natgillin/translations-raw huggingface dataset:
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.
Sklep o seznamu vprašanj V sklepu je CHMP opomnil, da predlagatelj med postopkom ni predložil nobenih novih podatkov, vendar se ni strinjal s predlagateljem, da dodatni podatki o klinični učinkovitosti in varnosti niso potrebni, saj zagovor v celoti temelji na premostitveni strategiji, ki predvideva, da je biološka razpoložljivost zdravila Rapinyl dvakrat večja kot biološka razpoložljivost pridobljena z zdravilom Actiq, pri enakem molarnem odmerku.
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.
Odbor za zdravila za uporabo v humani medicini je menil, da predloženi podatki tega niso ustrezno prikazali, saj je zanesljivost študije EN3267- 001 vprašljiva, ker podatki ne omogočajo vrednotenja biološke razpoložljivosti obeh pripravkov in ker zbranih analiz ni mogoče potrditi.
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.
Poleg tega so tudi
In addition, because limited PK data are available in patients, these data cannot be compared to the ones obtained in healthy volunteers.
13 farmakokinetični podatki pri bolnikih omejeni in jih ni mogoče primerjati s podatki, pridobljenimi pri zdravih prostovoljcih.
11 Responses to the LoOI and CHMP assessment
Odgovori na seznam odprtih vprašanj in vrednotenje CHMP
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.
Predlagatelj je uspel zagotoviti kot odgovor na seznam odprtih vprašanj vmesno analizo iz dveh potekajočih kliničnih študij o varnosti in učinkovitosti faze III (EN3267- 005 in EN3267- 007), ki ju je v Združenih državah Amerike izvedla družba Endo.
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).
Predlagatelj je prav tako zagotovil podatke s katerimi dokazuje, da je zdravilo Rapinyl doseglo tudi končni učinek primarne učinkovitosti (skupna razlika v jakosti bolečine od začetka do 30 minut kasneje (SPID30)) in rezultati pa so bili statistično zelo pomembni (p=0, 0004).
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).
Predloženi so bili tudi varnostni podatki iz študij EN3267- 005 in EN3267- 007 na osnovi vmesnega prereza zbirke varnostnih podatkov v januarju 2008, sestavljeni le iz resnih neželenih učinkov (SAEs).
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.
Predlagatelj je prepričan, da tudi rezultati študij EN3267- 005 in EN3267- 007 potrjujejo zaključke zasnovane na originalni premostitveni strategiji in kažejo, da lahko zdravilo Rapinyl uporablja za varno in učinkovito zdravljenje večkratnih epizod prebijajoče bolečine pri bolnikih, ki dobro prenašajo opioidne terapije.
The CHMP acknowledged the data submitted, noting and assessing the data from the clinical studies EN3267-005 and EN3267-007.
CHMP je predložene podatke ter podatke iz kliničnih študij EN3267- 005 in EN3267- 007 upošteval in ovrednotil.
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.
CHMP meni, da so predloženi
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.
14 farmakokinetični podatki primerjave med zdravimi prostovoljci in bolniki, omejeni, se pa kljub temu strinja, da razpoložljivi podatki ne kažejo alarmantnih razlik.
Furthermore, while the reasons given by the
Odbor za zdravila za uporabo v humani medicini meni, da mora predlagatelj predložiti analizo 30% in 50% odzivnostne stopnje pri 10 in 15 minutah, kar bo omogočilo boljše vrednotenje profila klinično relevantnega časovnega učinkovanja.
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.
Odbor za zdravila za uporabo v humani medicini sicer sprejema razloge predlagatelja za analiziranje le resnih neželenih dogodkov v tej fazi in pozitivno ocenjuje dejstvo, da se niso pojavila nobena nova varnostna vprašanja, hkrati pa meni, da mora predlagatelj predložiti tudi popolno varnostno analizo.
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.
Predlagatelj je potrdil, da so tablete, uporabljene v fazi III študij Endo, EN3267- 005 in EN3267- 007, kvalitativno in količinsko istovetne tabletam, ki se trenutno nahajajo v postopku vrednotenja v Evropi ter da se v proizvodnem procesu uporablja enak fentanil citrat od istega proizvajalca, z enakimi specifikacijami.
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.
Predlagatelj je ponudil dodatna zagotovila o uporabi zdravila Rapinyl pri bolnikih z mukozitisom, zasnovana na podlagi publikacij in smernic, iz katerih izhaja, da bolniki z rahlim/ zmernim mukozitisom lahko uporabljajo peroralna zdravila, medtem ko oblike fentanila, ki prehajajo skozi sluznico niso primerne za bolnike z močnim mukozitisom in se priporočajo druge oblike dajanja analgetikov.
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.
Predlagatelj je upošteval predlagane spremembe v razdelku 4. 4 o opozorilih pri uporabi v povzetku glavnih značilnosti zdravila ter priporoča posebno pozornost med titracijo pri bolnikih z ranami v ustni votlini ali mukozitisom.
The CHMP considered that the number of patients successfully titrating to an effective dose is close to the one observed for both Actiq and Effentora and observed that as 97% of the patients successfully titrating to an effective dose were able to complete the randomisation phase of the study, no particular safety issues were identified.
CHMP je menil, da je število bolnikov z uspešno titracijo učinkovitega odmerka podobno številu zabeleženem tako pri zdravilu Actiq kot tudi zdravilu Effentora ter ocenil, da je pri 97% bolnikov titracija učinkovitega odmerka bila uspešna in da so ti bolniki uspešno zaključili randomizirano fazo študije, brez zaznav kakršnih koli varnostnih težav.
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.
Predlagatelj se je skliceval tudi na predloženo analizo Razlika v jakosti bolečine (PID) za zdravilo Rapinyl v primerjavi s placebom, od časovne točke 10 minut v študiji EN3267- 005.
While no analysis of 30% and 50% responders at 10 and 15 minutes was conducted in the interim analysis, this analysis was requested from the sponsor in the final clinical study report.
Medtem ko v vmesnih študijah ni bila izvedena nobena analiza 30% in 50% odzivnostne stopnje pri časovni točki 10 in 15 minut, je takšna analiza bila pri sponzorju naročena pri končnem poročilu o klinični študiji.
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.
Zaradi pomanjkanja teh podatkov je naročnik ponudil podatke, ki prikazujejo neposredno korelacijo med analizo 33% odzivnih in Razliko v jakosti bolečine ter uporabil trenutno razpoložljive podatke o bolečini in vrednosti razlik v jakosti bolečine, za ocenitev količnika med aktivnim in placebo zdravljenjem v zgodnejših časovnih točkah.
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.
15 statistično pomembnih izboljšav v razlikah v jakosti bolečine pri 10 in 15 minutah v študiji EN3267 - 005 ustrezna in klinično pomembna meritev zgodnje učinkovitosti zdravila Rapinyl ter da se izboljšava razlike v jakosti bolečine neposredno kaže v povečanju razmerja sodelujočih.
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.
Predlagatelj je tudi obširno predstavil podatke izpostavljenosti za 131 bolnikov, pri katerih je bila titracija v študijah EN3267- 005 in EN3267- 007 uspešna in za bolnike, ki so zaključili 3 - in 12- mesečna poštudijska obdobja.
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.
Predlagatelj je tudi obravnaval predhodno predstavljene podatke o resnih neželenih učinkih do 18. januarja 2008, ko je prišlo do prekinitve varnostne študije ter meni, da novi podatki o varnosti dopolnjujejo premostitveno strategijo in so v skladu z nadaljnjimi pregledi podatkov o resnih neželenih učinkih, ki so se pojavili do 15. maja 2008.
The CHMP was reassured by the 13 absence of safety signals related to SAEs were reported but requested the Applicant to submit a full safety analysis as conditions to the Marketing Authorisations.
CHMP je odsotnost varnostnih znakov v zvezi z resnimi neželenimi učinki, o katerih se je sicer poročalo, pomirila, vendar je od predlagatelja kljub temu zahteval popolno varnostno analizo kot pogoj za pridobitev dovoljenja za promet z zdravilom.
One patient had a successful suicide attempt but while suicidal ideation is known to be more common in patients with cancer than in the general population, neither suicide nor suicidal ideation has been reported as an adverse event associated with Actiq nor with Fentora/ Effentora and based on the similar pharmacokinetic profile of Rapinyl and Actiq, the Applicant believes that this was a sporadic case, consistent with the investigator’ s assessment as being unrelated.
En bolnik je storil samomor in čeprav je mišljenje o samomoru pogostejše pri bolnikih z rakavimi obolenji kot v splošni populaciji, se o samomoru niti o samomorilskih namenih ni poročalo kot o neželenih učinkih, povezanih z zdravilom Actiq ali zdravilom Effentora, na osnovi podobnega farmakokinetičnega profila zdravila Rapinyl in zdravila Actiq, pa je predlagatelj prepričan, da je to bil osamljen primer, v skladu z oceno preiskovalca, da primer ni povezan s sodelovanjem v študiji.
Due to the low number of patients exposed for a long time, the final results of the studies EN3267-005 and EN3267-007 should be provided as conditions to the Marketing Authorisations.
Zaradi majhnega števila bolnikov, ki so bili zdravilu izpostavljeni dalj časa, je kot pogoj za pridobitev dovoljenja za promet z zdravilom potrebno predložiti tudi končne rezultate študij En3267 -
From the efficacy and safety data provided, Rapinyl seems to be comparable to other fentanyl containing products (Actiq and Effentora) for the treatment of BTP in cancer patients.
Iz predloženih podatkov o varnosti in učinkovitosti je razvidno, da je zdravilo Rapinyl primerljivo z drugimi zdravili, ki vsebujejo fentanil (Actiq in Effentora) za zdravljenje prebijajočih bolečin pri bolnikih z rakom.
However, due to the quite low number of patients exposed for a long time, the Applicant was asked to provide the final results of the studies EN3267-005 and EN3267-007 and the full safety analysis data on SAEs as conditions to the Marketing Authorisations.
Zaradi majhnega števila bolnikov, ki so bili zdravilu izpostavljeni dalj časa, mora predlagatelj kot pogoj za pridobitev dovoljenja za promet z zdravilom predložiti končne rezultate študij EN3267- 005 in EN3267- 007 ter popolne podatke varnostne analize o resnih neželenih učinkih.
Based on the review of the data and on the Applicant responses to list of outstanding issues and to the remaining issues, the CHMP considered the benefit/ risk ratio of Rapinyl to be positive and the application for Rapinyl sublingual tablet 50, 100, 200, 300, 400, 600 and 800 μ g to be approvable, provided that the Applicant implements the amendments made to the text of the Product Information and fulfills the conditions to the Marketing Authorisation as described in Annex IV.
Na podlagi pregledanih podatkov in odgovorov predlagatelja na vprašanja iz seznama odprtih vprašanj ter preostalih odprtih tem, CHMP meni, da je razmerje med koristmi in tveganji za zdravilo Rapinyl pozitivno, ter da se vloga za odobritev zdravila Rapinyl 50, 100, 200, 300, 400, 600 in 800 lahko potrdi, pod pogojem da predlagatelj ustrezno spremeni besedilo v informacijah o zdravilu in izpolni pogoje za pridobitev dovoljenja za promet z zdravilom, določene v Dodatku IV.
- the responses provided by the Applicant, in particular the additional clinical data submitted during
- so ponujeni odgovori predlagatelja, zlasti dodatni klinični podatki, predloženi med napotitvenim
the CHMP referral procedure, successfully addressed the CHMP concerns,
postopkom Odbora za zdravila za uporabo v humani medicini, uspešno odpravili zadržke, ki jih je imel CHMP,
- the dose range of Rapinyl and the dose proportionalilty between Actiq and Rapinyl was considered
- sta razpon odmerkov zdravila Rapinyl in sorazmernost odmerkov med zdravilom Actiq in zdravilom
as established
Rapinyl ustrezno dokazana,
- and provided that the Applicant fulfils the conditions to the Marketing Authorisation as listed in
- bo predlagatelj izpolnil pogoje, navedene v Dodatku IV, za pridobitev dovoljenja za promet,
- the CHMP considered the benefit/ risk of Rapinyl to be positive
- CHMP meni, da je razmerje med koristmi in tveganji za zdravilo Rapinyl pozitivno,
the CHMP has recommended the amendment of the Summaries of Product Characteristics and the granting of the Marketing Authorisations for which the Summary of Product Characteristics, labelling and package leaflet are set out in Annex III for Rapinyl and associated names (see Annex I).
je CHMP priporočil dopolnitev povzetka glavnih značilnosti zdravila in odobritev dovoljenja za promet z zdravilom za katero so povzetek glavnih značilnosti zdravila, označevanja in navodila za uporabo, navedeni v Dodatku III za zdravilo Rapinyl in z njim povezana imena (glejte Dodatek I).
15 ANNEX III
17 DODATEK III
16 SUMMARY OF PRODUCT CHARACTERISTICS
18 POVZETEK GLAVNIH ZNAČILNOSTI ZDRAVILA
Rapinyl and associated names (see Annex I) 50 microgram sublingual tablets [See Annex I - To be completed nationally]
Rapinyl in povezana imena (glejte Dodatek I) 50 mikrogramske podjezične tablete < [Glejte Dodatek I - Izpolni država članica] >
Each sublingual tablet contains 50 micrograms fentanyl (as citrate) 100 micrograms fentanyl (as citrate) 200 micrograms fentanyl (as citrate) 300 micrograms fentanyl (as citrate) 400 micrograms fentanyl (as citrate) 600 micrograms fentanyl (as citrate) 800 micrograms fentanyl (as citrate)
100 mikrogramov fentanila v obliki fentanilijevega citrata 200 mikrogramov fentanila v obliki fentanilijevega citrata 300 mikrogramov fentanila v obliki fentanilijevega citrata 400 mikrogramov fentanila v obliki fentanilijevega citrata 600 mikrogramov fentanila v obliki fentanilijevega citrata 800 mikrogramov fentanila v obliki fentanilijevega citrata
50 microgram sublingual tablet is a white pentagon-shaped tablet 100 microgram sublingual tablet is a white round tablet 200 microgram sublingual tablet is a white oval-shaped tablet 300 microgram sublingual tablet is a white triangle-shaped tablet 400 microgram sublingual tablet is a white diamond-shaped tablet 600 microgram sublingual tablet is a white “ D” -shaped tablet 800 microgram sublingual tablet is a white capsule-shaped tablet
800 mikrogramska podjezična tableta je bela tableta v obliki kapsule.
Rapinyl sublingual tablets should be administered directly under the tongue at the deepest part.
20 Rapinyl podjezične tablete se daje neposredno pod jezik na najgloblji del.
Rapinyl sublingual tablets should not be swallowed, but allowed to completely dissolve in the 18 sublingual cavity without chewing or sucking.
Rapinyl podjezične tablete se ne sme pogoltniti, temveč je treba pustiti, da se v celoti raztopijo pod jezikom, ne da bi se jih žvečilo ali sesalo.
The 50 microgram strength sublingual tablet may be used for an intermediate dose-titration step.
Za vmesni korak pri titraciji odmerka se lahko uporabi 50 mikrogramska sublingvalna tableta.
Patients should be carefully monitored until an appropriate dose is reached, i. e. that provides adequate analgesia with acceptable adverse reactions for each episode of breakthrough pain.
Bolnike je treba skrbno nadzorovali toliko časa, dokler ustrezni odmerek ni dosežen t. j. dokler ni dosežena ustrezna analgezija s sprejemljivimi neželenimi učinki za vsako epizodo prebijajoče bolečine.
Switching from other fentanyl containing products to Rapinyl must not occur at a 1:1 ratio because of different absorption profiles.
Z drugih zdravil, ki vsebujejo fentanil, se na Rapinyl ne sme preiti v razmerju 1: 1 zaradi razlik v absorpcijskih profilih.
If adequate analgesia is not obtained within 15-30 minutes of administration of a single sublingual tablet, a second 100 microgram sublingual tablet may be administered.
Če v času 15 - 30 minut po odmerku ene podjezične tablete ni dosežena primerna analgezija, se sme odmeriti še eno 100 mikrogramsko sublingvalno tableto.
This titration should follow the course of administering a single sublingual tablet, with administration of a supplemental second sublingual tablet after 15-30 minutes, if inadequate pain relief is obtained.
Titriranje naj se izvaja z odmerkom ene same sublingvalne tablete, ki ji po 15- 30 minutah sledi dodatna sublingvalna tableta, v kolikor z uporabo ene tablete ne dosežemo želenega olajšanja bolečine.
Strength (micrograms) of first sublingual
Jakost (v mikrogramih) prve podjezične
Strength (micrograms) of supplemental
Jakost (v mikrogramih) dodatne (druge)
tablet per episode of breakthrough pain
tablete na epizodo prebijajoče bolečine
(second) sublingual tablet to be taken 15-30 minutes after first tablet, if required
podjezične tablete, ki se jo da 15- 30 minut po prvi tableti, če je to potrebno
In order to minimise the risk of opioid– related adverse reactions and to identify the appropriate dose, it is imperative that patients be monitored closely by health professionals during the titration process.
Da bi zmanjšali nevarnost z opioidi povezanih neželenih učinkov in določili ustrezen odmerek, morajo zdravstveni delavci med postopkom titracije bolnike skrbno nadzorovati.
19 Maintenance therapy:
21 Vzdrževalno zdravljenje:
If more than four episodes of breakthrough pain are experienced per day over a period of more than four consecutive days, then the dose of the long acting opioid used for persistent pain should be re- evaluated.
Če se tekom štirih zaporednih dni prebijajoča bolečina pojavi več kot štirikrat, potem je treba pretehtati uporabo dolgo delujočega opioida, ki se ga uporablja za vztrajajočo bolečino.
Use in elderly patients Dose titration needs to be approached with particular care and patients observed carefully for signs of fentanyl toxicity (see section 4.4).
Titracije odmerka se je treba lotiti posebno pazljivo in bolnike skrbno opazovati, glede znakov toksičnosti fentanila (glejte poglavje 4. 4).
Use in patients with renal and hepatic impairment Patients with kidney or liver dysfunction should be carefully observed for signs of fentanyl toxicity during the Rapinyl titration phase (see section 4.4).
Bolnike z okvaro ledvic ali jeter je treba med postopkom titracije odmerka skrbno opazovati glede znakov toksičnosti fentanila (glejte poglavje 4. 4).
Patients and their carers must be instructed that Rapinyl contains an active substance in an amount that can be fatal to a child, and therefore to keep all tablets out of the reach and sight of children.
4. 4 Posebna opozorila in previdnostni ukrepi Bolnike in njihove skrbnike je treba poučiti, da Rapinyl vsebuje zdravilno učinkovino v količini, ki je lahko smrtna za otroka, zato je treba vse tablete shranjevati otrokom nedostopno.
Before Rapinyl therapy is initiated, it is important that the patient’ s long-acting opioid treatment used to control their persistent pain has been stabilised.
Preden se začne s terapijo z Rapinylom, je pomembno, da je bolnikovo dolgotrajno zdravljenje z opioidi, katerega cilj je kontrola kronične bolečine, stabilno.
Upon repeated administration of opioids such as fentanyl, tolerance and physical and/ or psychological dependence may develop.
22 Pri ponavljajočem jemanju opioidov, kot je fentanil, se lahko razvije toleranca in fizična in/ ali psihična odvisnost.
20 In common with all opioids, there is a risk of clinically significant respiratory depression associated with the use of Rapinyl.
Kot za vse opioide, obstaja tudi pri uporabi Rapinyla tveganje za klinično pomembno depresijo dihanja.
Particular caution should be exercised during dose titration with Rapinyl in patients with chronic obstructive pulmonary disease or other medical conditions predisposing them to respiratory depression (e. g. myasthenia gravis) because of the risk of further respiratory depression, which could lead to respiratory failure.
Še posebej je potrebna previdnost med postopkom titracije odmerkov Rapinyla pri bolnikih s kronično obstruktivno boleznijo pljuč ali drugimi zdravstvenimi stanji, zaradi katerih imajo ti bolniki več možnosti, da se pri njih razvije depresija dihanja (npr. miastenia gravis), saj pri njih obstaja tveganje za nadaljnjo depresijo dihanja, ki bi lahko imela za posledico odpoved dihal.
There should be no noticeable effects on cessation of treatment with Rapinyl, but possible symptoms of withdrawal are anxiety, tremor, sweating, paleness, nausea and vomiting.
Pri ukinitvi zdravljenja z Rapinylom ne bi smelo biti opaznejših učinkov, kljub temu so možni odtegnitveni simptomi kot so strah, tremor, potenje, bledica, slabost in bruhanje.