natgillin/translations-raw huggingface dataset:
With regards the risk minimisation measures proposed by the applicant, the experts considered them generally welcome although some may be less realistic, notably the measure restricting the packaging to 4 days of treatment which may be difficult to handle in the clinical practice, and the contraindications about severe psychiatric disorders and poly-addicts which was not considered appropriate given the target population.
Kar zadeva ukrepe za zmanjševanja tveganja, ki jih je predlagal predlagatelj, so strokovnjaki menili, da so načeloma dobrodošli, vendar pa so nekateri manj realistični, zlasti ukrep o omejevanju pakiranja na štiridnevno zdravljenje, ki bi bil v klinični praksi težko izvedljiv, in kontraindikacije za resne psihiatrične motnje in večkratno zasvojenost, kar glede na ciljno populacijo ni bilo ocenjeno kot primerno.
Risks of abuse / misuse are higher in polymedication users (cocaine or heroin) and/or patients with severe psychiatric comorbidities.
Tveganja za zlorabo/napačno uporabo so višja pri uporabnikih, ki sočasno uporabljajo več snovi (kokain ali heroin) in/ali bolnikih s hudimi sočasnimi psihiatričnimi boleznimi.
Regarding safety, concerns were expressed with regards to the potential risk of misuse/abuse/dependence, and other identified safety issues, which considered too substantial and difficult to mitigate by the proposed RMMs.
V zvezi z varnostjo so bili izraženi pomisleki o morebitnem tveganju za napačno uporabo/zlorabo/odvisnost in druga vprašanja o varnosti, ki so preveč pomembna in težavna, da bi jih lahko obvladali s predlaganimi ukrepi za zmanjšanje tveganj.
However these data were considered too sparse, not consistent or sufficiently robust to support the indication maintenance of alcohol abstinence in this Very High DRL patient population.
Vendar so bili ti podatki ocenjeni kot preskopi, neskladni ali ne dovolj robustni za podporo indikaciji za vzdrževanje abstinence od alkohola pri tej skupini bolnikov z zelo visoko stopnjo tveganja za zlorabo alkohola.
However the objecting concerned Member States (CMSs) were of the view that although there were trends towards positive results across a few of the studies submitted and some level of statistical significance, there were also some failed studies.
Vendar pa so nekatere zadevne države članice ugovarjale, saj so menile, da je bilo kljub trendom v smeri pozitivnih rezultatov v nekaterih predloženih študijah in določeni stopnji statistične značilnosti tudi nekaj neuspešnih študij.
In order to demonstrate the efficacy of sodium oxybate granules in Very High DRL patients - the target population that was identified post-hoc, the applicant performed several post-hoc subgroup analyses and meta-analyses of the data obtained in clinical trials in medium and long-term maintenance of abstinence.
Za dokaz učinkovitosti natrijevega oksibata v obliki zrnc pri bolnikih z zelo visoko stopnjo tveganja za zlorabo alkohola - ciljni populaciji, ki so jo opredelili post-hoc -, je predlagatelj opravil več naknadnih analiz podskupin in metaanaliz podatkov, pridobljenih v kliničnih preskušanjih pri srednje- in dolgoročnem vzdrževanju abstinence.
Furthermore, safety was considered to be acceptable taking into account the proposed risk minimisation measures (RMM).
Varnost je bila z upoštevanjem predlaganih ukrepov za zmanjševanje tveganj ocenjena kot sprejemljiva.
Considering the modest responder rates in the posthoc subgroup analyses in the short-term, there is a potential risk that Very High DRL patients will not sufficiently respond to Alcover, but would still have the potential to become dependent on sodium oxybate in the longer term.
Glede na kratkoročne zmerne stopnje odzivnosti v post-hoc analizah podskupin obstaja tveganje, da se bolniki z zelo visoko stopnjo tveganja za zlorabo alkohola ne bodo v zadostni meri odzvali na zdravilo Alcover, še vedno pa bi obstajalo tveganje, da dolgoročno postanejo odvisni od natrijevega oksibata.
Grounds for the CHMP opinion following the re-examination procedure
Podlaga za mnenje odbora CHMP po postopku ponovne preučitve
Therefore, the Committee recommends the refusal of the marketing authorisation for Alcover and associated names, 750 mg, 1250 mg, 1750 mg granules in sachets.
Zato odbor priporoča zavrnitev vloge za pridobitev dovoljenja z zdravilom Alcover in povezana imena, 750 mg, 1 250 mg, 1 750 mg zrnca v vrečkah.
Alcover granules in sachet contains the active substance sodium oxybate, which is the sodium salt of Gamma-hydroxybutyric acid (GHB), a derivative of gamma-aminobutyric acid (GABA).
Zdravilo Alcover zrnca v vrečki vsebuje zdravilno učinkovino natrijev oksibat, tj. natrijevo sol gamahidroksimaslene kisline (GHB), derivata gama-aminomaslene kisline (GABA).
Taking into account all the available evidence submitted by the applicant and at the oral explanation before the CHMP, it was concluded that the data does not establish the efficacy of Alcover granules in the claimed indications.
Z upoštevanjem vseh razpoložljivih dokazov, ki jih je predložil predlagatelj, in ustnih pojasnil pred odborom CHMP je bilo zaključeno, da na podlagi podatkov ni mogoče potrditi učinkovitosti zdravila Alcover v obliki zrnc pri predloženih indikacijah.
• With regards to the identified and potential risks related to the use of Alcover granules in sachets, the Committee considered the proposed risk minimisation measures, mainly to mitigate the potential risk of abuse, switch of addiction/ dependence and withdrawal in the light of the proposed indications;
• v zvezi z ugotovljenimi in morebitnimi tveganji, povezanimi z uporabo zdravila Alcover zrnca v vrečkah, je odbor preučil predlagane ukrepe za zmanjševanje tveganj, predvsem za zmanjšanje morebitnega tveganja za zlorabo, prehod na drugo zasvojenost/odvisnost in odtegnitvene težave glede na predlagane indikacije;
The results of the submitted efficacy studies cannot be considered to provide sufficiently robust evidence to establish the efficacy of Alcover (sodium oxybate) granules in the maintenance of alcohol abstinence and treatment of alcohol withdrawal syndrome (AWS).
Ni mogoče šteti, da rezultati predloženih študij o učinkovitosti zagotavljajo dovolj robustne dokaze za potrditev učinkovitosti zdravila Alcover (natrijev oksibat) v obliki zrnc pri vzdrževanju abstinence od alkohola in zdravljenju alkoholnega odtegnitvenega sindroma.
Craving and cognitive aspects may also be considered as secondary outcome measures.
Merila sekundarnega izida bi lahko bila hlepenje in kognitivni vidiki.
The comment was also made with regards to the fact that for patients with benzodiazepines, dependence sodium oxybate could have a role.
Podali pa so tudi pripombe glede dejstva, da bi lahko natrijev oksibat imel vlogo pri bolnikih z odvisnostjo od benzodiazepinov.
These data are therefore considered insufficient to establish the efficacy of Alcover, granules in sachets, in the proposed indications;
Ti podatki torej ne zadoščajo za ugotovitev učinkovitosti zdravila Alcover zrnca v vrečkah pri predloženih indikacijah;
With regards to the identified and potential risks related to the use of Alcover granules, in particular the risks of diversion, abuse, switch of addiction and toxicity if co-administered with alcohol, the Committee considered that the feasibility, proportionality and effectiveness of the proposed risk minimisation measures cannot be deemed evident in the absence of a demonstrated efficacy in the claimed indications.
Kar zadeva prepoznana in morebitna tveganja, povezana z uporabo zdravila Alcover v obliki zrnc, zlasti tveganja za preusmeritev, zlorabo, preklop zasvojenosti in toksičnost ob sočasni uporabi z alkoholom, je odbor menil, da se izvedljivost, sorazmernost in učinkovitost predlaganih ukrepov za zmanjševanje tveganj v odsotnosti dokazane učinkovitosti pri predloženih indikacijah ne morejo šteti za dokazane.
Based on the above, the Committee concluded to maintain its previous opinion that the benefit-risk balance of this medicinal product is negative for both proposed indications.
Na podlagi zgoraj navedenega je odbor sklenil, da bo še dalje zastopal svoje predhodno mnenje, da je razmerje med tveganji in koristmi tega zdravila negativno za obe predlagani indikaciji.
The applicant has proposed to further reduce them by contraindicating the use of Alcover granules specifically in patients with severe psychiatric disorders and patients with past or present co-addiction to opiates or cocaine.
Predlagatelj je predlagal, da tveganja nadalje zmanjša z navedbo kontraindikacije pri uporabi zdravila Alcover v obliki zrnc pri bolnikih s hudimi psihiatričnimi motnjami in bolnikih s trenutno ali preteklo sočasno zasvojenostjo z opiati ali kokainom.
CHMP discussion on grounds for re-examination
Razprava odbora CHMP v zvezi z razlogi za ponovno proučitev
One of the experts with extensive experience with the use of marketed Alcover liquid considered the efficacy of sodium oxybate to be clinically shown and suggested to perform a study in the post-approval setting.
Eden od strokovnjakov z obširnimi izkušnjami z uporabo zdravila Alcover v tekoči obliki, ki je na trgu, je menil, da je učinkovitost natrijevega oksibata klinično dokazana, in predlagal izvedbo študije po odobritvi zdravila.
Regarding the safety of Alcover granules, the risk of Abuse / Misuse / Diversion / Overdose / Dependence / CNS / Respiratory Depression in Very High HDRL patients is well-recognized.
V zvezi z varnostjo zdravila Alcover v obliki zrnc je tveganje za zlorabo/napačno uporabo/preusmeritev/preveliko odmerjanje/odvisnost/centralni živčni sistem/depresijo dihanja pri bolnikih z zelo visoko stopnjo tveganja za zlorabo alkohola dobro znano.
The CHMP thoroughly assessed the detailed grounds for re-examination submitted by the applicant for the use of Alcover granules in the long-term maintenance of alcohol abstinence in AD patients with a very high Drinking Risk Level (VH-DRL) and the treatment of acute alcohol withdrawal syndrome (AWS) and took into consideration the outcome of the consultation of an ad-hoc expert group on 4 October 2017.
Odbor CHMP je temeljito ovrednotil podrobno opisane razloge za ponovno preučitev, ki jih je predložil predlagatelj, pri uporabi zdravila Alcover v obliki zrnc pri dolgoročnem vzdrževanju abstinence od alkohola pri bolnikih, odvisnih od alkohola, z zelo visoko stopnjo tveganja za zlorabo alkohola in pri zdravljenju akutnega alkoholnega odtegnitvenega sindroma ter je pri tem upošteval izid posvetovanja ad hoc strokovne skupine, ki je potekalo 4. oktobra 2017.
The trials submitted with active arm comparators (Gate 1, Nava 2007, Addolorato 1999 and Nimmerrichter 2002) had several methodological flaws such as open label, small sample size, heterogeneity in the studies' population, lack of protocol or defined primary endpoints, assessment of large number of outcomes, and long enrolment period, which lead to conclusions based on post-hoc analysis that do not provide sufficient evidence to establish the efficacy for the use of sodium oxybate granules in the treatment of AWS.
Predložena preskušanja z aktivnimi primerjalnimi skupinami (Gate 1, Nava 2007, Addolorato 1999 in Nimmerrichter 2002) so imela več metodoloških pomanjkljivosti, kot so odprta zasnova, majhna velikost vzorca, heterogenost študijskih populacij, odsotnost protokola ali opredeljenih primarnih opazovanih dogodkov, ocenjevanje velikega števila izidov in dolgo obdobje vključevanja, kar je privedlo do zaključkov na podlagi post-hoc analize, ki ne zagotavljajo zadostnih dokazov za potrditev učinkovitosti uporabe natrijevega oksibata v obliki zrnc pri zdravljenju alkoholnega odtegnitvenega sindroma.
In order to further mitigate these risks in the clinical practice, the applicant has proposed additional risk minimization measures in addition to the warnings/guidance in the product information; dose reduction at the end of treatment to prevent risk of withdrawal; inpatient setting in the treatment of AWS; warnings and guidance in case of concomitant alcohol consumption, and implementation of a restricted prescribing, controlled distribution system and a packaging containing only 4 days treatment.
Za nadaljnje obvladovanje teh tveganj v klinični praksi je predlagal dodatne ukrepe za zmanjševanje tveganj poleg opozoril/navodil v informacijah v zdravilu, in sicer zmanjšanje odmerka na koncu zdravljenja za preprečitev tveganja za odtegnitvene težave, hospitalizacijo pri zdravljenju alkoholnega odtegnitvenega sindroma, opozorila in navodila v primeru sočasnega uživanja alkohola ter uvedbo omejenega predpisovanja, nadzorovanega sistema distribucije in pakiranja, ki vsebuje količino zdravila za štiridnevno zdravljenje.
Evaluation of patients' compliance was regarded as important.
Kot pomembno so ocenili ovrednotenje bolnikovega upoštevanja navodil pri jemanju zdravila.
While the methodological challenges to run a randomised clinical trial in this field were acknowledged by the experts, they recommended the conduction of a prospective, multicentre placebo-controlled, feasible study in order to confirm the results in the subpopulation of interest.
Strokovnjaki so sicer priznali metodološke izzive pri izvedbi randomiziranega kliničnega preskušanja na tem področju, vendar so za potrditev rezultatov v želeni podpopulaciji priporočili izvedbo prospektivne, multicentrične, s placebom nadzorovane študije.
The Committee concluded that in the absence of demonstration of efficacy for Alcover granules in sachets, the benefit-risk balance of this medicinal product is not favourable in the proposed indications.
je odbor zaključil, da zaradi pomanjkanja dokazov o učinkovitosti zdravila Alcover zrnca v vrečkah razmerje med tveganji in koristmi za to zdravilo pri predlaganih indikacijah ni ugodno.
There was a consensus among the experts on the clinical unmet need in the management of maintenance of abstinence from alcohol, and the need for more pharmacological treatment alternatives in this setting.
Strokovnjaki so se strinjali, da pri vzdrževanju abstinence od alkohola obstaja neizpolnjena klinična potreba in da je pri tej indikaciji potrebnih več možnosti farmakološkega zdravljenja.
Overall, the CHMP maintains its initial opinion that the results of the submitted clinical studies are not sufficient to establish the efficacy of Alcover (sodium oxybate) granules in the maintenance of alcohol abstinence and treatment of alcohol withdrawal syndrome (AWS) as there are several drawbacks in the design of these clinical studies, including open-label designs, small sample size, choice of patient population and absence of clearly defined, statistically significant outcomes, DRL not being recorded at baseline, low dose of comparator, and lack of assessment of effects on seizures or delirium as the most concerning events in alcohol withdrawal.
Odbor CHMP ohranja svoje prvotno mnenje, da rezultati predloženih kliničnih študij ne zadoščajo za potrditev učinkovitosti zdravila Alcover (natrijev oksibat) v obliki zrnc pri vzdrževanju abstinence od alkohola in zdravljenju alkoholnega odtegnitvenega sindroma, saj ima zasnova teh študij več pomanjkljivosti, kot so odprta zasnova, majhna velikost vzorca, izbira populacije bolnikov in odsotnost jasno opredeljenih, statistično značilnih izidov, nebeleženje izhodiščne stopnje tveganja za zlorabo alkohola, majhen odmerek primerjalnega zdravila ter odsotnost ocenjevanja učinkov na epileptične napade ali delirij, kar sta najbolj zaskrbljujoča dogodka pri odtegnitvi od alkohola.
With regards to the indication alcohol withdrawal syndrome (AWS), the efficacy of sodium oxybate granules in Very High DRL patients has also not been established.
V zvezi z indikacijo za alkoholni odtegnitveni sindrom učinkovitost natrijevega oksibata v obliki zrnc pri bolnikih z zelo visoko stopnjo tveganja za zlorabo alkohola prav tako ni bila ugotovljena.
The applicant Debrégeas & Associés (D&A) submitted an application for marketing authorisation (MAA) for Alcover 750 mg, 1250 mg and 1750 mg through the Decentralised Procedure (DCP) under the legal basis of Article 8(3) of Directive 2001/83/EC, as a full-mixed application for the treatment of long-term maintenance of alcohol abstinence and alcohol withdrawal syndrome in alcohol-dependent adult patients.
Predlagatelj, družba Debrégeas & Associés (D&A), je predložil vlogo za pridobitev dovoljenja za promet z zdravilom za zdravilo Alcover 750 mg, 1250 mg in 1750 mg po decentraliziranem postopku na pravni podlagi člena 8(3) Direktive 2001/83/ES.
In light of the above and the identified risks related to the product, the CHMP was of the opinion that the benefit-risk balance for Alcover granules in sachets, and associated names is not favourable.
Glede na zgoraj navedeno in glede na ugotovljena tveganja, povezana z zdravilom, je odbor CHMP presodil, da razmerje med tveganji in koristmi zdravila Alcover zrnca v vrečkah in povezanih imen ni ugodno.
A design focusing on either of these endpoints with only supplementary data on the other might be acceptable.
podatki o drugem pa bi bili le dopolnilni.
• The Committee reviewed the totality of the data provided by the applicant in writing and in the oral explanations and related to the efficacy and safety of Alcover and associated names, 750 mg, 1250 mg, 1750 mg granules in sachets in the proposed indications for the maintenance of alcohol abstinence and the treatment of alcohol withdrawal syndrome; The Committee also considered the grounds submitted by the applicant within the re-examination procedure, and the views from an ad-hoc expert group.
• odbor je pregledal vse podatke, ki jih je predložil predlagatelj v pisni in ustni obrazložitvi, povezane z učinkovitostjo in varnostjo zdravila Alcover in povezanih imen, 750 mg, 1 250 mg, 1 750 mg zrnca v vrečkah, pri predlaganih indikacijah za vzdrževanje abstinence od alkohola in zdravljenje alkoholnega odtegnitvenega sindroma.
The applicant has proposed two prospective Post-Authorisation Efficacy Studies (PAES) to confirm the efficacy of sodium oxybate in the treatment of AWS in alcohol dependent patients and its longterm benefits in the maintenance of alcohol abstinence.
Predlagatelj je za potrditev učinkovitosti natrijevega oksibata pri zdravljenju alkoholnega odtegnitvenega sindroma pri bolnikih, odvisnih od alkohola, in njegovih dolgoročnih koristih pri vzdrževanju abstinence od alkohola predlagal dve prospektivni študiji učinkovitosti po odobritvi.
In conclusion, further to the initial assessment and the re-examination procedure, the CHMP maintains its initial opinion that the benefit-risk balance of this medicinal product is not favourable in both of the proposed indications.
Zaključki odbora CHMP Po začetnem ocenjevanju in postopku ponovnega pregleda odbor CHMP ohranja svoje prvotno mnenje, da razmerje med koristmi in tveganjem za to zdravilo pri nobeni od predlaganih indikacij ni ugodno.
There were several drawbacks in the design of these studies, including small sample size, choice of patient population and absence of clearly defined, statistically significant outcomes, and although some of the studies showed trends to positive results, there were also some that were clearly failed studies.
Pri zasnovi teh študij je bilo več pomanjkljivosti, vključno z majhno velikostjo vzorca, izbiro populacije bolnikov in odsotnostjo jasno opredeljenih, statistično značilnih izidov.
The meta-analysis that included GATE 2, SMO032/10/03, Gallimberti 1992 and Di Bello 1995 have several methodological flaws and quality concerns such as GATE 2 did not evaluate the population of interest; SMO032/10/03 trial included only a subset of High/Very High DRL patients and failed to meet its primary endpoint; Gallimberti trial did not report primary endpoint or follow-up time; Di Bello had a very small sample size (total n=17) and failed to specify the primary endpoint.
V študiji GATE 2 na primer niso ovrednotili želene populacije, preskušanje SMO032/10/03 je vključevalo le podskupino bolnikov z visoko/zelo visoko stopnjo tveganja za zlorabo alkohola in ni doseglo primarnega opazovanega dogodka, v Gallimbertijevem preskušanju niso poročali o primarnem opazovanem dogodku in času spremljanja, v Di Bellovi študiji pa je bila velikost vzorca zelo majhna (skupni n = 17) in primarni opazovani dogodek ni bil opredeljen.
The Gallimberti 1989 trial was the only placebo-controlled RCT to evaluate sodium oxybate in the treatment of AWS, which had a small sample (n=11 oxybate vs n= 12 placebo), that evaluated the first 7 hours of treatment, showing favourable results for the active arm.
Vzorec je bil majhen (n = 11 za oksibat v primerjavi z n = 12 za placebo), vrednotili so prvih sedem ur zdravljenja, rezultati v aktivno zdravljeni skupini pa so bili ugodni.
Referring to the results in abstinence rate from study SMO032/10/03, Gallimberti 1992, GATE 2 and Di Bello 1995, apart from different study designs, post-hoc chosen patient groups, different study duration, it cannot be concluded whether continuous abstinence was measured, and whether responders (a posteriori defined as completers with a DRL<high or who did not relapse to heavy drinking) are actually the group of people aimed at with full abstinence in mind.
razen različnih zasnov študij, naknadno izbranih skupin bolnikov in različnega trajanja študij, ni mogoče zaključiti, ali so izmerili neprekinjeno abstinenco in ali so odzivni bolniki (naknadno opredeljeni kot bolniki z manj kot visoko stopnjo tveganja za zlorabo alkohola ali tisti, ki se niso vrnili k hudi zlorabi alkohola) dejansko tista skupina ljudi, ki naj bi bila ciljna skupina za popolno abstinenco.
Talk to your doctor.
Posvetujte se z zdravnikom.
• Postpone start of consolidation course.
• Odložite začetek konsolidacijskega cikla.
• Infections (including serious infections)
• okužbe (vključno z resnimi okužbami)
Frequency unknown (frequency cannot be estimated from the available data):
Neznana pogostnost (pogostnosti iz razpoložljivih podatkov ni mogoče oceniti):
Second induction (if required)
Druga indukcija (če je potrebna)
g. Based on Fisher's exact test.
Na podlagi Fisherjevega natančnega testa.
As with all therapeutic proteins, there is potential for immunogenicity.
Kot pri vseh terapevtskih beljakovinah obstaja možnost imunogenosti.
Grade 3/4
Stopnja 3/4
Patients should be monitored for hepatotoxicity as recommended in section 4.4.
Bolnike je treba spremljati glede hepatotoksičnosti, kot je priporočeno v poglavju 4.4.
The median study size was 15 patients, with a range of 5-105 patients.
Mediana velikost študije je bila 15 bolnikov z razponom 5-105 bolnikov.
Age, race, and gender
Starost, rasa in spol
Some infections may be serious and may be life-threatening.
Nekatere okužbe so lahko resne in življenjsko ogrožajoče.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 19 April 2018
Datum prve odobritve: 19. april 2018
Not reported
niso poročali
The detection of ADAs is highly dependent on the sensitivity and specificity of the assay.
Zaznavanje ADA je zelo odvisno od občutljivosti in specifičnosti preskusa.
Day 1 (as per standard medical practice)
do 7. dne na 1. dan (v skladu z običajno medicinsko prakso)
d: Within 30 days from the last dose of MYLOTARG.
d: V 30 dneh po zadnjem odmerku zdravila MYLOTARG.
MYLOTARG will be stored by the health professionals at the hospital or clinic.
Zdravilo MYLOTARG bodo shranili zdravstveni delavci v bolnišnici ali kliniki.
Therefore, caution should be exercised when driving or operating machines.
Zato je med vožnjo ali upravljanjem strojev potrebna previdnost.
Other side effects may include:
Drugi neželeni učinki so lahko:
Pharmacokinetics in specific groups of subjects or patients
Farmakokinetika pri posebnih skupinah preskušancev ali bolnikov
Tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines.
Obvestite zdravnika ali medicinsko sestro, če jemljete, ste pred kratkim jemali ali pa boste morda začeli jemati katerokoli drugo zdravilo.
Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS.
Če spremljate samo celokupni bilirubin, morda ne boste odkrili vseh bolnikov, pri katerih obstaja tveganje za VOD/SOS.