Annex I List of the names, pharmaceutical form, strengths ...
Transcript of 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
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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
0.75 mg Tablet Oral use
Austria Laboratoire HRA Pharma 15. rue Béranger FR-75003 Paris France
Vikela 1,5 Milligramm- Tablette
1.5 mg Tablet Oral use
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
0.75 mg Tablet Oral use
Belgium Sandoz N.V. Telecom Gardens Medialaan 40 1800 Vilvoorde Belgium
Levodonna 1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
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
Norlevo 1.5 mg Tablet Oral use
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
Postinor 0.75 mg Tablet Oral use
Bulgaria Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Escapelle 1.5 mg Tablet Oral use
Bulgaria Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Ramonna 1.5 mg Tablet Oral use
Bulgaria Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Postinor-Duo 0.75 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
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
Escapelle 1.5 mg Tablet Oral use
Cyprus Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 0.75 mg Tablet Oral use
Cyprus Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Czech Republic Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Escapelle 1.5 mg Tablet Oral use
Czech Republic Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Postinor-2 0.75 mg Tablet Oral use
Czech Republic Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Ramonna 1.5 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
Norlevo 0.75 mg Tablet Oral use
Denmark Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Denmark Sandoz A/S Edvard Thomsens Vej 14 DK-2300 København S Denmark
Levodonna 1.5 mg Tablet Oral use
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
0.75 mg Tablet Oral use
Estonia Orivas UAB J.Jasinskio 16B LT-01112 Vilnius Lithuania
ELISTREL 1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Finland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 0.75 mg Tablet Oral use
Finland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 1.5 mg Tablet Oral use
France Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
ANTHIA 750 microgrammes, comprimé
0.75 mg Tablet Oral use
France Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
LEVONORGESTREL BIOGARAN 1500 microgrammes, comprimé
1.5 mg Tablet Oral use
France MYLAN SAS 117, allée des Parcs 69800 Saint-Priest France
LEVONORGESTREL MYLAN 1,5 mg, comprimé
1.5 mg Tablet Oral use
France Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NORLEVO 1,5 mg, comprimé
1.5 mg Tablet Oral use
France Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NORLEVO 750 microgrammes, comprimé
0.75 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
France Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
VIKELA 1,5 mg, comprimé 1.5 mg Tablet Oral use
France Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
VIKELA 750 microgrammes, comprimé
0.75 mg Tablet Oral use
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
1.5 mg Tablet Oral use
Germany Hexal Aktiengesellschaft Industriestr. 25 83607 Holzkirchen Germany
unofem HEXAL 1,5 mg Tabletten
1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Germany Laboratorios Leon Farma, SA Poligono Industrial Navatejera C/La Vallina s/n 24008 Navatejera - Villaquilambre Spain
Etiyone 1500 Mikrogramm Tabletten
1.5 mg Tablet Oral use
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
NORLEVO 1.5 mg Tablet Oral use
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
Escapelle 1.5 mg Tablet Oral use
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
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
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
Norlevo 1.5 mg Tablet Oral use
Iceland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 0.75 mg Tablet Oral use
Iceland Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Postinor 1.5 mg Tablet Oral use
Ireland Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Levonelle 1500 microgram Tablet
1.5 mg Tablet Oral use
Ireland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NORLEVO 750 micrograms tablet
0.75 mg Tablet Oral use
Ireland Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NORLEVO 1.5 mg tablet 1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Ireland Laboratorios Leon Farma, S.A. C/ Roa de la Vega 15, 1 24008 Leon Spain
Tyedra 1500 micrograms tablet
1.5 mg Tablet Oral use
Italy Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NORLEVO 0.75 mg Tablet Oral use
Italy Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NORLEVO 1.5 mg Tablet Oral use
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
Latvia Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Ramonna 1500 micrograms tablets
1.5 mg Tablet Oral use
Latvia Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Postinor-Duo 750 micrograms tablets
0.75 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Latvia UAB „Orivas“ J. Jasinskio g. 16B LT- 01112 Vilnius Lithuania
Elistrel 1500 micrograms tablets
1.5 mg Tablet Oral use
Latvia UAB „Orivas“ J. Jasinskio g. 16B LT- 01112 Vilnius Lithuania
Levidon 750 micrograms tablets
0.75 mg Tablet Oral use
Latvia Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjördur Iceland
Levonorgestrel Actavis 750 micrograms tablets
0.75 mg Tablet Oral use
Lithuania Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
ESCAPELLE 1.5 mg Tablet Oral use
Lithuania Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
RAMONNA 1.5 mg Tablet Oral use
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
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
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
Lithuania Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
POSTINOR-DUO 0.75 mg Tablet Oral use
Luxembourg Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 0.75 mg Tablet Oral use
Luxembourg Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 1.5 mg Tablet Oral use
Luxembourg Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Postinor 0.75 mg Tablet Oral use
Luxembourg Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Postinor 1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Norway Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NORLEVO 0.75 mg Tablet Oral use
Norway Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NORLEVO 1.5 mg Tablet Oral use
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
1.5 mg Tablet Oral use
Poland Gedeon Richter Polska Sp. z o.o. 5 Ks. J. Poniatowskiego Street 05-825 Grodzisk Mazowiecki Poland
Ramonna 1.5 mg Tablet Oral use
Portugal Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 0.75 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Portugal Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
Norlevo 1.5 mg Tablet Oral use
Portugal Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Postinor 1.5 mg Tablet Oral use
Romania Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
ESCAPELLE 1.5 mg Tablet Oral use
Romania Gedeon Richter Romania S.A. Str. Cuza-Vodă nr. 99-105 Târgu Mureş 540306 Romania
RAMONNA 1.5 mg Tablet Oral use
Romania Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
POSTINOR-2 750 micrograme
0.75 mg Tablet Oral use
Slovak Republic
Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
ESCAPELLE 1.5 mg Tablet Oral use
Slovak Republic
Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Ramona 1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
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
0.75 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
Spain CHIESI ESPAÑA, S.A. Plaça d´Europa, 41-43 planta 10 08908 L´Hospitalet de Llobregat (Barcelona) Spain
Norlevo 1500 microgramos comprimido
1.5 mg Tablet Oral use
Spain Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Postinor 1500 microgramos comprimido
1.5 mg Tablet Oral use
Spain Actavis Group PTC ehf Reykjavikurvegi 76-78 220 Hafnarfjördur Iceland
Julirona 1,5 mg comprimido EFG
1.5 mg Tablet Oral use
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
Levodonna 1.5 mg Tablet Oral use
Sweden Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Postinor 1.5 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
The Netherlands
Laboratoire HRA Pharma 15, rue Béranger FR-75003 Paris France
NorLevo, tabletten 0,75 mg
0.75 mg Tablet Oral use
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
1.5 mg Tablet Oral use
The Netherlands
Perryment Ltd 42-46 High street Esher, KT10 9QY Surrey United Kingdom
Vikela, tabletten 750 microgram
0.75 mg Tablet Oral use
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
Gedeon Richter Plc. Gyömröí út 19-21 HU-1103 Budapest Hungary
Upostelle 1500 Microgram Tablets
1.5 mg Tablet Oral use
United Kingdom
Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Levonelle-2 750 Microgram Tablet
0.75 mg Tablet Oral use
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Member State (in EEA)
Marketing Authorisation Holder Invented name Strength Pharmaceutical Form
Route of administration
United Kingdom
Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Levonelle 1500 Microgram Tablet
1.5 mg Tablet Oral use
United Kingdom
Medimpex UK Limited 127 Shirland Road London W9 2EP United Kingdom
Levonelle One Step 1500 Microgram Tablet / Boots Emergency Contraceptive 1.5 mg Tablet
1.5 mg Tablet Oral use
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
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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.
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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.
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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
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[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)
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
[….]
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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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