natgillin/translations-raw huggingface dataset:
Indehaver af markedsføringstilladelsen: Udfyldes nationalt
Marketing authorisation holder and manufacturer responsible for batch release: To be completed nationally
Kræver recept.
To be supplied only on veterinary prescription.
Kyllinger Kalkuner
Chickens Turkeys
Navn
1 vial
EU-nummer
MA (EU) number (Invented) name
Seasonique er godkendt i visse lande uden for EU.
Seasonique is authorised in some countries outside the European Union (EU).
CHMP foretog ingen yderligere ændringer.
No additional modifications were made by the CHMP.
Blødningsmønster
Bleeding pattern
Samlet resumé af den videnskabelige vurdering af Seasonique og relaterede navne (se bilag I)
Overall summary of the scientific evaluation of Seasonique and associated names (see Annex I)
Tysklands fandt, at udstedelsen af markedsføringstilladelsen udgør en potentiel alvorlig risiko for den offentlige sundhed
Germany considered that the granting of the marketing authorisation constitutes a potential serious risk to public health.
Risikostyringsplan
Risk management plan
Ved analysen blev denne periode opdelt i to perioder på 28 dage og én periode på 35 dage.
For the analysis, this period was split in two 28-day and a 35-day periods.
Kritisk vurdering
Critical evaluation
Den totale compliance for alle behandlede patienter var ≥ 97 % i hovedundersøgelsen og ≥ 98 % i den støttende undersøgelse.
The overall treatment compliance for all treated patients was ≥ 97% in the pivotal study and ≥ 98% in the supportive study.
Den decentrale ansøgning om markedsføringstilladelse blev indgivet i henhold til artikel 28, stk. 3, i direktiv 2001/83/EF, i overensstemmelse med artikel 10b i direktiv 2001/83/EF.
The decentralised marketing authorisation application was submitted under Article 28(3) of Directive 2001/83/EC in accordance with Article 10b of Directive 2001/83/EC.
• udvalget behandlede anmeldelsen af den indbringelse, der var indledt af Frankrig i medfør af artikel 29, stk. 4, i direktiv 2001/83/EF.
• The Committee considered the notification of the referral triggered by France under Article 29(4) of Directive 2001/83/EC.
Den ansøgte indikation for Seasonique var »oral antikonception«.
The proposed indication for Seasonique was “oral contraception”.
CHMP forhørte sig hos arbejdsgruppen vedrørende biostatistik (BSWP) om validiteten af denne metode i det pågældende tilfælde.
The CHMP requested advice from the Biostatistics Working Party (BSWP) on the validity of this method in the present case.
Resultaterne af de kliniske undersøgelser med Seasonique støttes yderligere af data efter markedsføring.
The results obtained in clinical trials with Seasonique are further supported by post-marketing data.
Antikonceptiv virkning
Contraceptive efficacy
Begge aktive stoffer er allerede godkendt i denne kombination, dels i denne dosis, dels i en lavere dosis (levonorgestrel 100 µg/ethinylestradiol 20 µg).
Both active substances are already authorised in this combination, at this dosage and at a lower dosage (LGN 100 µg/ EE 20 µg).
Det Pearl-indeks, der var beregnet med Poisson-metoden, blev derfor anset for acceptabelt i betragtning af, at det udvidede regime i Seasonique kun er en mindre ændring af et eksisterende produkt.
The PI calculated with the Poisson method was therefore considered acceptable taking into account that the extended regimen in Seasonique is only a minor modification of an existing product.
Desuden var den iagttagne graviditetsrate i de kliniske fase III-undersøgelser relativt lav (Pearl-indeks <1), og der blev ikke fundet noget signal på nedsat virkning i de omfattende erfaringer efter markedsføring.
Moreover the pregnancy rate observed in the phase III clinical trial was relatively low (PI<1), and no signal of a reduced efficacy was detected in the large experience obtained post-marketing.
Trods disse begrænsninger taler denne publikation i det mindste ikke for ringere antikonceptiv virkning af 84/7-regimet.
In spite of these limitations, this publication at least does not support a reduced contraceptive efficacy associated with the 84/7 regimen.
Ansøgeren blev derfor anmodet om at foretage supplerende analyser af blødningsmønsteret baseret på tre ekstrapolationsregler med henblik på at inkludere kvinder, som havde fået seponeret behandlingen i utide, og at ekstrapolere disse data til hele den planlagte varighed på 1 år af undersøgelse PSE-302.
Hence the applicant was asked to conduct additional analyses of the bleeding pattern based on three extrapolation rules to include women who prematurely discontinued treatment and to extrapolate those data to the total planned study duration of PSE-302 of one year.
CHMP var af den opfattelse, at risk/benefit-forholdet for Seasonique og relaterede navne er positivt.
The CHMP was of the opinion that the benefit-risk balance of Seasonique and associated names is considered to be favourable
Undersøgelse PSE-302 omfattede et begrænset antal cyklusser med eksponering og var ikke udformet med henblik på vurdering af Pearl-indeks.
Study PSE-302 included a limited number of cycles of exposure and was not designed for PI evaluation.
Samlet vurdering af benefit/risk-forholdet
Overall benefit-risk balance
På linje med disse resultater viste laboratorieprøverne, at Seasoniques profil for uventede blødninger/pletblødninger ikke førte til klinisk betydningsfulde forandringer.
In line with these findings, the laboratory results demonstrated that the unscheduled bleeding/spotting profile with Seasonique did not lead to clinically significant changes.
Af data uden for EU fremgår det, at den skønnede eksponering fra den første godkendelse i 2006 og frem til december 2013 er 385 901 kvindeår, men at der kun blev indberettet 10 graviditeter svarende til en indberettet graviditetsrate på 0,0026 %.
From data outside the EU, since the first authorisation in 2006 until December 2013, while the estimated exposure is 385,901 women-years, only 10 pregnancies were reported resulting in a pregnancy reporting rate of 0.0026 %.
• anbefalede CHMP udstedelse af markedsføringstilladelse(r), for hvilke produktresuméet, etiketteringen og indlægssedlen er uændrede i forhold til de endelige versioner, der er fastlagt ved behandlingen i koordinationsgruppen, som anført i bilag III for Seasonique og relaterede navne (se bilag I).
the CHMP has recommended the granting of the marketing authorisation(s) for which the summary of product characteristics, labelling and package leaflet remain as per the final versions achieved during the Coordination group procedure as mentioned in Annex III for Seasonique and associated names (see Annex I).
Den decentrale procedure blev afsluttet på dag 210, hvor konklusionerne i referencemedlemsstatens vurderingsrapport fik tilslutning fra størstedelen af de berørte medlemsstater bortset fra Tyskland, som rejste betænkelighed ved en potentiel alvorlig risiko for den offentlige sundhed.
The decentralised procedure was closed on day 210, with most of the Concerned Member States (CMS) agreeing with the conclusions of the RMS except Germany which raised a potential serious risk to public health.
Nogle medlemmer af CHMP fandt ikke denne publikation acceptabel som dokumentation for den antikonceptive virkning af udvidede doseringsregimer, da denne type undersøgelser ofte er behæftet med forskellige konfunderende faktorer (anvendelsesvarigheden af de forskellige kombinerede orale kontraceptiva, graviditetsønsker, anvendelse til andre formål end antikonception).
Some CHMP members considered that this publication is not acceptable as proof of contraceptive efficacy of extended cycle regimens as this type of study is prone to various kinds of confounders (duration of use of the different COCs, intention of pregnancy, use for other reasons than contraception).
I DP3-84/30-armen i undersøgelse PSE-301 kunne der imidlertid ikke aflægges medicinregnskab for 3 ud af de 9 graviditeter, der indgik i analysen som »i behandling«; ud fra de foreliggende data kunne disse graviditeter betragtes som »ude af behandling«.
However in the DP384/30 arm of study PSE-301, for 3 out of the 9 pregnancies included in the analysis as ‘on-treatment', drug accountability could not be performed; indeed, based on the available data, these pregnancies might be considered ‘off-treatment'.
Hormonkombinationen levonorgestrel 150 µg/ethinylestradiol 30 µg har således været godkendt som kontraceptivum i EU i over 35 år, og virkningen er veldokumenteret.
Indeed the LNG 150 µg/ EE 30 µg hormonal combination has been approved as a contraceptive in the EU for over 35 years and its efficacy is well documented.
På grund af sit lave østrogenindhold hører præparatet til de såkaldte kombinerede orale lavdosis-kontraceptiva.
Due to the low estrogen content, the preparation belongs to the so-called low-dose combined oral contraceptives (COCs).
Det kliniske udviklingsprogram for Seasonique omfattede to randomiserede fase III-undersøgelser, hovedundersøgelsen PSE-301 samt en støttende undersøgelse, PSE-302, specifikt vedrørende vurderingen af endometriebiopsier, som blev foretaget i USA.
The clinical development program for Seasonique included two phase III randomised clinical trials, the pivotal study PSE-301 and a supportive study, PSE-302, specifically designed to assess endometrial biopsy results, which were performed in the United States.
Under den decentrale procedure var den indsigende medlemsstat af den opfattelse, at den antikonceptive virkning af Seasonique ikke var tilstrækkeligt påvist.
During the decentralised procedure, the Objecting Member State (OMS) was of the view that the contraceptive efficacy of Seasonique had not been sufficiently demonstrated.
Af disse grunde anså CHMP ikke dette højere Pearl-indeks for at være relevant for vurderingen af Seasoniques virkning.
For these reasons the CHMP did not consider this higher PI as relevant in the assessment of the efficacy of Seasonique.
Farmakodynamiske data viste, at den ovariehæmmende virkning af Seasonique ligger inden for det område, der er iagttaget for andre godkendte kombinerede hormonale kontraceptiva.
PD data showed that the ovarian inhibiting efficacy of Seasonique is within the range of that observed for other approved combined hormonal contraceptives.
Tysklands hovedbetænkelighed kunne således ikke ophæves ved indbringelsen for CMD(h), og sagen blev derfor indbragt for Udvalget for Lægemidler til Mennesker (CHMP).
Thus, the major concern raised by Germany could not be solved during the CMDh referral and the issue was therefore referred to the CHMP.
Efter gennemgang af samtlige oplysninger fra ansøgeren og udtalelsen fra BSWP fandt CHMP den antikonceptive virkning af Seasonique tilstrækkeligt påvist.
Having considered all the data submitted by the applicant, and the view of the BSWP, the CHMP considered that the contraceptive effectiveness of Seasonique was adequately demonstrated.
CHMP tilsluttede sig udtalelsen fra BSWP, som anså bootstrapping for sædvanligvis at være uegnet til beregning af sikkerhedsintervallet for et Pearl-indeks, navnlig i dette eksempel, hvor det ikke var præspecificeret og først blev taget i brug, efter at sædvanlig analyse havde givet negative resultater.
The CHMP supported the position of the BSWP, which considered that the bootstrap method is generally inappropriate for calculating confidence intervals for a PI; even more so in this example where it was not pre-specified, and was employed only after negative results were seen for the more conventional analysis.
I litteraturen er det desuden påvist, at udeladelse af den hormonfrie periode er forbundet med bedre hæmning af den ovarielle aktivitet.
It has also been shown in the literature that the elimination of the HFI is associated with a better inhibition of the ovarian activity.
CHMP fandt derfor virkningen af Seasonique tilstrækkeligt godtgjort.
Therefore the CHMP considered the efficacy of Seasonique adequately demonstrated.
CHMP fandt desuden, at blødningsmønsteret ved anvendelse af Seasonique hverken var et sikkerhedsmæssigt problem eller forringede virkningen.
The CHMP also considered that the bleeding pattern associated with the use of Seasonique neither constituted a safety issue, nor impaired efficacy.
Koncentrationerne af follikelstimulerende hormon (FSH), luteiniserende hormon (LH), estradiol og inhibin B blev mere effektivt supprimeret, når det hormonfrie interval blev afkortet fra 7 dage til 3 eller 4 dage i hver 28dages behandlingscyklus (Willis, 2006).
Levels of folliclestimulating hormone (FSH), luteinizing hormone (LH), estradiol, and inhibin B were suppressed more effectively when the duration of the HFI was shortened from 7 days to 3 or 4 days per 28-day treatment cycle (Willis, 2006).
Desuden viste flere publicerede farmakodynamiske undersøgelser, at graden af ovulationshæmning øges ved at gøre den hormonfri periode kortere.
Additionally several published pharmacodynamic studies demonstrated that the degree of ovulation inhibition is increased with a shorter HFI.
• udvalget finder, at de foreliggende data underbygger virkningen af Seasonique og relaterede navne som udvidet doseringsregime for et eksisterende kombineret oralt kontraceptivum
• The Committee is of the opinion that the available data is supportive of the efficacy of Seasonique and associated names as an extended regimen of an existing combined oral contraceptive.
I undersøgelse PSE-302 var der samme udtrædelsesrate i gruppen på Seasonique (51,6 %) som i gruppen på sammenligningspræparatet (49,5 %).
Comparable withdrawal rates were observed in Study PSE-302 for the Seasonique group (51.6%) and for the comparator group (49.5%).
Det samlede antal dage med blødning/pletblødning i løbet af undersøgelsens planlagte varighed på 1 år var højere for gruppen på Seasonique end for gruppen på sammenligningspræparatet (gennemsnitligt 61-62 mod 55-56, afhængigt af ekstrapolationsregel).
The total number of days with bleeding/spotting within the planned study duration of 1 year was higher for the Seasonique group than for the comparator group (mean 61-62 vs. 55-56 depending on the extrapolation rule).
Levonorgestrel er et gestagen, der vides at hæmme ovulation, mens østrogenet ethinylestradiol i lav dosis sikrer tilfredsstillende kontrol med suppression af de ovarielle follikler og stabiliserer endometriet, så gennembrudsblødning minimeres.
Levonorgestrel (LGN) is a progestogen known to inhibit ovulation, whilst the low dose ethinylestradiol (EE), an estrogen, ensures control over ovarian follicular suppression and provides stability to the endometrium in order to minimise breakthrough bleeding.
Ved den forudgående decentrale procedure for Seasonique blev der forelagt og vedtaget en risikostyringsplan.
A risk management plan was submitted and agreed upon during the preceding Decentralised Procedure on Seasonique.
En 1-årig retrospektiv undersøgelse hos kvinder i alderen 15 til 40 år viste desuden lavere indberettet graviditetsrate med orale kontraceptiva med udvidet regime (84/7) end med »standardregimerne« 21/7 og 24/4.
In addition, a 1-year retrospective study in women 15 to 40 years of age, showed that reported pregnancy rates were lower with extended regimen OC (84/7) than with ‘standard' regimens (21/7 and 24/4).
Dette støttedes yderligere af, at der ikke var anæmi eller klinisk vigtige forskelle i laboratorieresultaterne i forhold til det kombinerede orale 21/7-dages kontraceptivum.
This was further supported by the absence of anaemia or clinically important changes in the laboratory results compared to the 21/7-day COC.
Seasonique er et oralt antikonceptivum med et 91-dages udvidet doseringsregime bestående af en fast kombination af levonorgestrel 150 µg/ethinylestradiol 30 µg i 84 dage, efterfulgt af ethinylestradiol, filmovertrukne tabletter, 10 µg, i 7 dage.
Seasonique is a 91-day extended regimen oral contraceptive consisting of a fixed dose combination of levonorgestrel 150 µg/ ethinylestradiol 30 µg for 84 days followed by ethinylestradiol 10 µg film-coated tablets for 7 days.
• udvalget gennemgik alle data fra ansøgeren til dokumentation af virkningen af Seasonique og relaterede navne ved oral antikonception som udvidet doseringsregime
• The Committee reviewed all the data submitted by the applicant in support of the efficacy of Seasonique and associated names in oral contraception as an extended regimen.
Denne mere udtalte suppression blev også påvist med et 24/4regime bestående af drospirenon 3 mg/ethinylestradiol 2 µg sammenlignet med et 21/7standardregime (Klipping, 2008), for et oralt 24/4-regime med nomegestrolacetat/17b-estradiol sammenlignet med et 21/7-regime (Christin-Maitre, 2011) og for et 23-dages regime med 0,075 mg gestoden/20 µg ethinylestradiol sammenlignet med et 21-dages regime (Spona, 1996).
This more pronounced suppression was also demonstrated with 24/4 drospirenone 3 mg/EE 2 µg regimen compared to a standard 21/7 regimen (Klipping, 2008), for the 24/4 oral regimen with a nomegestrol acetate/17b-estradiol compared to the 21/7 regimen (ChristinMaitre, 2011), and for a 23-day regimen of 0.075 mg gestodene/20 µg EE compared with a 21-day regimen (Spona, 1996).
Derudover udførte ansøgeren en ikke-sammenlignende farmakodynamisk undersøgelse DR-105-101 under én forlænget cyklus på 91 dage (84 dage med levonorgestrel/ethinylestradiol efterfulgt af 7 dage med ethinylestradiol alene).
Moreover the applicant conducted a non-comparative pharmacodynamic (PD) study DR-105-101 during one extended cycle of 91 days (84 days of LNG/EE, followed by 7 days of EE only).
Bedømt på antallet af kvinder, der gennemgik et års behandling, var seponering på grund af blødning/pletblødning hyppigere i gruppen på Seasonique (7,4 %) end i gruppen på sammenligningspræparatet (1,1 %), skønt det gennemsnitlige samlede antal dage med blødning/pletblødning (forventet og uventet) pr. patientmåned var 4,4 dage for både Seasonique og sammenligningspræparatet.
Although, based on women who completed one year of treatment discontinuation due to bleeding/spotting adverse events was more frequent in the Seasonique group (7.4%) than the comparator group (1.1%), the mean total number of days of bleeding/spotting (including scheduled and unscheduled) per patient month was similar, i.e. 4.4 days for both Seasonique and the comparator.
Den manglende hormonfrie periode anses således ikke for at forringe den antikonceptive virkning, og CHMP fandt, at den veldokumenterede antikonceptive virkning med et 28-dages kombinationspræparat af levonorgestrel 150 µg/ethinylestradiol 30 µg kan ekstrapoleres til doseringsregimet for Seasonique.
Thus the absence of HFI is not considered to decrease the contraceptive efficacy and the CHMP considered that the well- documented contraceptive efficacy with 28-day LGN 150 µg/ EE 30 µg combination can be extrapolated to the Seasonique regimen.
CHMP fandt derfor, at blødningsmønsteret med Seasonique hverken udgør et sikkerhedsmæssigt problem for kvinden eller forringer den antikonceptive virkning, og at der i forvejen gives tilstrækkelige oplysninger herom i den påtænkte produktinformation.
Therefore the CHMP considered that the bleeding pattern with Seasonique neither constitutes a safety issue for women nor impairs the contraceptive efficacy and adequate information in this respect is already included in the proposed product information.
Den etårige graviditetsrate var statistisk signifikant lavere med 84/7-regimet end med 21/7regimet (4,4 % mod 7,3 %; p<0,0001) og 24/4-regimet (4,4 % mod 6,9 %, p<0,0001).
One-year pregnancy rates were statistically significantly lower with the 84/7 regimen compared with the 21/7 (4.4% vs. 7.3%; p<0.0001) and with the 24/4 (4.4% vs. 6.9%, p<0.0001) regimens.
Det større antal dage med uventet blødning/pletblødning med Seasonique syntes ikke at medføre anderledes compliance end med andre 21/7-dages orale kontraceptiva.
The increased number of unscheduled bleeding/spotting days with Seasonique appeared not to have an effect on compliance compared to other 21/7-day OC.
Der var ingen forskel mellem grupperne i antallet af patienter, der uanset sværhedsgrad berettede om uventet blødning: 64 (80,0 %) mod 69 (78,4 %) for let blødning, 42 (52,5 %) mod 42 (47,7 %) for moderat blødning og 14 (17,5 %) mod 13 (14,8 %) for svær blødning for henholdsvis gruppen på Seasonique og gruppen på sammenligningspræparatet.
Similar number of patients reported unscheduled bleeding of each severity: 64 (80.0%) and 69 (78.4%) for light bleeding, 42 (52.5%) and 42 (47.7%) for moderate bleeding and 14 (17.5%) and 13 (14.8%) for heavy bleeding, for Seasonique and for the comparator groups, respectively.
Den indsigende medlemsstat fandt derudover, at blødningsmønsteret var ugunstigt, og at det ikke kunne udelukkes, at dette havde indflydelse på compliance med behandlingen og på den antikonceptive virkning.
In addition, the OMS considered that the bleeding pattern is not favourable and could not rule out a potential impact on treatment compliance and contraceptive efficacy.
En publiceret undersøgelse med tre arme med tre forskellige kombinerede orale kontraceptiva viste, at kvinder ved et kontinuerligt 28-dages regime fik mere udtalt follikelsuppression end kvinder, der enten fik 10 µg ethinylestradiol i 5 dage eller en 7-dages hormonfri periode (Schlaff, 2004).
A published study with 3 different combined oral contraceptives (COCs) arms, reported that women treated with a continuous 28-day regimen had more pronounced follicular suppression than women who were either supplemented with 5 days of 10 µg EE or had a 7-day HFI (Schlaff, 2004).
Undersøgelsen omfattede 52 664 kvinder (gennemsnitsalder på 27,3 år), hos hvem 84/7 blev sammenlignet med 21/7 (n=26,332 i begge grupper), samt 50 694 kvinder (gennemsnitsalder på 27,8 år), hos hvem 84/7 blev sammenlignet med 24/4 (n=25 347 i begge grupper).
This study included 52,664 women (mean age, 27.3 years) in the 84/7 vs. 21/7 analysis (n=26,332 in both groups) and 50,694 (mean age, 27.8 years) in the 84/7 vs. 24/4 analysis (n=25,347 in both groups).
Den manglende sammenligningsarm fandtes berettiget på baggrund af, at virkningsmekanismen af denne hormonale kombination i denne dosis er velkendt, og at de eneste forskelle mellem Seasonique og eksisterende kombinationsprodukter med levonorgestrel/ethinylestradiol er behandlingsvarigheden (hhv. 84 og 21 dage) og administration af 10µg ethinylestradiol i hhv. de første 7. dag af cyklussen og en hormonfri periode.
The absence of a comparator arm was considered justified given that the mechanism of action of this hormonal combination in this dose is well known, that the only differences between Seasonique and existing LNG/EE combination products are the treatment duration (84 days versus 21 days, respectively) and the administration of 10µg EE during the last 7 days of the cycle instead of an hormone free interval (HFI), respectively.
Ud fra omfattende resultater fra publicerede kliniske undersøgelser og i betragtning af, at det udvidede regime i Seasonique er en mindre ændring i forhold til eksisterende produkter, konkluderes det, at Seasonique trods den manglende sammenligningsarm i den farmakodynamiske undersøgelse forventes at udøve større kontrol over ovulationen end de eksisterende levonorgestrel/ethinylestradiolkombinationsprodukter, hvis virkning er veldokumenteret.
In conclusion, although the PD study did not include a comparative arm, based on extensive results from published clinical studies and considering that the extended regimen in Seasonique is a minor modification from existing products, Seasonique is expected to have a greater control over ovulation compared to the existing LNG/EE combination products for which the efficacy is well documented.
Som nævnt forelagde ansøgeren under den decentrale procedure en supplerende analyse med bootstrapping og opnåede derved tilstrækkelig præcision af antikonceptiv virkning, som det fremgår af 95 % sikkerhedsintervallet [0,0; 1,76], men det blev betvivlet, at denne post hoc-analyse kunne anses for dækkende.
As mentioned, the applicant presented during the DCP additional analysis with the bootstrap method reaching adequate precision for contraceptive methods as shown by the 95 % CI: 0.0 - 1.76, however concerns were raised regarding the coverage probability properties of this posthoc analysis.