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Public Assessment Report

Scientific discussion

Sildenafil Amneal 25 mg, 50 mg and 100 mg

film-coated tablets

(sildenafil citrate)

NL/H/3394/001-003/DC

Date: 19 September 2016

This module reflects the scientific discussion for the approval of Sildenafil Amneal 25
mg, 50 mg and 100 mg film-coated tablets. The procedure was finalised on 4 February
2016. For information on changes after this date please refer to the ‘steps taken after
finalisation’ at the end of this PAR.
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List of abbreviations
ASMF Active Substance Master File
CMD(h) Coordination group for Mutual recognition and Decentralised procedure for
human medicinal products
CMS Concerned Member State
EDMF European Drug Master File
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 Sildenafil Amneal 25 mg, 50 mg and 100 mg film-coated tablets from
Amneal Pharma Europe Limited.

The product is indicated in adult men with erectile dysfunction, which is the inability to achieve or
maintain a penile erection sufficient for satisfactory performance. In order for Sildenafil Amneal to be
effective, sexual stimulation is required.

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 product Viagra 25 mg, 50 mg and 100 mg, film-coated tablets which has been registered in
the EU through centralised procedure EMEA/H/C/000202 by Pfizer Ltd. The date of authorisation was
on 14 September 1998.

The concerned member states (CMS) involved in this procedure were Germany, Denmark, Spain,
Finland, Norway and Sweden.

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

II. QUALITY ASPECTS

II.1 Introduction

Sildenafil Amneal is a light blue to blue, oval shaped film-coated tablet debossed with ‘AN 1019’ (25
mg), ‘AN 1020’ (50 mg) or ‘AN 1021’ (100 mg) on one side and plain on the other side. Each tablet
contains sildenafil citrate equivalent to 25 mg, 50 mg or 100 mg sildenafil.

The film-coated tablets are packed in PVC-PVdC/Aluminium blisters.

The excipients are:

Tablet core – anhydrous calcium hydrogen phosphate, microcrystalline cellulose, croscarmellose
sodium, hypromellose and magnesium stearate.
Tablet coating – polyvinyl alcohol (partially hydrolysed), titanium dioxide (E171), macrogol 4000, talc
(E553b) and indigo carmine aluminium lake (E132).

The different tablet strengths are fully dose proportional.

II.2 Drug Substance

The active substance is sildenafil citrate, an established active substance described in the European
Pharmacopoeia (Ph.Eur.). Sildenafil citrate is a white or almost white and slightly hygroscopic powder.
It is slightly soluble in water and in methanol and practically insoluble in hexane. Sildenafil citrate has
no chiral centres and does not exhibit stereoisomerism. The drug substance is a crystalline powder
and is consistently manufactured having the same polymorphic form.

The Active Substance Master File (ASMF) procedure is used for the active substance. The main
objective of the ASMF procedure, commonly known as the European Drug Master File (EDMF)
procedure, is to allow valuable confidential intellectual property or ‘know-how’ of the manufacturer of
the active substance (ASM) to be protected, while at the same time allowing the applicant or
marketing authorisation holder (MAH) to take full responsibility for the medicinal product, the quality
and quality control of the active substance. Competent Authorities/EMA thus have access to the
complete information that is necessary to evaluate the suitability of the use of the active substance in
the medicinal product.

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Manufacturing process
The manufacturing process consists of four chemical steps followed by a purification step. No heavy
metal catalysts or Class I organic solvents are used in the process. The active substance has been
adequately characterised and acceptable specifications have been adopted for the starting materials,
solvents and reagents.

Quality control of drug substance

The active substance specification is considered adequate to control the quality and meets the
requirements of the monograph in the Ph.Eur. on sildenafil citrate and the specification from the ASMF
with additional tests microbiological quality, particle size distribution and identity and polymorphic form.
Batch analytical data demonstrating compliance with this specification have been provided for 2 full
scaled batches.

Stability of drug substance

Stability data on the active substance have been provided for at least 3 full scaled batches in
accordance with applicable European guidelines stored at 25°C/60% RH (60 months) and 40°C/75%
RH (6 months). No trends of changes were observed for any of the tested parameters at both storage
conditions. Based on the data submitted, a retest period could be granted of 60 months with the
storage condition: ‘Store in well closed container below 25°C’.

II.3 Medicinal Product

Pharmaceutical development
The development of the product has been described, the choice of excipients is justified and their
functions explained. The main development studies performed were the characterisation of the
reference product Viagra, selection and optimisation of the components and the performance of
comparative dissolution studies. The choice of the packaging is justified.

A bioequivalence study was performed between test product Viagra 100 mg and the reference product
Sildenafil Amneal 100 mg. Both the test and reference batch are manufactured according to the
finalised formulation and manufacturing process. Similar dissolution profiles were confirmed between
the test and reference batch in pH 1.2 and pH 4.5 media (>85% dissolved in 15 minutes) Though
similarity in dissolution was not shown in pH 6.8 medium (f2 <50)., no objection is made as the results
of the in vivo studies prevail.
For the 25 mg and 50 mg strengths a biowaiver was requested. In vitro dissolution studies show
similarity in dissolution between these strengths and the 100 mg test batch in 0.1N HCl (pH 1.2) and
pH 4.5 dissolution media (>85% dissolved in 15 minutes). In pH 6.8 medium the dissolution is similarly
poor for the test product and the additional strengths.

Manufacturing process
The manufacturing process has been validated accordingly. The main steps in the manufacturing
process are wet granulation, blending, lubrication, compression and film-coating. Process validation
data on the product have been presented for 2 production scaled batches of common blend that were
used for compression of 2 pilot scale batches of each finished product strength. The product is
manufactured using conventional manufacturing techniques. Process validation for full-scale batches
will be performed post authorisation.

Control of excipients
The excipients comply with Ph.Eur. or in-house specifications. These 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, identification, disintegration time, dissolution,
assay, uniformity of dosage units, related substances, loss on drying and microbiological quality.
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 2 pilot scale batches per strength from the proposed production site have
been provided, demonstrating compliance with the specification.

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Stability of drug product
Stability data on the product have been provide for 2 pilot scaled batches per strength stored at
25°C/60% RH (12 months) and 40°C/75% RH (6 months) in accordance with applicable European
guidelines. The batches were stored in the proposed packaging. Except for an increase in loss on
drying at both storage conditions, no clear changes or trends were observed in any of the tested
parameters. Results of the photostability study showed that the drug product is not sensitive to light
exposure. The proposed shelf-life of 2 years without any special storage requirements is justified.

Specific measures concerning the prevention of the transmission of animal spongiform

encephalopathies
There are no substances of ruminant animal origin present in the product nor have any been used in
the manufacturing of this product, so a theoretical risk of transmitting TSE can be excluded.

II.4 Discussion on chemical, pharmaceutical and biological aspects

Based on the submitted dossier, the member states consider that Sildenafil Amneal 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 Sildenafil Amneal 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 Viagra 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.

IV. CLINICAL ASPECTS

IV.1 Introduction

Sildenafil citrate 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 one bioequivalence study which is discussed
below.

IV.2 Pharmacokinetics

The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product
Sildenafil Amneal 100 mg, film-coated tablets (Amneal Pharma Europe Limited, Ireland) is compared
with the pharmacokinetic profile of the reference product Viagra 100 mg (Pfizer Ltd, UK).

The choice of the reference product in the bioequivalence study is accepted, as has been registered
trough a centralised procedure. The formula and preparation of the bioequivalence batch is identical to
the formula proposed for marketing.

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Biowaiver
The MAH has carried out the bioequivalence study on the highest strength (100 mg). A biowaiver is
requested for other strengths (25 mg and 50 mg) as sildenafil citrate exhibits linear kinetics in the
studied dose range and as all the following general biowaiver criteria are fulfilled:

 The tablets are dose proportional

 The tablets are manufactured by the same manufacturer and manufacturing process
 Over the 25–100 mg dose range, cinacalcet shows linear pharmacokinetics
 In vitro dissolution data shows comparable dissolution for the 25 mg, 50 mg and 100 mg strengths
in different media (pH 1.2, 4.5 and 6.8)

Bioequivalence study
Design
A single-dose, randomised, open label, balanced, two-period, two-treatment, two-sequence, two way,
crossover bioequivalence study was carried out under fasted conditions in 48 healthy male subjects,
aged 19 - 44 years. Each subject received a single dose (100 mg) of one of the 2 sildenafil citrate
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 7 days.

Blood samples were collected pre-dose and at 0.17, 0.33, 0.5, 0.67, 0.83, 1, 1.25, 1.5, 1.75, 2, 2.25,
2.5, 3, 3.5, 4, 6, 8, 10, 12, 16, 20 and 24 hours after administration of the products.

The design of the study is acceptable. Next to sildenafil citrate, the active metabolite N-desmethyl
sildenafil has been analysed. As the data on parent are pivotal, the metabolite data are considered
supportive data.

When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in tmax of 60
minutes and a mean reduction in Cmax of 29% after administration. Therefore the tablet may be taken
with or without food, but if taken with food the onset of activity may be delayed. The bioequivalence
study under fasted conditions is therefore appropriate and in accordance with
CPMP/EWP/QWP/1401/98 Note for Guidance on the investigation of bioavailability and
bioequivalence.

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
One subject withdrew from the study on his own accord. Another subject tested positive for
barbiturates and was withdrawn from the study. Therefore, a total of 46 subjects completed the study
and were eligible for pharmacokinetic analysis.

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

(median, range)) of sildenafil citrate under fasted conditions.

Treatment AUC0-t AUC0-∞ Cmax tmax t1/2

N=46 ng.h/ml ng.h/ml ng/ml h h
1.0
Test 2756 ± 1057 2875 ± 1125 826 ± 374
(0.5 – 3.5)
5.8 ± 2.9

0.83
Reference 2829 ± 922 2995 ± 1043 882 ± 389
(0.33 – 2.5)
6.6 ± 4.4

*Ratio 0.96 0.93

-- -- --
(90% CI) (0.92 – 1.01) (0.83 – 1.04)
CV (%)
13.6 -- 33.5 -- --

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

Table 2. Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax

(median, range)) of N-desmethyl sildenafil under fasted conditions.

Treatment AUC0-t AUC0-∞ Cmax tmax t1/2

N=46 ng.h/ml ng.h/ml ng/ml h h
Test 1.25
3257 ± 1114 3389 ± 1191 664 ± 226 5.0 ± 1.0
(0.67 – 3.5)
Reference 1.0
3326 ± 1085 3459 ± 1150 664 ± 211 5.0 ± 1.0
(0.5 – 3.0)
*Ratio 0.97 0.99
-- -- --
(90% CI) (0.94 – 1.01) (0.92 – 1.08)
CV (%)
10.4 -- 23.3 -- --
AUC0-∞ area under the plasma concentration-time curve from time zero to infinity
AUC0-t area under the plasma concentration-time curve from time zero to t 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 study Sildenafil Amneal is considered
bioequivalent with Viagra.

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).

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 Sildenafil Amneal.

- Summary table of safety concerns as approved in RMP

Important identified risks - Nitrate interaction
Important potential risks - Non-arteritic anterior ischaemic optic
neuropathy (NAION)
- Sudden hearing loss
- Eye haemorrhage
Missing information - Severe hepatic impairment

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 Viagra. 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

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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
The package leaflet (PL) has been evaluated via a user consultation study in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. In order to test the readability of the
PL of Sildenafil Amneal 25 mg, 50 mg and 100 mg film-coated tablets, a total of 24 persons were
questioned: 4 persons during the preliminary round of testing, and 2 groups of each 10 persons during
the following 2 test rounds.
A questionnaire of 18 questions on the leaflet content was used, sufficiently addressing the key safety
and usage messages, with 3 additional questions to receive feedback on the format and user
friendliness of the leaflet.
Overall, the methodology of the user test is considered satisfactory. The participants overall gave
positive feedback on the traceability, comprehensibility, format and layout of the PL. The results show
that the PL meets the criteria for readability as set out in the Guideline on the readability of the label
and PL of medicinal products for human use.

VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION
Sildenafil Amneal 25 mg, 50 mg and 100 mg film-coated tablets a proven chemical-pharmaceutical
quality and are generic forms of Viagra 25 mg, 50 mg and 100 mg, film-coated tablets. Viagra 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 Sildenafil Amneal with the reference product, and have therefore
granted a marketing authorisation. The decentralised procedure was finalised with a positive outcome
on 4 February 2016.

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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY
Scope Procedure Type of Date of start Date of Approval/ Assessment
number modification of the end of the non report
procedure procedure approval attached

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