Annex I List of the names, pharmaceutical form, strengths ...

Annex I

List of the names, pharmaceutical form, strengths of the medicinal products, route of administration, marketing authorisation holders in the

Member States

1

Levonorgestrel-containing emergency contraceptive medicinal products Member State (in EEA)

Marketing Authorisation Holder Invented name Strength Pharmaceutical Form

Route of administration

Austria Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

Postinor 1500 Mikrogramm-Tablette

1.5 mg Tablet Oral use

Austria Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

Vikela 750 Mikrogramm- Tabletten


Austria Laboratoire HRA Pharma 15. rue Béranger FR-75003 Paris France

Vikela 1,5 Milligramm- Tablette


Austria Velvian Germany GmbH Carl-Zeiss-Ring 9 85737 Ismaning Germany

Velafam 1,5 mg Tabletten 1.5 mg Tablet Oral use

Austria Velvian Germany GmbH Carl-Zeiss-Ring 9 85737 Ismaning Germany

Velafam 750 Mikrogramm Tabletten


Belgium Sandoz N.V. Telecom Gardens Medialaan 40 1800 Vilvoorde Belgium

Levodonna 1.5 mg Tablet Oral use

2

Member State (in EEA)



Belgium Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

Norlevo 0.75 mg Tablet Oral use

Belgium Laboratoire HRA Pharma 15. rue Béranger FR-75003 Paris France


Belgium Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

Postinor 1.5 mg Tablet Oral use

Belgium Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom


Bulgaria Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary

Escapelle 1.5 mg Tablet Oral use


Ramonna 1.5 mg Tablet Oral use


Postinor-Duo 0.75 mg Tablet Oral use

3




Bulgaria Laboratorios Leon Farma SA Poligono Industrial Navatejera, La Vallina s/n, 24008 Villaquilambre,Leon Spain

Etiyone 1.5 mg Tablet Oral use

Bulgaria Laboratorios Leon Farma SA Poligono Industrial Navatejera, La Vallina s/n, 24008 Villaquilambre,Leon Spain

Melkidos 0.75 mg Tablet Oral use

Croatia Arenda d.o.o., Medarska ulica 56b Zagreb 10090 Croatia

Vikela 1,5 mg tableta 1.5 mg Tablet Oral use

Croatia Sandoz d.o.o. Maksimirska 120 Zagreb 10000 Croatia


Cyprus Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Cyprus Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


4




Czech Republic Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary



Postinor-2 0.75 mg Tablet Oral use



Czech Republic Egis Pharmaceuticals PLC Keresztúri út 30-38 H-1106 Budapest Hungary

Egianti 0,75 mg 0.75 mg Tablet Oral use

Czech Republic Laboratorios León Farma S.A. Calle La Vallina s/n Polígono Industrial Navatejera 24008 - Navatejera - León Spain

Nopregy 1,5 mg tablety 1.5 mg Tablet Oral use

Denmark Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Denmark Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


5




Denmark Sandoz A/S Edvard Thomsens Vej 14 DK-2300 København S Denmark


Estonia Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary

RAMONNA 1.5 mg Tablet Oral use

Estonia Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary

ESCAPELLE 1.5 mg Tablet Oral use

Estonia Orivas UAB J.Jasinskio 16B LT-01112 Vilnius Lithuania

LEVIDON 0.75 mg Tablet Oral use

Estonia Sandoz Pharmaceuticals Verovškova 57 1000 Ljubljana Slovenia

LEVODONNA 1.5 mg Tablet Oral use

Estonia Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjördur Iceland

LEVONORGESTREL ACTAVIS


Estonia Orivas UAB J.Jasinskio 16B LT-01112 Vilnius Lithuania

ELISTREL 1.5 mg Tablet Oral use

6




Finland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Finland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


France Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

ANTHIA 750 microgrammes, comprimé


France Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

LEVONORGESTREL BIOGARAN 1500 microgrammes, comprimé


France MYLAN SAS 117, allée des Parcs 69800 Saint-Priest France

LEVONORGESTREL MYLAN 1,5 mg, comprimé


France Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NORLEVO 1,5 mg, comprimé



NORLEVO 750 microgrammes, comprimé


7





VIKELA 1,5 mg, comprimé 1.5 mg Tablet Oral use


VIKELA 750 microgrammes, comprimé


Germany VELVIAN Germany GmbH Carl-Zeiss-Ring 9 85737 Ismaning Germany

Navela 0,75 mg Tabletten 0.75 mg Tablet Oral use

Germany VELVIAN Germany GmbH Carl-Zeiss-Ring 9 85737 Ismaning Germany

Navela 1,5 mg Tabletten 1.5 mg Tablet Oral use

Germany Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

PiDaNa 1,5 mg Tablette 1.5 mg Tablet Oral use

Germany Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

Postinor 1500 Mikrogramm Tablette


Germany Hexal Aktiengesellschaft Industriestr. 25 83607 Holzkirchen Germany

unofem HEXAL 1,5 mg Tabletten


8




Germany Laboratorios Leon Farma, SA Poligono Industrial Navatejera C/La Vallina s/n 24008 Navatejera - Villaquilambre Spain

Etiyone 1500 Mikrogramm Tabletten


Greece Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NORLEVO 0.75 mg Tablet Oral use

Greece Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Greece Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

POSTINOR 1.5 mg Tablet Oral use

Hungary Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary


Hungary Egis Pharmaceuticals PLC Keresztúri út 30-38 H-1106 Budapest Hungary

Empil 0,75 mg tabletta 0.75 mg Tablet Oral use

Hungary Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjördur Iceland

Helibona 1.5 mg Tablet Oral use

9




Hungary Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary

Rigesoft 0.75 mg Tablet Oral use

Iceland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Iceland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Iceland Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom


Ireland Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

Levonelle 1500 microgram Tablet


Ireland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NORLEVO 750 micrograms tablet


Ireland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NORLEVO 1.5 mg tablet 1.5 mg Tablet Oral use

10




Ireland Laboratorios Leon Farma, S.A. C/ Roa de la Vega 15, 1 24008 Leon Spain

Tyedra 1500 micrograms tablet


Italy Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Italy Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Italy Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

LONEL 1.5 mg Tablet Oral use

Latvia Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary

Escapelle 1,5 mg tablets 1.5 mg Tablet Oral use


Ramonna 1500 micrograms tablets



Postinor-Duo 750 micrograms tablets


11




Latvia UAB „Orivas“ J. Jasinskio g. 16B LT- 01112 Vilnius Lithuania

Elistrel 1500 micrograms tablets


Latvia UAB „Orivas“ J. Jasinskio g. 16B LT- 01112 Vilnius Lithuania

Levidon 750 micrograms tablets


Latvia Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjördur Iceland

Levonorgestrel Actavis 750 micrograms tablets


Lithuania Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary




Lithuania UAB „Orivas“ J. Jasinskio g. 16B LT- 01112 Vilnius Lithuania

Elistrel 1.5 mg Tablet Oral use

Lithuania UAB „Orivas“ J. Jasinskio g. 16B LT- 01112 Vilnius Lithuania

Levidon 0.75 mg Tablet Oral use

12




Lithuania UAB Inteli Generics Nord Šeimyniškių 3 LT-09312 Vilnius Lithuania

Avodele 0.75 mg Tablet Oral use

Lithuania UAB Inteli Generics Nord Šeimyniškių 3 LT-09312 Vilnius Lithuania

Avodele 1.5 mg Tablet Oral use


POSTINOR-DUO 0.75 mg Tablet Oral use

Luxembourg Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Luxembourg Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Luxembourg Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom


Luxembourg Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom


13




Norway Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Norway Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Norway Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

POSTINOR 1.5 mg Tablet Oral use

Norway Sandoz A/S Edvard Thomsens Vej 14 DK-2300 København S Denmark

Isteranda 1.5 mg Tablet Oral use

Poland Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary

Escapelle tabletka 1500 mikrogramów


Poland Gedeon Richter Polska Sp. z o.o. 5 Ks. J. Poniatowskiego Street 05-825 Grodzisk Mazowiecki Poland


Portugal Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


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Portugal Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France


Portugal Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom


Romania Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary


Romania Gedeon Richter Romania S.A. Str. Cuza-Vodă nr. 99-105 Târgu Mureş 540306 Romania


Romania Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary

POSTINOR-2 750 micrograme


Slovak Republic

Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary


Slovak Republic


Ramona 1.5 mg Tablet Oral use

15




Slovak Republic

Egis Pharmaceuticals PLC Keresztúri út 30-38 H-1106 Budapest Hungary

EGIANTI 0,75 mg tablety 0.75 mg Tablet Oral use

Slovak Republic

Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjördur Iceland

Helibona 1,5 mg 1.5 mg Tablet Oral use

Slovenia Gedeon Richter Plc. Gyömrői út 19-21. H-1103 Budapest Hungary

Escapelle 1,5 mg tableta 1.5 mg Tablet Oral use

Slovenia Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NORLEVO 1,5 mg tableta 1.5 mg Tablet Oral use

Slovenia Gedeon Richter Plc. Gyömrői út 19-21. H-1103 Budapest Hungary

Ramonna 1,5 mg tableta 1.5 mg Tablet Oral use

Spain CHIESI ESPAÑA, S.A. Plaça d´Europa, 41-43 planta 10 08908 L´Hospitalet de Llobregat (Barcelona) Spain

Norlevo 750 microgramos comprimidos


16




Spain CHIESI ESPAÑA, S.A. Plaça d´Europa, 41-43 planta 10 08908 L´Hospitalet de Llobregat (Barcelona) Spain

Norlevo 1500 microgramos comprimido


Spain Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

Postinor 1500 microgramos comprimido


Spain Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjördur Iceland

Julirona 1,5 mg comprimido EFG


Sweden Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NorLevo 0.75 mg Tablet Oral use

Sweden Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NorLevo 1.5 mg Tablet Oral use

Sweden Sandoz A/S Edvard Thomsens Vej 14 DK-2300 København S Denmark


Sweden Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom


17




The Netherlands

Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NorLevo, tabletten 0,75 mg


The Netherlands

Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France

NorLevo 1,5 mg, tabletten 1.5 mg Tablet Oral use

The Netherlands

Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom

Postinor 1500 microgram, tablet


The Netherlands

Perryment Ltd 42-46 High street Esher, KT10 9QY Surrey United Kingdom

Vikela, tabletten 750 microgram


United Kingdom

Sandoz Limited Frimley Business Park Frimley, Camberley Surrey GU16 7SR United Kingdom

Isteranda 1.5mg Tablets 1.5 mg Tablet Oral use

United Kingdom


Upostelle 1500 Microgram Tablets


United Kingdom


Levonelle-2 750 Microgram Tablet


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United Kingdom


Levonelle 1500 Microgram Tablet


United Kingdom


Levonelle One Step 1500 Microgram Tablet / Boots Emergency Contraceptive 1.5 mg Tablet


United Kingdom

Laboratorios Leon Farma SA Calle La Vallina S/N Poligono Industrial Navatejera Navatejera, Leon E-24008 Spain

Melkine 1.5mg Tablet 1.5 mg Tablet Oral use

19

Annex II

Scientific conclusions and grounds for variation to the terms of the marketing authorisations

20

Scientific conclusions

Overall summary of the scientific evaluation of emergency contraceptives medicinal products containing levonorgestrel or ulipristal acetate

Emergency contraceptives can be used to prevent an unintended pregnancy following an unprotected sexual intercourse or in case of failure of a contraceptive method. The emergency contraceptives can be divided into levonorgestrel (LNG)- and ulipristal acetate (UPA)-containing emergency contraceptives and they act by inhibiting and/or delaying ovulation.

The use of emergency contraception is an occasional method that is far less effective compared with most contraceptive products used on a regular basis, e.g. combined hormonal contraceptives, gestagen-only pills and various long-acting methods like intra-uterine devices and implants.

On 16 January 2014 the Swedish Agency sent a notification for a referral under Article 31 of directive 2001/83 EC regarding all emergency contraceptives containing LNG or UPA asking the CHMP to give its opinion on whether the marketing authorisations should be maintained, varied, suspended or withdrawn. The CHMP was requested to assess whether the efficacy of emergency contraceptives is affected in relation to body weight and/or body mass index (BMI) of the women.

The CHMP reviewed all data from clinical studies, published literature, post-marketing experience, including responses submitted by the marketing authorisation holders (MAHs), on the efficacy of emergency contraceptive medicinal products containing LNG or UPA, in particular with regards to the relation of high weight/BMI of women.

Levonorgestrel (LNG)

LNG is a synthetic progestagen. For emergency contraception one tablet of 1.5 mg LNG needs to be taken, or two tablets of 0.75 mg LNG at once. The products are indicated for emergency contraception within 72 hours (3 days) of unprotected sexual intercourse or contraceptive failure, and have been approved in more than 100 countries worldwide and used for more than 30 years.

Eight relevant studies with LNG-containing emergency contraceptives are available in public literature.

During the data submission an analysis was provided on three WHO studies (Von Hertzen et al., 1998 1 and 2002 2; Dada et al., 2010 3) as well as an analysis on two other studies (Creinin et al., 2006 4; Glasier et al., 2010 5).

The rest of the studies have been submitted in the form of published literature.

There are limited and inconclusive data from clinical trials that evaluated the effect of high body weight/high BMI on the contraceptive efficacy. In the meta-analysis including the three WHO studies, primarily including African and Asian women, no trend for a reduced efficacy with increasing body weight/BMI was observed (Table 1). In contrast, in the two comparative studies of Creinin and colleagues (2006) and Glasier and colleagues (2010), primarily including Caucasian women, a reduced contraceptive efficacy was observed with increasing body weight or BMI (Table 2). Both meta-analyses

1 von Hertzen H et al. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet, 1998; 352: 428-33.

2 von Hertzen H et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet, 2002; 360: 1803-10

3 Dada OA et al. A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria. Contraception 2010; 82: 373–378.

4 Creinin MD et al. Progesterone receptor modulator for emergency contraception: a randomized controlled trial. Obstet Gynecol 2006;108: 1089–97.

5 Glasier A et al. Ulipristal acetate versus levonorgestrel for emergency contraception: a randomized noninferiority trial and meta-analysis. Lancet 2010; 375: 555–62.

21

excluded intake later than 72 hours after unprotected intercourse (i.e. off-label use of LNG) and women who had further acts of unprotected intercourse.

Table 1: Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010)

BMI (kg/m2) Underweight 0 - 18.5

Normal 18.5-25

Overweight 25-30

Obese ≥ 30

N total 600 3952 1051 256 N pregnancies 11 39 6 3 Pregnancy rate 1.83% 0.99% 0.57% 1.17% Confidence Interval

0.92 – 3.26 0.70 – 1.35 0.21 – 1.24 0.24 – 3.39

Table 2: Meta-analysis on studies of Creinin et al., 2006 and Glasier et al., 2010

BMI (kg/m2) Underweight 0 - 18.5

Normal 18.5-25

Overweight 25-30

Obese ≥ 30

N total 64 933 339 212 N pregnancies 1 9 8 11 Pregnancy rate 1.56% 0.96% 2.36% 5.19% Confidence Interval

0.04 – 8.40 0.44 – 1.82 1.02 – 4.60 2.62 – 9.09

The data are currently too limited and therefore insufficiently precise to draw definite conclusions whether efficacy is negatively influenced by increased body weight and BMI; for instance for the obese category (BMI ≥30) three pregnancies were reported in the first analysis, and eleven pregnancies in the second. It is unknown what the explanation is for the contradicting results in both meta-analyses. All together, the current data are considered not robust enough to support the current recommendation of decreased efficacy in women with body weight above 75 kg and inefficacy in women with body weight above 80 kg as is currently included in the product information of one LNG-containing emergency contraceptive medicinal product (Norlevo).

A range of different factors have an impact on a woman´s fertility and the ability of emergency contraceptives to prevent a pregnancy, e.g. timing of intake of emergency contraception in relation to intercourse, conception probability, further acts of unprotected intercourse, age, ethnicity, previous infections of the genital tract, male fertility, etc. This is reflected in the wide range of estimates of prevented fraction across different studies. Therefore, even if data from some studies suggest a lower ability of LNG-containing emergency contraceptives to prevent pregnancies in women of higher weight/BMI, this is only one factor influencing the effect and it is difficult to define a certain cut-off for weight/BMI at which no effect is present.

Overall for of LNG-containing emergency contraceptives it is concluded that there is limited data on the effect of high body weight/high BMI on the contraceptive efficacy.

The CHMP proposed that a warning in section 4.4 of the summary of product characteristics (SmPC) is an appropriate routine risk minimisation measure to reflect that limited and inconclusive data are present regarding a possible reduced efficacy in women with a high body weight/BMI. Further, the data of the two meta-analyses should be reflected in section 5.1 of the SmPC. This information should also be reflected in the package leaflet. Further, since the limited data available do not support with any certainty the conclusion that their contraceptive effect is reduced in women with high bodyweight, no adjustment of the dose is recommended at this stage, and any information that already is included in the section 4.2 of the SmPC making reference to effect and body weight should be removed.

22

Ulipristal acetate (UPA)

Ulipristal acetate (UPA) (30 mg) (ellaOne) is an orally synthetic progesterone receptor modulator, which acts via high affinity binding to the human progesterone receptor. The product is indicated for emergency contraception within 120 hours (5 days) of unprotected sexual intercourse or contraceptive failure. UPA has been approved in 73 countries worldwide and it is being marketed for five years.

The data used in the analyses of effect of UPA in relation to weight/BMI are partly based on the same studies two abovementioned studies for LNG, and another randomised controlled study (HRA2914-507, HRA2914-508, HRA2914-513) as well as an open label study (HRA2914-509). Similar analyses were performed. A trend was observed in the UPA group for increasing number of pregnancies with increasing weight or BMI. However, the analyses are based on a limited number of women, especially in the highest body weight/BMI categories, which subsequently result in very wide and overlapping 95% confidence limits.

While the analyses of data from the three randomised controlled trials in which 2,098 women received UPA indicate a weak effect of body weight or BMI on pregnancy rates, the open label study (n=1,241) indicated no such effect. From these data there is no clear indication of an effect of weight or BMI on efficacy in general, or specifically among overweight or obese women.

The data are currently too limited and therefore insufficiently precise to draw definite conclusions whether efficacy is negatively influenced by increased body weight and BMI.

Table 3: Meta-analysis on four clinical studies conducted with UPA

BMI (kg/m2) Underweight

0 - 18.5

Normal

18.5 - 25

Overweight

25 - 30

Obese

30 -

N total 128 1866 699 467

N pregnancies 0 23 9 12

Pregnancy rate 0.00% 1.23% 1.29% 2.57%

95% Confidence

Interval 0.00 – 2.84 0.78 – 1.84 0.59 – 2.43 1.34 - 4.45

The CHMP concluded that a warning in section 4.4 of the SmPC is appropriate to indicate that limited and inconclusive data are present regarding a possible reduced efficacy in women with a high body weight/BMI and that in all women emergency contraception should be taken as soon as possible after unprotected intercourse, regardless of the woman’s body weight or BMI. Further, the data of the meta-analysis should be presented in section 5.1 of the SmPC.

The information in the SmPC should also be reflected in the package leaflet.

In addition the CHMP is of the opinion that conducting a pharmacodynamic/pharmacokinetic (PD/PK) study may provide some information which may help to further characterise the risk of decreased efficacy in women with high body weight/BMI and ovulation inhibition. Considering the need to further characterise this risk, the MAHs are strongly recommended to investigate the pharmacodynamic effect (ovulation inhibition) of LNG in obese women in the future.

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Overall conclusion

For LNG-containing emergency contraceptives overall it is concluded that there is limited and inconsistent data on the effect of high body weight/high BMI on the contraceptive efficacy. In the three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010) no trend for a reduced efficacy with increasing body weight/BMI was observed, whereas in the two other studies (Creinin et al., 2006 and Glasier et al., 2010) a reduced contraceptive efficacy was observed with increasing body weight or BMI. Both meta-analyses excluded off-label use of LNG-containing of emergency contraceptives, i.e. intake later than 72 hours after unprotected intercourse and women who had further acts of unprotected intercourse.

For UPA-containing emergency contraceptive products (ellaOne) it is concluded that limited and inconclusive data suggest that there may be reduced efficacy of UPA with increased body weight in women. Further, in all women emergency contraception should be taken as soon as possible after unprotected intercourse.

Benefit –risk balance

The Committee concluded that the benefit-risk balance of emergency contraceptive medicinal products containing LNG or UPA remains positive for all women regardless of body weight/BMI, subject to the warnings and changes to the product information agreed.

Grounds for the variation to the terms of the marketing authorisation

Whereas

• The Committee considered the procedure under Article 31 of Directive 2001/83/EC for the emergency contraceptive medicinal products containing LNG or UPA.

• The Committee reviewed all data from clinical studies, published literature, post-marketing experience, including responses submitted by the marketing authorisation holders (MAHs), on the efficacy of emergency contraceptive medicinal products containing LNG or UPA, in particular with regards to a possible effect of high weight/BMI of women.

• The CHMP concluded that the available data is limited and does not support a definite conclusion that increased bodyweight reduces efficacy of emergency contraceptives medicinal products containing LNG or UPA. Available data should be included in the product information, but no restrictions of use based on body weight/BMI are recommended at this stage.

• The Committee considered that in view of the currently available data, the benefit-risk balance of emergency contraceptive medicinal products containing LNG or UPA is favourable, subject to warnings and other changes to the product information. In particular, limited but inconclusive data suggest that there may be reduced efficacy of these medicinal products with increased body weight in women.

The Committee, as a consequence, concluded that the benefit-risk balance of emergency contraceptive medicinal products containing LNG or UPA remains positive, subject to the warnings and changes to the product information agreed.

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Annex III

Amendments to relevant sections of the summary of product characteristics and package leaflet

25

[The existing product information shall be amended (insertion, replacement or deletion of the text as appropriate) to reflect the agreed wording as provided below]

For Levonorgestrel-containing emergency contraceptive medicinal products

A. Summary of product characteristics Section 4.2 Posology and method of administration […] [the phrase below should be deleted from this section] Special population: body weight 75 kg or more In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg or more, and levonorgestrel was not effective in women who weighed more than 80 kg (see sections 4.4 and 5.1). […] Section 4.4 Special warnings and precautions for use […] Limited and inconclusive data suggest that there may be reduced efficacy of <invented name> with increasing body weight or body mass index (BMI) (see section 5.1). In all women, emergency contraception should be taken as soon as possible after unprotected intercourse, regardless of the woman’s body weight or BMI. […] In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg or more and levonorgestrel was not effective in women who weighed more than 80 kg (see sections 4.2 and 5.1). […] Section 5.1 Pharmacodynamic properties [….] [The information below should be deleted together with the table] In clinical trials, contraceptive efficacy was reduced in women weighing 75 kg or more and levonorgestrel was not effective in women who weighed more than 80 kg (see sections 4.2 and 4.4).

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Pregnancy rate (95% CI) according to weight categories

Weight (kg) <55 [55-65] [65-75] [75-85] ≥ 85

N total 349 608 426 155 193

N pregnancies 3 8 6 10 11

Pregnancy rate 0.9% 1.3% 1.4% 6.4% 5.7%

Confidence

Interval [0.2-2.5] [0.6-2.6] [0.5-3.0]

[3.1-11.5] [2.9-10.0]

[The information below should be added in this section together with the two tables which follow] There is limited and inconclusive data on the effect of high body weight/high BMI on the contraceptive efficacy. In three WHO studies no trend for a reduced efficacy with increasing body weight/BMI was observed (Table 1), whereas in the two other studies (Creinin et al., 2006 and Glasier et al., 2010) a reduced contraceptive efficacy was observed with increasing body weight or BMI (Table 2). Both meta-analyses excluded intake later than 72 hours after unprotected intercourse (i.e. off-label use of levonorgestrel) and women who had further acts of unprotected intercourse. Table 1: Meta-analysis on three WHO studies (Von Hertzen et al., 1998 and 2002; Dada et al., 2010)


0 - 18.5

Normal

18.5-25

Overweight

25-30

Obese

≥ 30

N total 600 3952 1051 256

N pregnancies

11 39 6 3

Pregnancy rate

1.83% 0.99% 0.57% 1.17%

Confidence Interval

0.92 – 3.26 0.70 – 1.35 0.21 – 1.24 0.24 – 3.39

Table 2: Meta-analysis on studies of Creinin et al., 2006 and Glasier et al., 2010


0 - 18.5

Normal

18.5-25

Overweight

25-30

Obese

≥ 30

N total 64 933 339 212

N pregnancies

1 9 8 11

Pregnancy rate

1.56% 0.96% 2.36% 5.19%

Confidence Interval

0.04 – 8.40 0.44 – 1.82 1.02 – 4.60 2.62 – 9.09

[….]

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B. Package leaflet […] When should emergency contraception be used? […] Studies suggest that <invented name> is less effective in women weighing 75 kg or more and not effective in women weighing more than 80 kg. Ask your doctor or pharmacist for advice on alternative methods of emergency contraception. 2. BEFORE YOU USE <invented name> <strength> TABLET

[…] Take special care with <invented name> <strength> tablet - […] - if you weigh 75 kg or more (see “What <invented name> <strength> tablet is and what it is used

for” for further details) […] In all women, emergency contraception should be taken as soon as possible after unprotected intercourse. There is some evidence that <invented name> may be less effective with increasing body weight or body mass index (BMI), but these data were limited and inconclusive. Therefore, <invented name> is still recommended for all women regardless of their weight or BMI. You are advised to speak to a healthcare professional if you are concerned about any problems related to taking emergency contraception. […]

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Date post:	26-Feb-2022
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Annex I List of the names, pharmaceutical form, strengths ...

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