natgillin/translations-raw huggingface dataset:
As requested by the CHMP, the applicant also performed a bibliographic search on the databases Medline and Embase.
Kot je zahteval CHMP, je predlagatelj opravil bibliografsko iskanje po zbirkah podatkov Medline in Embase.
For the sodium and potassium salt, and the acid, a food effect is evident in most studies.
Pri natrijevi in kalijevi soli ter kislini je vpliv hrane v večini študij očiten.
The mean Cmax reduction observed with food ranges from 21% to 69%.
Povprečno zmanjšanje Cmax, opaženo pri jemanju s hrano, je v razponu med 21 % in 69 %.
Therefore, the CHMP is of the view that the benefit-risk is negative.
Zato je CMHP menil, da je razmerje med koristmi in tveganji negativno.
Therefore, the Committee recommends the refusal of the marketing authorisation of Diclofenac (Altergon) in the reference and concerned Member States.
Odbor tako priporoča zavrnitev vloge za pridobitev dovoljenja za promet z zdravilom Diclofenac (altergon) v referenčni in zadevnih državah članicah.
The marketing authorisation application (MAA) for Diclofenac (epolamine) 50 mg immediate release tablets was submitted according to Article 10(1) of Directive 2001/83/EC.
Vloga za pridobitev dovoljenja za promet z zdravilom Diclofenac (epolamin) 50 mg tablete s takojšnjim sproščanjem je bila predložena v skladu s členom 10(1) Direktive 2001/83/ES.
Furthermore, comparative dissolution testing at pH 5.5 demonstrated immediate release from test and reference product, which was used to support the comparative rate and extent of absorption in vivo in the fed state.
Poleg tega so s primerjalnim preskusom raztapljanja pri pH 5,5 dokazali takojšnje sproščanje preskusnega in referenčnega zdravila, s čimer so podprli primerljivo hitrost in obseg absorpcije in vivo na poln želodec.
• The Committee reviewed the data submitted by the applicant in support of this particular medicinal product Diclofenac (Altergon) 50mg tablets;
• odbor je pregledal podatke, ki jih je v podporo tega konkretnega zdravila Diclofenac (altergon) 50 mg tablete predložil predlagatelj;
The results of the comparative bioavailability study under fasting conditions demonstrate bioequivalence between reference and test products for all pharmacokinetic parameters.
Rezultati primerjalne študije biološke uporabnosti na prazen želodec dokazujejo biološko enakovrednost referenčnega in preskusnega zdravila za vse farmakokinetične parametre.
The potential serious risk to public health (PSRPH) concern was maintained, and the procedure was referred by the RMS to the CMDh.
Pomislek o morebitnem resnem tveganju za javno zdravje je ostal in referenčna država članica je postopek napotila na skupino CMDh.
• The Committee therefore concluded that there was a lack of appropriate data to support the positive benefit-risk of this medicinal product Diclofenac 50mg tablets.
• odbor je zato zaključil, da ni dovolj ustreznih podatkov, ki bi podpirali pozitivno razmerje med koristmi in tveganji zdravila Diclofenac 50 mg tablete.
However the objecting EU Member States argued that the effect of food on Cmax may be formulationdependent in the case of diclofenac, and that from the available evidence the potential difference in bioavailability (Cmax decrease of up to 70%) may reach such a high level so as to compromise the safe and effective use of the drug.
Države članice EU, ki so ugovarjale, so trdile, da je vpliv hrane na Cmax v primeru diklofenaka lahko odvisen od formulacije in da razpoložljivi dokazi kažejo, da je morebitna razlika v biološki uporabnosti (zmanjšanje Cmax do 70 %) lahko tako velika, da ogrozi varno in učinkovito uporabo zdravila.
The CHMP endorsed the PKWP's advice.
CHMP je sprejel nasvet delovne skupine za farmakokinetiko.
In summary this review of literature by the applicant about the magnitude of the food-effect on the rate of absorption with diclofenac immediate release formulations, allowed to conclude that it reached on average, 50% decrease on Cmax and various delays on tmax, without any loss in the amount of systemic exposure.
Na podlagi tega pregleda literature, ki ga je opravil predlagatelj, o obsegu vpliva hrane na hitrost absorpcije pri formulacijah diklofenaka s takojšnjim sproščanjem je torej mogoče zaključiti, da se Cmax povprečno zmanjša za 50 %, zakasnitve tmax pa so različne, brez izgube obsega sistemske izpostavljenosti.
Section 4.2 of the proposed SmPC for Diclofenac (epolamine) 50 mg immediate release tablets is in line with the reference product, and recommends that: '… tablets should be swallowed whole with a glass of water, preferably during or after meals.
Poglavje 4.2 predlaganega povzetka glavnih značilnosti zdravila Diclofenac (epolamin) 50 mg tablete s takojšnjim sproščanjem je v skladu z besedilom za referenčno zdravilo in priporoča, da se: '… tablete zaužijejo cele, s kozarcem vode, najbolje med obrokom ali po njem.
This was a single-dose openlabel randomised 2x2 crossover study of acceptable design.
To je bila odprta, randomizirana navzkrižna študija 2x2 z enkratnim odmerjanjem in sprejemljivo zasnovo.
• The Committee was of the view that in this case bioequivalence of Diclofenac 50 mg tablets vs. the reference product Flector granules for oral solution should be demonstrated in fed conditions as well, in view of the available literature demonstrating that the Cmax of different formulations of diclofenac is affected differently in fed conditions;
• odbor je menil, da je treba v tem primeru dokazati biološko enakovrednost med zdravilom Diclofenac 50 mg tablete in referenčnim zdravilom Flector zrnca za peroralno raztopino tudi na poln želodec, saj razpoložljiva literatura dokazuje, da je vpliv hrane na Cmax pri različnih formulacijah diklofenaka različen;
Given the strong evidence of a food effect on the Cmax and Tmax, this effect is concluded to be both drug substance and formulation dependent.
Na podlagi močnih dokazov vpliva hrane na Cmax in Tmax se izpelje zaključek, da je ta vpliv odvisen tako od učinkovine kot od formulacije.
The Committee, as a consequence, considers that the benefit-risk balance of Diclofenac is not favourable.
Zato je odbor presodil, da razmerje med koristmi in tveganji zdravila Diclofenac ni ugodno.
A summary of the bioequivalence study in the fasted state was presented as well as a review of the literature submitted.
Predstavil je povzetek študije biološke enakovrednosti z jemanjem na prazen želodec in pregled predložene literature.
The advice of PKWP was also sought during this procedure.
Med postopkom so poiskali tudi nasvet delovne skupine za farmakokinetiko.
However no data was submitted to show the food effect between test and reference product to support this application, given that the SmPC recommendation in section 4.2 is that Diclofenac epolamine tablets should be swallowed whole with a glass of water, preferably during or after meals.
Vendar pa niso bili predloženi nobeni podatki, ki bi dokazali vpliv hrane pri preskusnem in referenčnem zdravilu in s katerimi bi podprli vlogo, saj priporočila v poglavju 4.2 povzetka glavnih značilnosti zdravila navajajo, da je zdravilo Diclofenac epolamine tablete treba zaužiti cele skupaj s kozarcem vode, najbolje med obrokom ali po njem.
Considering this, it was argued that it was necessary to request a fed study in order to rule out any risk of bio-in-equivalence under fed conditions.
Z upoštevanjem navedenega so trdile, da je treba zahtevati študijo z jemanjem zdravila na poln želodec, da se izključi tveganje za biološko neenakovrednost pri jemanju na poln želodec.
In summary, the view of the PKWP was that under fed conditions the Cmax is highly variable; Cmax ratio fed/fasted ranged from 26-73% for the different formulations, and formulations that are bioequivalent in the fasted state may not be bioequivalent in the fed state, especially if the dosage form is different.
Stališče delovne skupine za farmakokinetiko je bilo, da je vrednost Cmax na poln želodec močno spremenljiva, razmerje med Cmax na poln in prazen želodec je bilo pri različnih formulacijah namreč v razponu med 26 in 73 %, in formulacije, ki so na prazen želodec biološko enakovredne, na poln želodec morda niso biološko enakovredne, zlasti če je farmacevtska oblika drugačna.
Therefore as Diclofenac epolamine tablets and the reference product diclofenac epolamine granules for solution are different oral pharmaceutical formulations, and because literature data show that the food effect on Cmax of diclofenac is not only dependent on the drug substance but also on the formulation, in this case, bioequivalence can only be concluded if bioequivalence is shown under fed as well as fasted conditions.
Ker sta zdravilo Diclofenac epolamine tablete in referenčno zdravilo diklofenak epolamin zrnca za raztopino drugačni peroralni farmacevtski obliki in ker podatki iz literature kažejo, da vpliv hrane na Cmax diklofenaka ni odvisen samo od učinkovine, pač pa tudi od formulacije, se o biološki enakovrednosti lahko sklepa le, če se dokaže na poln in prazen želodec.
The pre-defined criteria for bioequivalence were met for both Cmax and AUC.
Vrednosti Cmax in AUC sta izpolnjevali vnaprej določena merila za biološko enakovrednost.
Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits prostaglandin synthesis via inhibition of both COX-1 and COX-2 isoenzymes of the arachidonic acid pathway.
Diklofenak je nesteroidno protivnetno zdravilo (NSAID), ki prek zaviranja izoencimov COX-1 in COX-2 v poti arahidonske kisline zavira sintezo prostaglandinov.
Although it was argued by the applicant that a failure of bioequivalence under fasting state is predictive of a failure of bioequivalence under fed state based on the submitted literature, the CHMP was of the view that the reverse argument could not be upheld i.e that bioequivalence under fasting state is predictive of bioequivalence under fed state, without any evidence to support it.
Čeprav je predlagatelj trdil, da na podlagi predložene literature neobstoj biološke enakovrednosti na prazen želodec napoveduje tudi neobstoj biološke enakovrednosti na poln želodec, je CHMP menil, da obratnega argumenta brez podpornih dokazov ni mogoče podpreti, tj. da biološka enakovrednost na prazen želodec napoveduje biološko enakovrednost na poln želodec.
Diclofenac 50 mg Tablets contain diclofenac epolamine, a salt of diclofenac, formed by the combination of diclofenamic acid with the tertiary amine N-(2-hydroxyethyl)-pyrrolidine.
Zdravilo Diclofenac 50 mg tablete vsebuje diklofenak epolamin, sol diklofenaka, ki nastane z reakcijo med diklofenaminsko kislino in terciarnim aminom N-(2-hidroksietil)-pirolidinom.
Therefore the CHMP is of the opinion that the bioequivalence of Diclofenac epolamine tablets and the reference product diclofenac epolamine granules for solution has not been demonstrated for this Article 10(1) marketing authorisation application, since bioequivalence cannot be concluded in the absence of a bioequivalence study in the fed state.
Zato je CHMP menil, da biološka enakovrednost zdravila Diclofenac epolamine tablete in referenčnega zdravila diklofenak epolamin zrnca za raztopino pri tej vlogi za pridobitev dovoljenja za promet v skladu s členom 10(1) ni bila dokazana, saj brez študije biološke enakovrednosti na poln želodec ni mogoče sklepati o biološki enakovrednosti.
Chen et al (2015)2 reported a 69% reduction in Cmax for a buffered potassium solution vs a 28% reduction for a potassium tablet, in the fed state vs. fasted state.
(2015)2 so poročali o 69-odstotnem zmanjšanju Cmax pri puferirani kalijevi raztopini in 28-odstotnem zmanjšanju pri kalijevih tabletah na poln želodec v primerjavi z vrednostmi na prazen želodec.
According to Desjardins et al (2015)1, there was 60% decrease in Cmax for a diclofenac acid capsule, compared to a 43% decrease in Cmax for a potassium tablet, in the fed state vs fasted.
(2015)1 je bilo zmanjšanje Cmax na poln želodec v primerjavi z vrednostjo na prazen želodec pri diklofenakovi kislini v kapsulah 60-odstotno, pri kalijevih tabletah pa 43-odstotno.
The applicant submitted data from one bioequivalence study of diclofenac epolamine tablets vs. Flector granules for oral solution in healthy volunteers under fasted conditions.
Predlagatelj je predložil podatke študije biološke enakovrednosti z diklofenak epolaminom v obliki tablet v primerjavi z zdravilom Flector v obliki zrnc za peroralno raztopino pri zdravih prostovoljcih na prazen želodec.
No food-effect study was identified with Diclofenac epolamine.
Za zdravilo Diclofenac epolamine niso našli študije, ki bi proučevala vpliv hrane.
The CHMP agreed with the applicant that the food effect on Cmax of diclofenac is both drug substance and formulation dependent, based on the review of the literature, which includes potassium and sodium salts, and the acid.
CMHP se je na podlagi pregleda literature, ki vključuje kalijeve in natrijeve soli ter kislino, strinjal s predlagateljem, da je vpliv hrane na Cmax diklofenaka odvisen od učinkovine in formulacije.
One study demonstrating the bioequivalence of diclofenac epolamine tablets vs. Flector (diclofenac epolamine) granules for oral solution in healthy volunteers in the fasted state was submitted by the applicant in support of this MAA.
Predlagatelj je v podporo tej vlogi predložil študijo, ki je dokazovala biološko enakovrednost diklofenak epolamina v obliki tablet v primerjavi z zdravilom Flector (diklofenak epolamin) v obliki zrnc za peroralno raztopino pri zdravih prostovoljcih na prazen želodec.
MA (EU) number (Invented) name Strength Pharmaceutical Form Route of Administration Immediate Packaging Pack size
Številka (EU) dovoljenja za promet
The therapeutic indication of Lartruvo is:
Terapevtska indikacija za zdravilo Lartruvo je:
Benefit-risk assessment and discussion
Ocena razmerja med tveganji in koristmi ter razprava
Even the post-discontinuation therapy is balanced.
Tudi zdravljenje po prekinitvi je uravnoteženo.
However, this remains higher in the investigational arm.
Ta torej ostaja višja v preiskovani skupini.
The EC requested the CHMP to give its opinion on whether the marketing authorisation for this product should be maintained, varied, suspended or revoked.
Evropska komisija je odbor CHMP prosila, naj poda mnenje glede tega, ali naj se dovoljenje za promet s tem zdravilom ohrani, spremeni, začasno umakne ali prekliče.
Baseline patient and disease characteristics appeared overall well balanced.
Izhodiščne značilnosti bolnikov in bolezni so se na splošno zdele dobro uravnotežene.
The results of the ANNOUNCE study confirmed the safety profile seen in the previous phase II study.
Rezultati študije ANNOUNCE so potrdili varnostni profil, ki so ga opazili v predhodni študiji II.
Therefore, pursuant to Article 116 of Directive 2001/83/EC, the Committee recommends the revocation of the marketing authorisation for Lartruvo.
Odbor zato v skladu s členom 116 Direktive 2001/83/ES priporoča preklic dovoljenja za promet z zdravilom Lartruvo.
The subgroup analyses do not reveal any subgroup of interest where there could be some benefit.
Analize podskupin ne razkrivajo interesne podskupine, ki bi lahko imela korist.
Safety analysis by age category (<65 vs >=65 years) showed higher toxicity in older subjects, although this occurred equally in both arms.
Analiza varnosti po kategoriji starosti (< 65 ali > = 65 let) je pokazala večjo toksičnost pri starejših preskušancih, čeprav se je ta v enaki meri pojavila v obeh skupinah.
Unfavourable effects
Neugodni učinki
All anaphylactic reactions occurred during the first olaratumab infusion.
Vse anafilaktične reakcije so se pojavile med prvim infundiranjem olaratumaba.
Furthermore, there was no clinical benefit in key secondary efficacy endpoints.
Poleg tega ni bilo klinične koristi pri ključnih sekundarnih opazovanih dogodkih učinkovitosti.
Immediate non-anaphylactic reactions were reported in 9.3% patients and were grade 1/2 in severity.
O takojšnjih neanafilaktičnih reakcijah so poročali pri 9,3 % bolnikov, pri čemer so bile stopnje resnosti 1/2.
The baseline characteristics appear to be evenly balanced, both in histology and disease at randomization.
Osnovne značilnosti se zdijo enakomerno uravnotežene tako histološko kot glede bolezni pri randomizaciji.
On 25 January 2019 the European Commission (EC) triggered a procedure under Article 20 of Regulation (EC) No 726/2004, and requested the CHMP to assess the above concerns and their impact on the benefit-risk balance of Lartruvo.
Evropska komisija je 25. januarja 2019 sprožila postopek v skladu s členom 20 Uredbe (ES) št. 726/2004 in od odbora CHMP zahtevala, da oceni zgornje pomisleke in njihov vpliv na razmerje med tveganji in koristmi pri zdravilu Lartruvo.
In January 2019, the marketing authorisation holder communicated to the European Medicines Agency high level preliminary results of the JGDJ study.
Januarja 2019 je imetnik dovoljenja za promet z zdravilom Evropski agenciji za zdravila poročal o predhodnih rezultatih študije JGDJ.
• The Committee considered the procedure under Article 20 of Regulation (EC) No 726/2004 for Lartruvo.
• odbor je obravnaval postopek v skladu s členom 20 Uredbe (ES) št. 726/2004 za zdravilo Lartruvo;
The strength of the evidence from the phase III ANNOUNCE study is necessarily higher due to higher patient numbers and the blinded design with no cross-over.
Moč dokazov iz študije III. faze ANNOUNCE je nedvomno večja zaradi večjega števila bolnikov in slepe zasnove brez navzkrižnega prehajanja.
Favourable effects
Ugodni učinki
STS is a disease which encompasses a wide range of different tumour histologies, some of them with different prognosis and specific treatments.
Sarkom mehkih tkiv je bolezen, ki zajema širok spekter različnih tumorskih histologij, od katerih imajo nekatere drugačno prognozo in posebno zdravljenje.
In addition, the rate of (consolidated) musculoskeletal pain was similar between the 2 treatment arms.
Poleg tega je bila med obema zdravljenima skupinama podobna stopnja (združene) mišično-skeletne bolečine.
However, the median duration of doxorubicin treatment was 18 weeks and 23 weeks for the investigational and control groups, respectively.
Mediana trajanja zdravljenja z doksorubicinom pa je bila 18 tednov pri preiskovani oziroma 23 tednov pri kontrolni skupini.
It was designed to confirm the OS benefit previously shown in the smaller phase 1b/2 study JGDG.
Zasnovano je bilo za potrditev podaljšanja skupnega preživetja, ki so ga predhodno ugotovili v manjši študiji JGDG faze 1b/2.
Lartruvo was granted a conditional marketing authorisation under Article 14(7) of Regulation (EC) No. 726/2004, valid throughout the European Union, on 9 November 2016.
Zdravilo Lartruvo je 9. novembra 2016 pridobilo pogojno dovoljenje za promet v skladu s členom 14(7) Uredbe (ES) št. 726/2004, veljavno po vsej Evropski uniji.
The heterogeneity could also play a role in the two studies.
Na rezultate v obeh študijah bi lahko vplivala tudi heterogenost.
Whereas
faze.
When excluding the event of oedema not associated with an AE suggestive of cardiac dysfunction or a significant decrease in left ventricular function, the true incidence of cardiac dysfunction was 9.3% in the investigational arm and 6.8% in the control arm.
Ob izključitvi edemov, ki niso bili povezani z neželenim dogodkom, ki je kazal na srčno disfunkcijo ali pomembno zmanjšanje funkcije levega prekata, je bila prava incidenca srčne disfunkcije 9,3 % pri preiskovani skupini in 6,8 % pri kontrolni skupini.
All the sensitivity analyses carried out in the ANNOUNCE study, both in the ITT population an in the LMS group, point in the same direction (no favourable effect of olaratumab).
Vse analize občutljivosti, ki so jih izvedli v študiji ANNOUNCE, in sicer pri populaciji z namenom zdravljenja in tudi pri skupini z LMS, kažejo v isto smer (brez ugodnega učinka olaratumaba).
Frequency of patients with TEAE leading to treatment discontinuation was similar in both arms (4.3% vs 4.4%).
Pogostost bolnikov z neželenimi dogodki zaradi zdravljenja, ki so vodili v prekinitev zdravljenja, je bila podobna v obeh skupinah (4,3 % oziroma 4,4 %).
The rate of haematological toxicities (neutropenia, thrombocytopenia, anaemia and febrile neutropenia) and gastrointestinal toxicities (nausea, vomiting and diarrhoea) was balanced between the treatment arms.
Stopnji hematološke toksičnosti (nevtropenija, trombocitopenija, anemija in febrilna anemija) in gastrointestinalne toksičnosti (slabost, bruhanje in diareja) sta bili med zdravljenima skupinama uravnoteženi.
Overall, the results of the ANNOUNCE study are mature and robust to draw the conclusion that the study showed lack of therapeutic efficacy associated with olaratumab treatment in the authorised indication.
Na splošno so rezultati študije ANNOUNCE dovolj zreli in trdni, da lahko sklepamo, da je študija pokazala pomanjkanje terapevtske učinkovitosti pri zdravljenju z olaratumabom ob odobreni indikaciji.
The ANNOUNCE (JGDJ) study was then requested as a specific obligation to confirm the efficacy and safety of olaratumab in same population for whom Lartruvo is currently indicated.
Študijo ANNOUNCE (JGDJ) je bilo nato treba izvesti kot posebno zahtevo za potrditev učinkovitosti in varnosti olaratumaba pri enaki populaciji, za katero je trenutno indicirano zdravilo Lartruvo.
Infusion related reactions, cardiac arrhythmia and cardiac dysfunction are considered events of special interest for olaratumab.
Z infuzijo povezane reakcije, srčne aritmije in srčna disfunkcija se štejejo za dogodke posebnega pomena za olaratumab.
There are also no data regarding the toxicity observed in subjects in the investigational arm when treated with olaratumab maintenance.
Prav tako ni podatkov o toksičnosti, ugotovljeni pri preskušancih v preiskovani skupini, zdravljenih z vzdrževalnim odmerkom olaratumaba.
No difference was seen in OS in the LMS population either.
Nobene razlike v skupnem preživetju niso opazili niti pri populaciji z LMS.
According to the protocol, doxorubicin 75 mg/m2 was to be administered (after olaratumab or placebo) on day 1 of cycles 1 to 8 (of 3 weeks each).
Po protokolu naj bi se doksorubicin v odmerku 75 mg/m2 dajal (po olaratumabu ali placebu) 1. dan ciklov od 1 do 8 (od teh naj bi vsak trajal tri tedne).
• The Committee reviewed the results of the ANNOUNCE (JGDJ) study, which was conducted to fulfil the specific obligation with a view to confirming a favourable benefit-risk balance for the conditional marketing authorisation for Lartruvo, pursuant to Article 14-a of Regulation (EC) No
• odbor je pregledal rezultate študije ANNOUNCE (JGDJ), ki je bila izvedena za izpolnitev posebne zahteve, da bi potrdili ugodno razmerje med tveganji in koristmi za pogojno dovoljenje za promet z zdravilom Lartruvo v skladu s členom 14(a) Uredbe (ES) št. 726/2004;
The patient disposition of the ANNOUNCE trial does not indicate major differences between arms in reasons for treatment discontinuation.
Razporeditev med bolniki v preskušanju ANNOUNCE ne kaže na večje razlike med skupinama glede razlogov za prekinitev zdravljenja.
Deaths due to adverse events were overall similar in both arms (7[2.7%] vs 6 [2.4%]).
Skupno število smrti zaradi neželenih dogodkov je bilo podobno pri obeh skupinah (7 [2,7 %] oziroma 6 [2,4 %]).
• The Committee, as a consequence, concluded that Lartruvo lacks therapeutic efficacy and that the benefit-risk of Lartruvo is not favourable.
• odbor je zato sklenil, da zdravilo Lartruvo ni klinično učinkovito in da razmerje med tveganji in koristmi pri zdravilu Lartruvo ni ugodno.
‘in combination with doxorubicin, for the treatment of adult patients with advanced soft tissue sarcoma who are not amenable to curative treatment with surgery or radiotherapy and who have not been previously treated with doxorubicin'.
„v kombinaciji z doksorubicinom pri odraslih bolnikih z napredovalim sarkomom mehkih tkiv, ki jih ni mogoče učinkovito zdraviti z operacijo ali radioterapijo in ki z doksorubicinom še niso bili zdravljeni.“
The median of the number of cycles received were higher in the control arm (6 vs 7) and the median of cumulative dose per body surface area (mg/m2) was also higher for the control group (409 vs 483).
Mediana števila prejetih ciklov je bila večja pri kontrolni skupini (6 oziroma 7), prav tako pa je bila pri kontrolni skupini večja mediana kumulativnega odmerka na telesno površino (mg/m2) (409 oziroma 483).