.3 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
Tadalafil Hexal.

Summary table of safety concerns as approved in RMP:

Important identified risks  Prolonged and painful erection

(priapism)
 Low blood pressure (hypotension /
increased hypotensive effect)
Important potential risks  Non-arteritic anterior ischaemic optic
neuropathy (NAION)
 Sudden decrease or loss of hearing
 Increased uterine bleeding
Missing information  Characterisation of adverse events in
elderly (≥65 years)

The member states agreed that routine pharmacovigilance activities and routine risk
minimisation measures are sufficient for the risks and areas of missing information.

IV.4 Discussion on the clinical aspects

For this authorisation, reference is made to the clinical studies and experience with the
innovator product Cialis. No new clinical studies were conducted. The MAH demonstrated
through a bioequivalence study that the pharmacokinetic profile of the product is similar to
the pharmacokinetic profile of this reference product. Risk management is adequately
addressed. This generic medicinal product can be used instead of the reference product.

V. USER CONSULTATION
A bridging report was provided to support the readability of the package leaflet (PL) for
Tadalafil Hexal. The MAH has indicated that the wording of the PL is in line with that of the
reference product Cialis, which is a centrally authorised product. Furthermore, the format of
the leaflet is similar to that of other user tested leaflets of the MAH. Altogether, the Member
States consider the bridging for user testing acceptable.

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VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT
AND RECOMMENDATION
Tadalafil Hexal 2.5 mg, 5 mg, 10 mg and 20 mg, film-coated tablets have a proven chemical-
pharmaceutical quality and are generic forms of Cialis 2.5 mg, 5 mg, 10 mg and 20 mg, film-
coated tablets. Cialis is a well-known medicinal product with an established favourable
efficacy and safety profile.

Bioequivalence has been shown to be in compliance with the requirements of European

guidance documents.

The Board followed the advice of the assessors.

There was no discussion in the CMD(h). Agreement between member states was reached
during a written procedure. The member states, on the basis of the data submitted,
considered that essential similarity has been demonstrated for Tadalafil Hexal with the
reference product, and have therefore granted a marketing authorisation. The decentralised
procedure was finalised with a positive outcome on 15 May 2019.

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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE –
SUMMARY
Scope Procedure Type of Date of Date of Approval Assessme
number modificatio start of the end of / nt report
n procedure the non attached
procedur approval
e

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