Version 10 february 2012

Public Assessment Report
Scientific discussion
Blugral 25, 50 & 100mg Film-coated Tablets
(Sildenafil Citrate)
IE/H/242/001-003/DC
Date: 11th January 2013

This module reflects the scientific discussion for the approval of Blugral 25, 50 & 100mg Film-
coated Tablets. The procedure was finalised on 26th November 2012. For information on
changes after this date please refer to the module ‘Update’.
INTRODUCTION


“Based on the review of the quality, safety and efficacy data, the Member States have granted
a marketing authorisation for Blugral, 25, 50 & 100mg Film-coated Tablets (sildenafil citrate),
from Niche Generics.
The product is indicated for: erectile dysfunction.
A comprehensive description of the indications and posology is given in the SmPC.”

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

Erectile dysfunction (ED) icharacterized by the inability to develop or maintain
of tduring sexual performance Most cases are due to narrowing of the arteries
supplying blood to the penis and the risk factors for erectile dysfunction are similar to those for
coronary heart disease.
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.

No discussions were held with CMDh during the procedure.
II.
QUALITY ASPECTS
Introduction
Sildenafil 25mg, 50mg and 100mg film-coated tablets are diamond shaped, blue coloured, biconvex,
film-coated tablets debossed with „U‟ on one side and „25‟/ „50‟/ „100‟ on the other side respectively for
the three strengths. The tablets are packaged in PVC/Aluminium blister foils.
II.2
Drug Substance
The drug substance is sildenafil citrate, an established active substance of chemical origin. It is not
currently monographed in the European Pharmacopoeia.
The active substance specification includes relevant tests and the acceptance limits have been
appropriately justified. The analytical methods applied are suitably described and validated.
Stability studies have been conducted and the data provided is sufficient to support the proposed retest
period.

II.3
Medicinal Product
The development of the drug product formulation is well described. The qualitative composition is similar to that of the reference product, Viagra. Comparative in vitro dissolution profiles of the generic product and the reference product support the claim for similarity. The excipients used in the product are all standard in the manufacture of tablets and are compliant with European Pharmacopoeia (or equivalent) requirements. The manufacturing process has been sufficiently described and critical steps identified. Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the finished products specifications are considered appropriate to control the quality of the finished product in relation to its intended purpose.
Stability studies under ICH conditions have been performed for tablets in the commercial packaging;
the data support the shelf life claimed in the SPC; 2 years when stored below 30°C and in the original
package.
II.4
Discussion on chemical, pharmaceutical and biological aspects
The chemical and pharmaceutical aspects of the application are acceptable and there are no objections
to the granting of the authorisation. There are no biological aspects to this application.
III.
NON-CLINICAL ASPECTS
Non-clinical overview
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. The non-clinical overview was written by appropriately qualified expert. It contains a review of 38
references published up to the year 2009 and covers all appropriate non clinical aspects. All relevant
non-clinical findings have been described adequately in the corresponding sections of the product
literature (SmPC).
III.2
Ecotoxicity/environmental risk assessment (ERA)
Since Blugral 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.3
Discussion on the non-clinical aspects

The non-clinical aspects of Blugral are expected to be similar to those of Viagra. There are no
objections to the approval of Blugral from a non-clinical perspective.
IV.
CLINICAL ASPECTS
Introduction
A bioequivalence study performed in the fasting state demonstrated bioequivalence between 100mg of
Blugral and 100mg of Viagra.
IV.2
Pharmacokinetics
In case of generic applications:
Biowaiver
A bioequivalence study for the highest strength (100 mg) was submitted. A biowaiver for the
25 mg and 50 mg strengths is appropriate. The pharmacokinetics are linear for the proposed
dosing range (25 mg to 100 mg). All of the remaining criteria for a biowaiver have been met
i.e: the products are manufactured by the same manufacturing process; the qualitive
composition of the different strengths is the same; the composition of the strengths are
quantitatively proportional; and in vitro dissolution profiles are comparable.
Bioequivalence studies
One bioequivalence study in the fasted state 10-VIN-218 was submitted. The applicant states
that the study was conducted under conditions of Good General Practice (GCP) and Good
Laboratory Practice (GLP).
The study (10-VIN-218) was an open label, balanced, randomized, two-treatment, two-period two-sequence, single dose bioequivalence study conducted in healthy adult males under fasting conditions which compared Blugral 100mg (sildenafil citrate) to Viagra 100mg. The study was conducted under standardised conditions. Pharmacokinetic parameters (non-transformed values; arithmetic
mean ± SD, tmax median, range)
Treatment
AUC0-∞
2788.179
± 2849.266 ± 932.7265
± 0.893 ± 0.5296
906.5790
325.8431
Reference
2778.292
± 2839.572 ± 946.6451
± 0.843 ± 0.6330
913.3381
324.3313
*Ratio (90% CI)
100.67% (96.19% - 101.90%
(96.21%-
105.36%)
(94.05%-
105.23%)
110.40%)
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
AUC0-∞
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
Cmax Maximum plasma concentration
tmax Time until Cmax is reached

Conclusion on bioequivalence studies:
Based on the submitted bioequivalence study BLUGRAL is considered bioequivalent with
Viagra
The results of study 10-VIN-218 with 100 mg formulation can be extrapolated to other
strengths 25 mg and 50mg, according to conditions in Guideline on the Investigation of
Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section 4.1.6.
The justification for BCS (Biopharmaceutics Classification System) - based biowaiver can be
accepted.
IV.3
Pharmacodynamics
Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus caverosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects. Studies in vitro have shown that sildenafil is selective for PDE5, which is involved in the erection process. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. At maximum recommended doses, there is an 80-fold selectivity over PDE1, and over 700-fold over PDE 2, 3, 4, 7,
8,9,10 and 11. In particular, sildenafil has greater then 4,000-fold selectivity for PDE5 over PDE3, the
cAMP-specific phosphodiesterase isoform involved in the control of cardiac contractility.
IV.4
Clinical efficacy
The clinical efficacy of sildenafil is well characterised.
IV.5
Clinical safety
Viagra (sildenafil) was first authorised centrally in 1998. The clinical safety of sildenafil is well
characterized.
IV.6
Discussion on the clinical aspects
This is an application for a generic version of a product which was first authorised in 1998.
The submission of abridged applications for generic products avoids the need for repetitive
tests on animals and humans.
Once bioequivalence has been demonstrated between the generic product and a reference
product (in this case Viagra) it can be expected that the generic product and the reference
product will have similar efficacy and safety. As bioequivalence has been demonstrated
between Blugral 100mg and Viagra 100mg and conditions for a biowaiver for the 25mg and
50mg of Blugral have been met it can be assumed that Blugral is likely to have similar
efficacy and safety to Viagra.


V.
Overall conclusion, benefit/risk assessment and recommendation
There were no discussions in CMDh, no Specific obligations, nor any follow-up measures. User consultation The package leaflet 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. The language used for the purpose of user testing the PIL was English. The results show that the package leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and package leaflet of medicinal products for human use.

Source: http://www.imb.ie/images/uploaded/swedocuments/~Blugral%2025,%2050%20&%20100mg%20Film-coated%20Tablets.pdf