natgillin/translations-raw huggingface dataset:
markedsføringstilladelserne forpligter sig til at undersøge muligheden af at lade vurderingen af fluoxetins indvirkning på kønsmodningen hos børn fra 8 til 12 år indgå i den protokol, der udarbejdes i Institute of Mental Health (NIMH’ s) regi i USA, og at drøfte en forbedring af undersøgelsens design med investigatorerne gennem forlængelse af opfølgningsperioden og forhøjelse af den øvre aldersgrænse for patienterne.
include the evaluation of the effect of fluoxetine on sexual maturation in children aged 8 – 12 years old within the protocol being developed under the auspices of National Institute of Mental Health (NIMH) in United States as well as to discuss with the study investigators the improvement of the trial design by extending the duration of the follow-up and increasing of the upper age range of patients in this study during.
Indehaverne af markedsføringstilladelserne forpligter sig endvidere til at undersøge, om der fra eksisterende registre i medlemsstaterne kan skaffes evaluerbare oplysninger om fluoxetins indvirkning på kønsmodningen.
be used to provide evaluable data on the effects of fluoxetine on sexual maturation.
61/ 61
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London, 21. august 2006 EMEA/ 311654/ 2006
London, 21 August 2006 EMEA/ 311654/ 2006
12,
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) OPINION FOLLOWING AN ARTICLE 6(12) REFERRAL
Internationalt fællesnavn (INN):
Prozac and associated names International Non-Proprietary Name (INN):
Prozac er i de fleste EU- medlemsstater godkendt til behandling af svære depressive episoder, obsessiv- kompulsiv tilstand og bulimia nervosa hos voksne.
Prozac is authorised in most EU Member States for the treatment of major depressive episodes, obsessive-compulsive disorder and bulimia nervosa in adults.
1084/ 2003 en sag for EMEA den 2. maj 2005.
On 2 May 2005, France referred the matter to the EMEA under Article 6(12) of Commission Regulation EC No 1084/ 2003.
Som rapportør og medrapportør udpegedes: henholdsvis dr.
The Rapporteur and Co-Rapporteur appointed were:
På grundlag af vurderingen af de aktuelt foreliggende oplysninger og evalueringsrapporterne fra rapportørerne var CHMP af den opfattelse, at fordelene ved Prozac er større end dets potentielle risici for denne befolkningsgruppe, og vedtog en udtalelse den 1. juni 2006, hvori det anbefaledes at udvide indikationen således:
Based on evaluation of the currently available data and the Rapporteurs’ assessment reports, the CHMP considered that the benefits of Prozac are greater than its potential risks in this population and therefore adopted an opinion on 1 June 2006 recommending the following extension of the indication:
Børn og unge fra 8- årsalderen og derover:
Children and adolescents aged 8 years and above:
Moderat til svær depressiv episode, hvis depressionen ikke reagerer på psykoterapi efter 4- 6 seancer.
Moderate to severe major depressive episode, if depression is unresponsive to psychological therapy after 4-6 sessions.
De faglige konklusioner findes i bilag II, det ændrede produktresumé findes i bilag III, og betingelserne for markedsføringstilladelserne findes i bilag IV.
The scientific conclusions are provided in the Annex II, together with the amended product information in the Annex III and the conditions of the marketing authorisations in the Annex IV.
Den endelige udtalelse blev omdannet til en afgørelse truffet af Europa- Kommissionen den 21. august 2006.
The final opinion was converted into a Decision by the European Commission on 21 August 2006.
(44- 20) 74 18 84 00 Fax (44- 20) 74 18 86 68 E- mail: mail@ emea. eu. int http: // www. emea. eu. int © EMEA 2006 Reproduction and/ or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged * Bemærkninger:
(44-20) 74 18 84 00 Fax (44-20) 74 18 86 68 E-mail: mail@emea. eu. int http: / /www. emea. eu. int © EMEA 2006 Reproduction and/ or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
LISTE OVER NAVNE, LÆGEMIDDELFORM, LÆGEMIDLETS STYRKE, INDGIVELSESVEJ, ANSØGER OG INDEHAVER AF MARKETINGSGODKENDELSE I MEDLEMSSTATERNE
LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANTS AND MARKETING AUTHORISATION HOLDER IN THE MEMBER STATES
Indehaver af marketingsgodkendelse
Marketing Authorisation Holder
ProStrakan Ltd, Galabank Business Park, Galashiels TD1 1QH Forenede Kongerige
ProStrakan Ltd, Galabank Business Galashiels TD1 1QH UK
Rapinyl
Park,
50µg 100µg 200µg 300µg 400µg 600µg 800µg
Rapinyl
Resoriblet, sublingual
50μ g 100μ g 200μ g 300μ g 400μ g 600μ g 800μ g
Sublingual anvendelse
Sublingual tablet Sublingual use
Rapinyl1
Rapinyl
50µg 100µg 200µg 300µg 400µg 600µg 800µg
Rapinyl 1
navn under behandling
1 Name approval pending
Indgivelsesvej
Czech Republic
Finland
Estonia
50µg 100µg 200µg 300µg 400µg 600µg 800µg
Rapinyl 2
3 Medlemsstat
2 Name approval pending 3 Member State
ProStrakan Ltd,
ProStrakan Ltd, Galabank Business Galashiels TD1 1QH UK
50µg
Rapinyl
Galabank Business Park, Galashiels TD1 1QH Forenede Kongerige
ProStrakan Ltd, Galabank Business Galashiels TD1 1QH UK
100µg 200µg 300µg 400µg 600µg 800µg
50μ g 100μ g 200μ g 300μ g 400μ g 600μ g 800μ g
Rapinyl3
Park,
50µg 100µg 200µg 300µg 400µg 600µg 800µg
Rapinyl 3
5 Medlemsstat
3 Name approval pending 5 Member State
Norge
Luxembourg
Indgivelsesvej
Portugal
Slovenien
Slovak Republic
Rapinyl4
Park,
Abstral
Park,
50µg 100µg 200µg 300µg 400µg 600µg 800µg
Rapinyl 4
7 Medlemsstat
4 Name approval pending 7 Member State
Forenede
Sweden
ProStrakan Ltd,
ProStrakan Ltd, Galabank Business Park, Galashiels TD1 1QH UK
Rapinyl
Abstral
Den farmakokinetiske karakteristik efter behandling med Rapinyl og farmakokinetiske sammenligninger af Rapinyl med Actiq er blevet brugt som baggrund for at bygge bro til de omfattende offentliggjorte data om klinisk effekt og sikkerhed for godkendte fentanyl - produkter.
Pharmacokinetic characterisation following treatment with Rapinyl and pharmacokinetic comparisons of Rapinyl versus Actiq have been used as a basis for bridging to the extensive published data regarding clinical efficacy and safety data for authorized fentanyl products.
En række berørte medlemsstater anså, at strategien om at bygge bro var uacceptabel og utilstrækkelig og mente, at den hurtige opløsning af Rapinyl- tabletten kunne være tegn på et højere Cmax og et kortere Tmax.
A number of Concerned Member States considered that the bridging strategy was unacceptable and insufficient and that the fast dissolution of the Rapinyl tablet might be indicative of a higher Cmax and shorter Tmax.
Som følge heraf var yderligere effekt - og sikkerhedsdata nødvendige med henblik på godkendelse af Rapinyl til behandling af gennembrudssmerter hos målpopulationen, og proceduren blev indbragt for Udvalget for Humanmedicinske Lægemidler (CHMP).
As a consequence, additional efficacy and safety data were required for the approval of Rapinyl for the management of breakthrough pain in the target population and the procedure was referred to the CHMP.
Ansøgeren leverede en oversigt over den aktuelle viden om gennembrudssmerter (BTP) ved cancer, hvor den nuværende tilgængelige behandling samt offentliggjorte data og tilgængelige sikkerheds - og effektdata for andre fentanyl- produkter blev beskrevet, og det blev konkluderet, at fentanyl er et ideelt analgesikum til behandling af gennembrudssmerter.
The Applicant provided an overview of the current knowledge of cancer breakthrough pain (BTP), describing the currently available treatment, and the published data and available safety and efficacy data for other fentanyl products, concluding that fentanyl is an ideal analgesic for treatment of breakthrough pain.
Ligeledes anså ansøgeren den kliniske sikkerhed af fentanyl- produkter for at være godt underbygget og godt tolereret af både frivillige og målpopulationen og fandt, at bivirkningsmønstret stemte overens med andre fentanyl- produkter, herunder de produkter der bruges til behandling af BTP.
Similarly, the Applicant considered the clinical safety of fentanyl products to be well established and well tolerated in both volunteers and the target population and that the pattern of side effects was consistent with other fentanyl products, including those used for treating BTP.
Ansøgeren betragtede yderligere den aktuelle strategi om at bygge bro som værende passende til godkendelse af Rapinyl i dosisområdet 100- 800 µg til behandling af BTP hos patienter, da Rapinyl frigiver fentanyl inden for et plasmakoncentrationsområde, der allerede er fastsat som sikkert og effektivt.
The Applicant further considered the current bridging strategy to be appropriate for the approval of Rapinyl over the 100-800µg dose range for the treatment of BTP in patients as Rapinyl delivers fentanyl within a plasma concentration range already established as safe and effective.
Ansøgeren mener derfor, at risk/ benefit- forholdet for Rapinyl er positivt, og at udfaldet af eventuelle yderligere kliniske sikkerheds - og effektforsøg med Rapinyl er forudsigelige og derfor unødvendige.
The Applicant therefore believes the benefit/ risk for Rapinyl to be positive and that the outcome of any further clinical safety and efficacy studies with Rapinyl are predictable and hence, unnecessary.
10 Desuden fremlagde sponsor en række uafhængige og i overvældende grad positive risk/ benefit - vurderinger fra eksperter inden for palliativ behandling.
In addition, the sponsor provided a number of independent overwhelmingly positive benefit/ risk judgements from experts in palliative care.
CHMP kunne ikke godkende ansøgerens påstande om et dosisforhold mellem Rapinyl og Actiq og kunne derfor heller ikke foretage en konklusion vedrørende sammenligneligheden af den systemiske eksponering opnået med Rapinyl og Actiq.
The CHMP not endorse the Applicant claims of dose-relationship between Rapinyl and Actiq and therefore could not conclude on the comparability of systemic exposure obtained with Rapinyl and 10 Actiq.
CHMP anså det også for nødvendigt at vurdere hele rapporten om analysen af sammenligneligheden mellem Rapinyl og Actiq, eftersom de tilgængelige PK- data ikke kunne understøtte ligheden mellem de to produkter.
The CHMP also considered it necessary to assess the full report of the analysis on the comparability of Rapinyl and Actiq, as the available PK data could not support the similarity of both products.
Derfor kunne effekt - / sikkerhedsprofilen for Rapinyl ikke fastsættes.
Therefore the efficacy/ safety profile of Rapinyl could be established.
I betragtning af den smalle terapeutiske bredde for fentanyl er effekt - / sikkerhedsprofilen stærkt afhængig af den systemiske eksponering for dette lægemiddel, og som følge heraf er sammenligneligheden af den systemiske eksponering afgørende.
Considering the narrow therapeutic margin of fentanyl, the efficacy/ safety profile is tightly dependant on systemic exposure to this drug and as a consequence the comparability of systemic exposure is pivotal.
Afslutningsvis fandt CHMP, at ansøgeren gav begrænsede oplysninger om patientbehandlingen (titrering imod en effektiv dosis, flere indgivelser, indgift op til højeste dosis), hvilket forhindrede en vurdering af effekten af og sikkerheden ved Rapinyl inden for de kliniske rammer og en karakteristik af den fulde klinisk relevante profil for tid- effekt for lægemidlet.
In conclusion, the CHMP considered that the Applicant provided limited information on the patient treatment (titration towards an efficient dose, multiple administrations, administration up to the highest dosage) which prevented an evaluation of efficacy and safety of Rapinyl in the clinical setting and characterisation of the full clinically relevant time effect profile of the drug.
Faktisk afhænger berettigelsen udelukkende af strategien om at bygge bro, hvor det formodes, at den biotilgængelighed, der opnås med Rapinyl, er dobbelt så høj som den, der opnås med Actiq ved samme molære dosis.
Conclusion on LoQ In conclusion, the CHMP noted that no new data was provided by the Applicant during the procedure but disagreed with the Applicant point of view that further clinical efficacy and safety data are not needed, indeed the justification relies entirely on a bridging strategy that assumes that the bioavailability obtained with Rapinyl is twice higher than that obtained with Actiq at the same molar dose.
CHMP anså ikke dette for at være påvist i de fremlagte data på grund af usikkerheden vedrørende pålideligheden af forsøg EN3267- 001, da dataene ikke giver mulighed for en vurdering af biotilgængeligheden af de to formuleringer, og da den puljede analyse ikke kan godkendes.
The CHMP considered that this was not demonstrated by the data provided due to the questionability of the reliability of study EN3267-001, because the data does not allow the evaluation of the bioavailability of the two formulations, and because the pooled analysis cannot be endorsed.
Derudover kan disse data på grund
Furthermore, the CHMP considered that the provided clinical data on the efficacy and safety of Rapinyl in the treatment of BTP under normal conditions are scarce and that no conclusion could be drawn from the clinical study provided.
11 af de begrænsede tilgængelige farmakokinetiske data fra patienterne ikke sammenlignes med dataene fra de raske frivillige.
In addition, because limited PK data are available in patients, these data cannot be compared to the ones obtained in healthy volunteers.
Derfor var CHMP ikke enig i, at sikkerheds - og effektprofilen for Rapinyl kunne forudses ud fra den leverede dokumentation.
Therefore, the CHMP was unable to agree that the safety and efficacy profile of Rapinyl could be anticipated from the provided documentation.
Svar på LoOI og CHMP- vurderingen
11 Responses to the LoOI and CHMP assessment
Ansøgeren var i stand til som svar på spørgsmålene på listen med uafklarede spørgsmål at fremskaffe interimanalyser fra to igangværende kliniske fase III- sikkerheds - og effektforsøg (EN3267- 005 og EN3267- 007) udført i USA af Endo.
The Applicant was able to provide in the response to the LoOI the interim analyses from 2 ongoing Phase III safety and efficacy clinical studies (EN3267-005 and EN3267-007), performed in the US by Endo.
Ansøgeren fremsendte også data, der påviste, at Rapinyl opfyldte det primære endepunkt for effekt (samlet forskel i smerteintensitet fra baseline til 30 minutter (SPID30)), og at resultaterne var yderst statistisk signifikante (p=0, 0004).
The Applicant also provided data demonstrating that Rapinyl met the primary efficacy endpoint (Sum of Pain Intensity Difference from baseline to 30 minutes (SPID30)) and that the results were highly statistically significant (p=0.0004).
Der kunne identificeres en effektiv dosis Rapinyl til patienterne, der med held kunne bruge midlet til at kontrollere flere episoder med gennembrudssmerter.
In addition, a clinically relevant time-effect profile appropriate for an episode of breakthrough painl and meaningful clinical benefits for the patients were shown; patients could identify an effective dose of Rapinyl and use it successfully to control multiple episodes of breakthrough pain.
Sikkerhedsdata fra EN3267- 005 og EN3267- 007 er også fremlagt på baggrund af et foreløbigt skæringstidspunkt for sikkerhedsdatabasen i januar 2008, der udelukkende omfatter alvorlige uønskede hændelser.
Safety data from EN3267-005 and EN3267-007 have also been provided based on an interim cut of the safety database in January 2008, comprising only serious adverse events (SAEs).
Ansøgeren forsvarede dosis på 800 µg og redegjorde for sikkerheden ved Rapinyl, når det blev tilføjet i en kontinuerlig fentanyl - eller ikke- fentanyl opioidsmertebehandling og anså den transmucosale frigivelse af fentanyl for at frembringe ensartede resultater uafhængig af typen af baselinebehandling.
The Applicant also defended the 800ug dose and discussed the safety of Rapinyl when superimposed on a continuous fentanyl or non-fentanyl opioid pain therapy and considered that the transmucosal delivery of fentanyl produces consistent results, independent of the type of baseline therapy.
Afslutningsvis fandt ansøgeren, at resultaterne fra forsøg EN3267- 005 og EN3267- 007 bekræfter konklusionerne baseret på den originale strategi om at bygge bro og påviser, at Rapinyl sikkert og effektivt kan bruges til at behandle flere episoder af gennembrudssmerter ved cancer hos opioidtolerante patienter.
In conclusion, the Applicant considered that the results from studies EN3267-005 and EN3267-007 confirm the conclusions based on the original bridging strategy and demonstrate that Rapinyl can be safely and effectively used to treat multiple episodes of cancer breakthrough pain in opioid-tolerant patients.
Ansøgeren mener, at den originale strategi om at bygge bro samt den signifikante mængde leverede bekræftende effekt - og sikkerhedsdata for cancerpatienter viser, at Rapinyl bestemt har en positiv risk/ benefit- profil.
The Applicant believes that the original bridging strategy plus the significant body of confirmatory efficacy and safety data in cancer patients provided demonstrate that Rapinyl does indeed have a positive benefit-risk profile.
CHMP anerkendte de fremsendte data og registrerede og vurderede dataene fra de kliniske forsøg EN3267- 005 og EN3267- 007.
The CHMP acknowledged the data submitted, noting and assessing the data from the clinical studies EN3267-005 and EN3267-007.
CHMP anså de
However, although the interim data support the proposed dose range for Rapinyl, the CHMP requested additional clinical data clearly demonstrating the efficacy/ safety of Rapinyl.
12 farmakokinetiske data for raske frivillige i forhold til patienter for at være begrænsede, men var enig i, at de tilgængelige data ikke viste alarmerende forskelle.
The CHMP considered the pharmacokinetic data in healthy volunteers vs. patients to be limited; however it agreed that the available data do not indicate alarming differences.
I dette forsøg ser de valgte primære kriterier (SPID) og tiden, der er valgt til vurdering af effekt (30 min.), ikke ud til at være passende til at vurdere effekten af en behandling på BTP- episoder, som er kendt for at have en middelvarighed på 30 min.
In this study, the primary criteria chosen (SPID) and the time chosen for assessment of efficacy (30 min) do not seem appropriate to evaluate the efficacy of a treatment on BTP episodes, which are known to present a median duration of 30 min.
CHMP var af den mening, at ansøgeren skulle fremlægge en analyse af 30% og 50% af de responderende efter 10 og 15 minutter for bedre at kunne vurdere den klinisk relevante profil for tid- effekt.
Furthermore, while the reasons given by the
Desuden skal ansøgeren fremsende en komplet sikkerhedsanalyse, selv om de af ansøgeren angivne årsager til kun at analysere alvorlige uønskede hændelser på dette stadie accepteres, og selv om de manglende nye væsentlige sikkerhedsproblemer af CHMP anses for at være acceptable.
12 Applicant for analyzing only SAEs at this stage are endorsed, and the absence of new important safety issues was considered re-assuring by the CHMP, a full safety analysis should be provided by the Applicant.
Svar på de resterende spørgsmål og CHMP- vurderingen
Responses to the Remaining Issues and CHMP assessment
Ansøgeren bekræftede, at de tabletter, der blev brugt i Endos fase III- forsøg EN3267- 005 og EN3267 - 007, er kvalitativt og kvantitativt identiske med de tabletter, der i øjeblikket undersøges i Europa, og at fremstillingsprocessen er den samme, idet der bruges fentanylcitrat fra samme leverandør og med identiske specifikationer.
The Applicant confirmed that the tablets used in the Endo Phase III studies, EN3267-005 and EN3267-007, are qualitatively and quantitatively identical to the tablets currently under review in Europe and that the manufacturing process is the same using fentanyl citrate from the same supplier, with identical specifications.
Ansøgeren gav yderligere forsikringer med hensyn til brugen af Rapinyl til patienter med mucositis på baggrund af publikationer og retningslinjer og konkluderede, at patienter med mild/ moderat mocositis kan bruge peroral medicin, mens transmucosale former for fentanyl ikke er egnet til brug til patienter med svær mucositis, hvor andre indgiftsveje for analgesi foretrækkes.
The Applicant provided further reassurances on the use of Rapinyl in patiens with mucositis, based on publications and guidelines, concluding that patients with mild/ moderate mucositis can use oral medication, while transmucosal forms of fentanyl are not suitable for use in patients with severe mucositis where other routes of analgesia administration are preferable.
4. 4 i produktresuméet, hvor ekstra forsigtighed under titreringen af patienter med sår i munden eller mucositis anbefales.
The Applicant implemented a revised a cautionary statement in section 4.4 of the SPC, recommending extra caution during the titration of patients with mouth wounds or mucositis.
08) og vurderede, at de udledte oplysninger kunne sammenlignes med de angivne værdier for Effentora og Actiq, selv om grunden til patientfrafaldet ikke blev angivet af sponsor.
The Applicant further described data from the time of the safety cut-off (Jan-08) and considered that the derived information compared favourably to values quoted for Effentora and Actiq, although the reason for patient drop-out was not provided by the sponsor.
Derudover blev mundhulen undersøgt af klinikeren eller sygeplejersken 15- 20 minutter efter behandlingen for at kontrollere, om der var lokal irritation, og ingen unormale resultater blev registreret, og tabletterne blev tolereret godt efter både enkeltdoser og gentagne doser.
In addition, the oral cavity was inspected by the clinician or nurse 15-20 minutes after treatment to check for local irritation, no abnormal results were identified and the tablets were well tolerated after both single and repeat doses.
Ansøgeren henviste til den fremsendte analyse af forskellen i smerteintensitet (PID) for Rapinyl sammenlignet med placebo fra 10- minutters- tidspunktet i EN3267- 005- forsøget.
The Applicant referred to the provided analysis of Pain Intensity Difference (PID) for Rapinyl compared to placebo from the 10 minute time point in the EN3267-005 study.
Da disse data ikke forelå, fremlagde ansøgeren data, der viste en direkte sammenhæng mellem en 33% - responsanalyse og PID og brugte de aktuelle tilgængelige data om smerter og PID- værdier til at estimere responsraterne mellem aktiv behandling og placebobehandling på tidligere tidspunkter.
In the absence of the data, the Applicant provided data demonstrating a direct correlation between 33% responder analysis and PID, and used the current available pain data and the PID values to estimate the responder rates between active and placebo treatment at earlier time points.
Ansøgeren forelagde også og foretog en omfattende redegørelse af
In conclusion, the Applicant believes that the demonstration of a statistically significant improvement in PID at 10 and 15 minutes in EN3267- 005 is the appropriate, clinically relevant measure of the early effectiveness of Rapinyl, and that an improvement in PID is directly reflected in an increase in responder rate.
13 eksponeringsdata for de 131 patienter med vellykket titrering i forsøg EN3267- 005 og 007 og for de patienter, der har gennemført opfølgningsperioderne på 3 og 12 måneder.
The Applicant also presented and extensively discussed exposure data for the 131 patients that successfully titrated in studies EN3267-005 and 007 and for the patients completing the 3 and 12-month follow-up periods.
15. maj 2008.
The Applicant discussed the previously provided SAE dataset up to the 18th January 2008 safety cut- off and considered that the new safety data supplemented the bridging strategy and was in line with a further review of SAE data up to the 15th May-08.