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Public Assessment Report
Scientific discussion
Desogestrel/Ethinylestradiol STADA 150/20
mcg and 150/30 mcg, tablets
(desogestrel/ethinylestradiol)
NL/H/3146/001-002/DC
Date: 26 August 2016
This module reflects the scientific discussion for the approval of
Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets. The
procedure was finalised on 8 June 2015. 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
CEP
CHMP
CMD(h)
CMS
EDMF
EDQM
EEA
ERA
ICH
MAH
Ph.Eur.
PL
RH
RMP
SmPC
TSE
Active Substance Master File
Certificate of Suitability to the monographs of the European Pharmacopoeia
Committee for Medicinal Products for Human Use
Coordination group for Mutual recognition and Decentralised procedure for
human medicinal products
Concerned Member State
European Drug Master File
European Directorate for the Quality of Medicines
European Economic Area
Environmental Risk Assessment
International Conference of Harmonisation
Marketing Authorisation Holder
European Pharmacopoeia
Package Leaflet
Relative Humidity
Risk Management Plan
Summary of Product Characteristics
Transmissible Spongiform Encephalopathy
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INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted a
marketing authorisation for Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets
from Stada Arzneimittel AG.
The product is indicated for oral contraception.
A comprehensive description of the indications and posology is given in the SmPC.
For the lowest strength the MAH claimed essential similarity with Mercilon 0.15/0.02 mg, tablets (NL
License RVG 11508) which has been registered in the Netherlands by N.V. Organon since 19
November 1987.
For the 150/30 micrograms strength, essential similarity is claimed with the innovator product
Marvelon 0.15/0.03 mg tablets (NL License RVG 08859) which has been registered in the Netherlands
by N.V.
Organon since 29 May 1981. In addition, reference is made to Mercilon and Marvelon authorisations
in the individual member states (reference product).
The concerned member states (CMS) involved in this procedure were Czech Republic and Spain.
The marketing authorisation has been granted pursuant to Article 10(1) of Directive 2001/83/EC.
II.
QUALITY ASPECTS
II.1
Introduction
Desogestrel/Ethinylestradiol STADA 150/20 mcg is a white to off-white, round, biconvex, uncoated
tablet. It contains 20 microgram ethinylestradiol and is debossed with ‘141’ on one side.
Desogestrel/Ethinylestradiol STADA 150/30 mcg is a white to off-white, round, biconvex, uncoated
tablet. It contains 30 microgram ethinylestradiol and is debossed with ‘142’ on one side.
The tablets are packed in clear transparent PVC/PVDC-Al blisters in tri-laminated pouches, with or
without a molecular sieve.
The excipients are: anhydrous lactose, potato starch, povidone K30 (E1201), stearic acid (E570), αTocopherol (E370), colloidal silicon dioxide (E551).
II.2
Drug Substances
Desogestrel
The active substance desogestrel is an established active substance described in the European
Pharmacopoeia (Ph.Eur.). Desogestrel is a white or almost white powder or crystals. It is slightly
soluble in ethanol (96%) and in ethyl acetate, sparingly soluble in n-Hexane and practically insoluble in
water. Desogestrel has six chiral centres. It exhibits polymorphism. Because the drug substance is
dissolved before the manufacture of the drug product, information on polymorphism and particle size
distribution is not considered necessary.
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 European Pharmacopoeia.
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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. with additional tests on residual solvents. Batch
analytical data demonstrating compliance with this specification have been provided for 6 batches.
Stability of drug substance
For one supplier The MAH submitted stability testing results in support of a retest period of 5 years
without any special storage conditions. For the other supplier no retest period was included on the
CEP.
Ethinylestradiol
The active substance is ethinylestradiol, an established active substance described in the European
Pharmacopoeia (Ph.Eur.). Ethinylestradiol is a white to practically white powder. It is freely soluble in
dioxane, diethyl ether, acetone and ethanol; soluble in chloroform and practically insoluble in water.
Ethinylestradiol has five chiral centres and does not exhibit polymorphism.
The CEP procedure is also used for this active substance.
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. with additional tests on residual solvents, visible
particles, heavy metals, any other impurity and particle size distribution. Batch analytical data
demonstrating compliance with this specification have been provided for one production batch.
Stability of drug substance
A retest period of 5 years is applied, 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 development of the product has been adequately described, the choice of excipients is justified
and their functions explained. The pharmaceutical development of the product has been adequately
performed. The development of the clinical batches is discussed, comparative dissolution profiles at
different pHs are provided. The dissolution profiles of desogestrel do not fully support bioequivalence,
however, the in vivo data prevail. Equivalence of the reference product used in the bioequivalence
studies with the innovator products from all member states has been demonstrated.
Manufacturing process
The drug product is manufactured by a wet non-aqueous granulation process. The active substances
and some excipients are mixed together. The premix is further mixed, granulated, then air dried and
sifted. The final blend is compressed and packed. The provided in-process controls are deemed
acceptable.
The manufacturing process has been adequately validated according to relevant European guidelines.
The product is manufactured using conventional manufacturing techniques, but given the low
concentration of active substance in the drug product, the process can be considered as nonstandard. Full-scale process validation results have been provided.
Control of excipients
The excipients are tested in accordance with their respective Ph. Eur. Monograph. The specifications
are acceptable.
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Quality control of drug product
The drug product specifications includes tests for appearance, identification, identification and assay
of vitamin E, dissolution, assay, related substances, uniformity of dosage units (content uniformity),
residual isopropyl alcohol, microbiological requirements and water content. The shelf-life specifications
are the same as the release specification, with the exception of the limit for assay of ethinylestradiol,
related substances and vitamin E content. The analytical methods have been adequately described
and validated.
Batch analytical data from the proposed production site have been provided on three pilot scaled
batches of each tablet strength, demonstrating compliance with the release specifications.
Stability of drug product
Stability data on the product have been provided for three pilot scale batches for each tablet strength .
The data cover up to 24 months stored at 25°C/60%RH and 6 months stored at 40°C/75%RH. The
conditions used in the stability studies are according to the ICH stability guideline. The batches were
stored in clear transparent PVC/PVDC-Al blisters in tri-laminated pouches; sub batches of each batch
for a packaging with molecular sieve and without the molecular sieve.
The accelerated conditions demonstrate that the drug product is slightly sensitive to elevated
temperatures. However, it stayed well within the specifications and no restrictive storage temperatures
are required.
Under all conditions, a decrease in assay and dissolution and an increase in impurities are observed.
As demonstrated by forced degradation studies the product is light sensitive and moisture sensitive.
An in-use stability study demonstrated that the packaging is adequate to protect the product from light
and moisture. The shelf-life of 24 months with the storage conditions “Store in the original package in
order to protect from moisture and light” when stored in clear transparent PVC/PVDC-Al blisters in trilaminated pouches; with or without the molecular sieve can be granted.
Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies
Lactose anhydrous is the only excipient of animal origin. A TSE declaration has been provided. The
excipient magnesium stearate is of vegetable origin.
II.4
Discussion on chemical, pharmaceutical and biological aspects
Based on the submitted dossier, the member states consider that Desogestrel/Ethinylestradiol STADA
150/20 mcg and 150/30 mcg have a proven chemical-pharmaceutical quality. Sufficient controls have
been laid down for the active substances and finished product. No post-approval commitments were
made.
III.
III.1
NON-CLINICAL ASPECTS
Ecotoxicity/environmental risk assessment (ERA)
Since Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg tablets are 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
These products are generic formulations of Mercilon and Marvelon, tablets which are 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.1
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CLINICAL ASPECTS
Introduction
Desogestrel and ethinylestradiol are well-known active substances 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 two bioequivalence studies, one for each tablet
strength, which are discussed below.
IV.2
Pharmacokinetics
Study 1 – 150/30 micrograms
The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product
Desogestrel/Ethinylestradiol STADA 150 mcg/30 mcg Tablets (Stada Arzneimittel AG, Germany) is
compared with the pharmacokinetic profile of the reference product Marvelon 0.15 mg/0.03 mg tablets
(N.V. Organon, the Netherlands).
The choice of the reference product
The choice of the reference product in the bioequivalence study has been justified.
The formula and preparation of the bioequivalence batch is identical to the formula proposed for
marketing.
Design
A open label, balanced, single-dose, randomised, two-period, two-treatment, two-sequence,
crossover, comparative bioequivalence study was carried out under fasted conditions in 34 healthy
female subjects. Each subject received a single dose (2 x 150 mcg/30 mcg) of one of the 2
desogestrel/ethinylestradiol formulations. The tablet was orally administered after an overnight fasting
period of at least 10 hours. There were 2 dosing periods, separated by a washout period of 29 days.
Blood samples were collected pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4, 5, 6, 8, 12,
16, 24, 36, 48, 72 and 96 hours post dose after administration of each dose.
The design of the study under fasted conditions is acceptable. The plasma samples were analysed for
3-ketodesogestrel (etonogestrel) and ethinylestradiol. The measurement of the active metabolite 3ketodesogrestrel is agreed as desogestrel is rapidly absorbed and completely converted into 3ketodesogestrel.
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
Nine subjects discontinued from the study on medical grounds (vomiting). One subject withdrew from
the study of her own accord. A total of 24 subjects completed both study periods and were eligible for
pharmacokinetic analysis. The number of drop out subjects is high. The reasons for discontinuation
were given for all subjects and were according to protocol; therefore the high number of drop out
subjects was accepted.
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Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of 3-ketodesogestrel under fasted conditions.
Treatment
N=24
Test
Reference
*Ratio (90%
CI)
AUC0-t
AUC0-∞
Cmax
tmax
pg*h/ml
pg*h/ml
pg/ml
h
h
39783 ± 15176
54748 ± 21563
2978 ± 1253
1.5
(1.0 – 4.0)
57 ± 22
37193 ± 15674
50558 ± 23684
3243 ± 1395
56 ± 21
1.09
(0.99 - 1.20)
1.10
(0.99 – 1.22)
0.95
(0.83 – 1.09)
2.0
(1.0 - 3.5)
--
20
21
27
--
--
CV (%)
t1/2
--
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 ethinylestradiol under fasted conditions.
Treatment
N=24
Test
Reference
*Ratio (90%
CI)
AUC0-t
AUC0-∞
Cmax
tmax
pg.h/ml
pg.h/ml
pg/ml
h
h
1849 ± 650
1906 ± 665
153 ± 47
1.5
(1.0-3.5)
17 ± 3
1896 ± 625
1946 ± 637
166 ± 49
16 ± 3
0.97
(0.95 – 0.99)
0.97
(0.95 – 1.00)
0.91
(0.88 – 0.96)
1.5
(1.0-2.5)
--
5
5
9
--
--
CV (%)
t1/2
--
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
half-life
t1/2
CV
coefficient of variation
*ln-transformed values
Study 2 – 150/20 micrograms
The MAH conducted a bioequivalence study in which the pharmacokinetic profile of the test product
Desogestrel/Ethinylestradiol STADA 150 mcg/20 mcgTablets (Stada Arzneimittel AG, Germany) is
compared with the pharmacokinetic profile of the reference product Mercilon 0.15 mg/0.02 mg tablets
(N.V. Organon, the Netherlands).
The choice of the reference product
The choice of the reference product in the bioequivalence study has been justified.
The formula and preparation of the bioequivalence batch is identical to the formula proposed for
marketing.
Design
A open label, balanced, single-dose, randomised, two-period, two-treatment, two-sequence,
crossover, comparative bioequivalence study was carried out under fasted conditions in 34 healthy
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female subjects. Each subject received a single dose (2 x 150 mcg/20 mcg) of one of the 2
desogestrel/ethinylestradiol formulations. The tablets were orally administered with 240 ml water after
an overnight fasting period of at least 10 hours. There were 2 dosing periods, separated by a washout
period of 28 days.
Blood samples were collected 0.0 (pre-dose) and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4, 5, 6,
8, 12, 16, 24, 36, 48, 72 and 96 hours post dose after administration of each dose.
The design of the study under fasted conditions is acceptable. The plasma samples were analysed for
3-ketodesogestrel (etonogestrel) and ethinylestradiol. The measurement of the active metabolite 3ketodesogrestrel is agreed as desogestrel is rapidly absorbed and completely converted into 3ketodesogestrel.
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
Three subjects discontinued on the grounds of protocol deviation. One subject withdrew on medical
grounds (fever) and one subject discontinued of her own accord. A total of 30 subjects were eligible
for pharmacokinetic analysis.
Table 3.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of 3-Ketodesogestrel under fasted conditions.
Treatment
N=30
Test
Reference
*Ratio (90%
CI)
CV (%)
AUC0-t
AUC0-∞
Cmax
tmax
t1/2
pg.h/ml
pg.h/ml
pg/ml
h
h
55045 ± 16642
73744 ± 21683
4703 ± 1751
1.5
(1.0 – 3.5)
57434 ± 18628
78100 ± 28858
5124 ± 2321
0.96
(0.90 – 1.03)
0.95
(0.87 – 1.04)
0.93
(0.93 – 1.03)
1.5
(1.0 – 2.5)
--
--
19
26
30
--
--
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 4.
Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
(median, range)) of ethinylestradiol under fasted conditions.
Treatment
N=30
Test
Reference
*Ratio (90%
CI)
CV (%)
AUC0-t
AUC0-∞
Cmax
tmax
pg.h/ml
pg.h/ml
pg/ml
h
h
935 ± 391
1021 ± 406
101 ± 34
1.5
16 ± 6
938 ± 392
1009 ± 407
96 ± 32
1.5
14 ± 5
1.01
(0.95 – 1.07)
1.03
(0.97 – 1.08)
1.05
(0.99 – 1.12)
--
--
--
--
--
--
--
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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
Conclusion on bioequivalence studies
In both studies the 90% confidence intervals calculated for AUC0-t, AUC0-∞ and Cmax of 3Ketodesogestrel and ethinylestradiol are within the bioequivalence acceptance range of 0.80 – 1.25.
Based on the submitted bioequivalence studies Desogestrel/ Ethinylestradiol STADA 150/20 mcg and
150/30 mcg, tabletsare considered bioequivalent with respectively Mercilon and Marvelon tablets.
The MEB has been assured that the bioequivalence studies have 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 Desogestrel/Ethinylestradiol STADA 150/20
mcg and 150/30 mcg, tablets.
- Summary table of safety concerns as approved in RMP
Important identified risks
 Venous thromboembolism
 Arterial thromboembolism
 Benign and malign liver tumours
 Breast cancer, Cervical cancer
 Effect on hereditary angioedema
 Disturbance of liver function
 Pancreatitis
 Increased blood pressure
Important potential risks
 Worsening of endogenous
depression/depressed mood
 Crohn’s disease and ulcerative colitis
Important missing information
none
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
products Mercilon and Marvelon tablets. No new clinical studies were conducted. The MAH
demonstrated through bioequivalence studies 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
Due to the usage of the already tested and approved package leaflet texts of another
Desogestrel/Ethinylestradiol 150/20 mcg and 150/30 mcg tablet product of STADA
(NL/H/2236+2246/001-002/DC) and implementation of the user-tested STADA layout, the MAH
considers that the proposed package leaflet is compliant with Article 59(3) of Directive 2001/83/EC
and therefore, an additional user-test is not required. The minor differences in wording and word order
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in the proposed package leaflet as compared to already tested and approved package leaflet are due
to the new QRD template. These differences do not affect readability. This conclusion is agreed.
VI.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30 mcg, tablets have a proven chemicalpharmaceutical quality and are generic forms of Mercilon and Marvelon 150/20 mcg and 150/30 mcg.
Mercilon and Marvelon tablets are a well-known medicinal products 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 Desogestrel/Ethinylestradiol STADA 150/20 mcg and 150/30
mcg, tablets with the reference product, and have therefore granted a marketing authorisation. The
decentralised procedure was finalised with a positive outcome on 8 June 2015.
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STEPS TAKEN AFTER THE FINALISATION OF THE INITIAL PROCEDURE - SUMMARY
Scope
Procedure
number
Type of
modification
11/11
Date of start
of the
procedure
Date of
end of the
procedure
Approval/
non
approval
Assessment
report
attached