natgillin/translations-raw huggingface dataset:
Article 6(12) of Regulation (EC) 1084/2003 as amended, referral on a variation to a marketing authorisation
1 Člen 6(12) Uredbe (ES) 1084/2003, kakor je bila spremenjena, napotitev zaradi spremembe dovoljenja za promet z zdravilom.
Based on evaluation of the currently available data and the scientific discussion within the Committee, the CHMP concluded that the variation to the marketing authorisation for Extraneal can be approved in all concerned Member States.
Na podlagi ocene trenutno dostopnih podatkov in znanstvene razprave v okviru Odborua je CHMP zaključil, da se lahko sprememba dovoljenja za promet z zdravilom Extraneal odobri v vseh zadevnih državah članicah.
22 October 2009
22. oktobra 2009
Extraneal is used in particular in patients who cannot be treated with solutions containing glucose.
Zdravilo Extraneal se uporablja zlasti pri bolnikih, ki jih ne moremo zdraviti z raztopinami, ki vsebujejo glukozo.
Icodextrin is a type of sugar that is used to keep blood glucose at the correct level.
Ikodekstrin je vrsta sladkorja, ki se uporablja za uravnavanje pravilne ravni glukoze v krvi.
Questions and answers on the referral for Extraneal icodextrin 7.5% solution for peritoneal dialysis
Vprašanja in odgovori v zvezi z napotitvenim postopkom za zdravilo Extraneal ikodekstrin 7,5 % raztopina za peritonealno dializo
The European Medicines Agency has completed an arbitration procedure for Extraneal 7.5% solution for peritoneal dialysis.
Evropska agencija za zdravila je zaključila arbitražni postopek za zdravilo Extraneal 7,5 % raztopina za peritonealno dializo.
Extraneal is a solution that contains icodextrin as the active substance, as well as sodium lactate, sodium chloride, calcium chloride and magnesium chloride.
Zdravilo Extraneal je raztopina z zdravilno učinkovino ikodekstrinom ter natrijevim laktatom, natrijevim kloridom, kalcijevim kloridom in magnezijevim kloridom.
Peptidoglycans had been linked to cases of inflammation of the peritoneum (the lining of the abdomen) in some patients receiving Extraneal.
Peptidoglikani so povezani s primeri vnetja peritoneja (trebušne mrene) pri nekaterih bolnikih, ki so prejeli zdravilo Extraneal.
Extraneal is a solution that is used in peritoneal dialysis.
Zdravilo Extraneal je raztopina, ki se uporablja pri peritonealni dializi.
This is a blood clearance technique used in patients with long-term kidney failure, when a solution is pumped into the abdomen and an internal body membrane filters the blood.
To je tehnika čiščenja krvi, ki se uporablja pri bolnikih z dolgoročnim odpovedovanjem ledvic, pri kateri se tekočina načrpa v trebuh in membrana v telesu prefiltrira kri.
The grounds for the referral were that more sensitive tests than those proposed by the company could be used to detect peptidoglycans in the medicine, and that one of the currently approved manufacturers of the active substance should modify the manufacturing process of icodextrin to ensure that peptidoglycans are removed.
Razlogi za napotitev so bili, da se lahko za odkrivanje peptidoglikana v zdravilu uporabijo občutljivejši testi od tistih, ki jih je predlagala družba, in da mora eden od odobrenih izdelovalcev zdravilne učinkovine spremeniti postopek izdelave ikodekstrina, da bi zagotovili odstranitev peptidoglikanov.
The Agency's Committee for Medicinal Products for Human Use (CHMP) has concluded that the change to the marketing authorisation for Extraneal to include a peptidoglycan test can be granted, and that the use of the active substance icodextrin sourced from one of the currently approved manufacturers should cease.
Odbor za zdravila za uporabo v humani medicini (CHMP) pri Agenciji je zaključil, da se lahko odobri sprememba dovoljenja za promet z zdravilom Extraneal z vključitvijo testa za peptidoglikan in prekine uporaba zdravilne učinkovine (ikodekstrina) enega od trenutno odobrenih izdelovalcev.
The company applied for a change (variation) to the marketing authorisation to include a test to measure the level of an impurity called peptidoglycan during the medicine's production process.
Imetnik dovoljenja za promet z zdravilom je vložil vlogo za spremembo dovoljenja za promet z vključitvijo testa, s katerim se meri raven nečistoče, imenovane peptidoglikan, v postopku izdelave zdravila.
Company responses provided on: 31 August 2009 Opinion date:
Datum izdaje mnenja:
MA (EU) number (Invented) name Strength Pharmaceutical Form Route of Administration Immediate Packaging Pack size EU/1/15/1037/001 Pemetrexed Sandoz 100 mg Powder for concentrate for solution for infusion
Številka (EU) dovoljenja za promet
However, the consequences of these findings are unclear.
Vendar pa pomen teh ugotovitev ni jasen.
Steatosis
Steatoza
Additional data will be collected in on-going and proposed studies.
Predlagatelj bo pridobil dodatne podatke iz trenutnih in predlaganih študij;
The quality of this product is considered to be acceptable.
Kakovost zdravila velja za sprejemljivo.
Summary of the applicant's grounds for re-examination:
Povzetek razlogov predlagatelja za zahtevek za ponovni pregled:
Overall summary of the scientific evaluation of Kynamro
Splošni povzetek znanstvenega vrednotenja zdravila Kynamro
Liver enzyme increase
Povišanje jetrnih encimov
The CHMP concluded that such data has not been presented by the applicant at this time point.
Odbor CHMP je zaključil, da do tega trenutka predlagatelj ni predložil tovrstnih podatkov.
This view was also supported by the experts who considered the extrapolation as only hypothetical.
S to ugotovitvijo so se strinjali tudi strokovnjaki, ki so menili, da je ekstrapolacija zgolj hipotetična.
The CHMP is of the opinion that the safety and efficacy of the above mentioned medicinal product is not properly or sufficiently demonstrated.
je odbor CHMP menil, da varnost in učinkovitost zgoraj navedenega zdravila nista bili ustrezno oziroma zadovoljivo dokazani.
This is based on the consideration that in a high risk population a larger proportion of events could be expected also in the placebo group.
Ta pomislek temelji na dejstvu, da bi pri populaciji z visokim tveganjem pričakovali večje število tovrstnih dogodkov tudi v skupini s placebom.
The CHMP considered the following:
Odbor CHMP je obravnaval naslednje:
With respect to the Kynamro Patient Support programme, the CHMP considered that its usefulness, suitability and applicability in different EU countries are difficult to foresee.
Glede podpornega programa za bolnike, ki uporabljajo zdravilo Kynamro, je odbor CHMP menil, da je njegovo koristnost, primernost in uporabnost v različnih državah EU težko predvideti.
Such conditional Marketing Authorisation could therefore not be recommended.
Pogojne odobritve dovoljenja za promet z zdravilom zato ni bilo mogoče priporočiti.
Therefore, the CHMP concluded on 13 December 2012 that the benefit/risk ratio of mipomersen is negative.
Zato je odbor CHMP 13. decembra 2012 zaključil, da je razmerje med tveganji in koristmi za mipomersen negativno.
This is regarded by the CHMP as a major deficiency, and was also criticized by the expert advisory group.
Po mnenju odbora CHMP gre za veliko pomanjkljivost, kritiko pa je izrazila tudi svetovalna strokovna skupina.
The numerically higher number of neoplasms and cancer raises an additional safety concern.
Pojav večjega števila novotvorb in primerov raka predstavlja dodatno skrb glede varnosti.
Although most of the relevant risks are identified within the risk management plan, the risk management system is considered inadequate and the proposed risk minimization measures are deficient in a number of important areas.
Čeprav je v načrtu za obvladovanje tveganja obravnavana večina pomembnih tveganj, je sistem za obvladovanje tveganja nezadosten, predlagani ukrepi za zmanjševanje tveganja pa so pomanjkljivi na številnih pomembnih področjih.
Potential effect of LDL reduction
Možni učinek znižanja holesterola LDL
In all phase 3 studies, patients were excluded for “significant hepatic disease”.
V vseh študijah 3. faze so bolnike izločali zaradi „hujših bolezni jeter‟.
Nevertheless, the relevance of the direct comparison to mipomersen within the two trials must not be disregarded.
Kljub temu ni mogoče spregledati pomembnosti neposredne primerjave z mipomersenom v dveh preskušanjih.
Exclusion criteria were also in place to ensure adequate hepatic function based on laboratory values (ALT, ALT > 1.5 x ULN).
Določeni so bili tudi izločilni kriteriji, ki naj bi zagotovili ustrezno delovanje jeter na podlagi laboratorijskih vrednosti (ALT, ALT > 1,5 x ULN).
Physicochemical and biological aspects relevant to the uniform clinical performance of the product have been investigated and are controlled in a satisfactory way.
Fizikalno-kemijski in biološki vidiki, pomembni za nespremenljivo klinično učinkovitost zdravila, so zadovoljivo raziskani in nadzorovani.
Therefore, pursuant to Article 12 of Regulation (EC) No 726/2004, the CHMP has recommended the refusal of the granting of the marketing authorisation for Kynamro.
Zato je v skladu s členom 12 Uredbe (ES) št. 726/2004 priporočil zavrnitev dovoljenja za promet z zdravilom Kynamro.
The experts felt, however, that potentially a restricted prescription programme in dedicated centres capable of providing support on individual patient basis might be helpful.
Na drugi strani so strokovnjaki menili, da bi bil morda lahko koristen program omejenega predpisovanja v strokovnih centrih, ki so zmožni zagotoviti podporo bolnikom glede na posameznikove potrebe.
The applicant has proposed a Patient Support Programme (a broad adherence support programme) to help address this concern.
Predlagatelj je kot rešitev predlagal podporni program za bolnike (obsežen program za pomoč pri vztrajanju pri zdravljenju).
Following the CHMP scientific conclusions adopted on 13 December 2012 that Kynamro was not approvable for the treatment of
Na podlagi znanstvenih zaključkov, ki jih je odbor CHMP sprejel 13. decembra 2012, se lahko sklepa, da zdravila Kynamro ni mogoče odobriti za zdravljenje
on 31 January 2013, the applicant submitted its detailed grounds for the request for re-examination of the CHMP opinion recommending the refusal of the granting of the marketing authorisation.
Na podlagi zgoraj navedenih razlogov je predlagatelj 31. januarja 2013 predstavil podrobne razloge za zahtevek za ponovni pregled mnenja, v katerem je odboru CHMP priporočil zavrnitev dovoljenja za promet z zdravilom.
Mipomersen may be immunogenic and antibodies were detected in 65% of subjects taking the product.
Mipomersen je lahko imunogen; protitelesa so opazili pri 65 % bolnikov, ki so uporabljali zdravilo.
The CHMP assessed all the detailed grounds for re-examination and argumentations presented by the applicant and considered the views of the PRAC (PRAC meeting 4-7 February 2013) and the advisory expert group held on 12 March 2013.
Preučil je podrobne razloge za ponovni pregled in utemeljitve predlagatelja ter upošteval mnenje Odbora za ocenjevanje tveganja na področju farmakovigilance (s sestanka odbora, ki je potekal od 4.-7. februarja 2013) in svetovalne strokovne skupine, ki se je sestala 12. marca 2013.
From the available data, it is also not clear whether patients´ ALT or AST levels reached a maximal effect (plateau).
Iz razpoložljivih podatkov tudi ni jasno, ali so ravni ALT in AST pri bolnikih dosegle najvišjo vrednost (konstantno raven).
The adopted Guideline on Clinical Investigation of Medicinal Products in the Treatment of Lipid Disorders (CPMP/EWP/3020/03/2004), states on the matter that the safety database should be large enough to reasonably rule out any suspicion of a detrimental effect of the new drug on mortality and that this requirement acquires special relevance in case of drugs belonging to a new therapeutic class.
V veljavnih smernicah za klinična preskušanja zdravil za zdravljenje motenj lipidov (CPMP/EWP/3020/03/2004) je v zvezi s tem vprašanjem navedeno, da mora biti zbirka podatkov o varnosti dovolj velika, da se lahko utemeljeno izključi vsakršen sum o negativnem vplivu novega zdravila na stopnjo umrljivosti, in da je izpolnjevanje te zahteve še zlasti pomembno pri zdravilih, ki spadajo v novo terapevtsko skupino.
Furthermore, the guideline also states that “a new lipid-modifying agent is only acceptable for authorisation if there is no suggestion of a detrimental effect on morbidity and mortality.
V smernicah je navedeno tudi, da „se lahko zdravilo, ki vpliva na lipide, odobri samo, če ni nobenih znakov negativnega vpliva na obolevnost in stopnjo umrljivosti.
The CHMP concluded that such type of Marketing Authorisation could not be recommended in the present case as it does not fulfil the requirements of Article 14(8) of Regulation (EC) No 726/2004, in particular, as the applicant would be able to provide comprehensive data on the efficacy and safety under normal condition of use of Kynamro.
Zaključil je, da tovrstne odobritve dovoljenja za promet z zdravilom v tem primeru ni mogoče priporočiti, ker niso izpolnjene zahteve iz člena 14(8) Uredbe (ES) št. 726/2004, predvsem zato, ker predlagatelj ne more predložiti izčrpnih podatkov o učinkovitosti in varnosti zdravila Kynamro pri običajni uporabi.
For 14 (5.4%) of these patients, dosing with mipomersen was stopped (stopping rules were ≥8 x ULN for AST/ALT on one occasion, ≥5 x ULN for AST/ALT over 7 days, or ≥3 x ULN for AST/ALT and elevated bilirubin).
Pri 14 (5,4 %) od teh bolnikov so zdravljenje z mipomersenom prekinili (pravila za prekinitev so bila ≥ 8 x ULN za AST/ALT pri enem merjenju, ≥ 5 x ULN za AST/ALT več kot 7 dni ali ≥ 3 x ULN za AST/ALT in povišan bilirubin).
Therefore, the lack of predefined adjudication of CVS events is clearly a deficiency and, if a marked difference in CVS events is observed, this may raise a concern despite a small database.
Zato je odsotnost vnaprej določenega spremljanja kardiovaskularnih dogodkov brez dvoma pomanjkljivost in če so prisotne opazne razlike glede kardiovaskularnih dogodkov, je to lahko razlog za zaskrbljenost kljub majhni podatkovni zbirki.
The CHMP also discussed whether a conditional Marketing Authorisation for the claimed restricted indication could be considered.
CHMP je preučil tudi možnost pogojne odobritve dovoljenja za promet z zdravilom za navedeno omejeno indikacijo.
The applicant claims that in the majority of patients ALT and AST levels stabilize or decrease even with continued treatment or they return to (near) baseline following discontinuation of mipomersen treatment.
Predlagatelj trdi, da se pri večini bolnikov ravni ALT in AST stabilizirajo ali znižajo celo pri neprekinjenem zdravljenju oziroma se po prekinitvi zdravljenja z mipomersenom vrnejo na (ali skoraj na) izhodiščne vrednosti.
Numerical imbalance in CVS events
Številčno neravnovesje kardiovaskularnih dogodkov
According to literature (e.g. as summarised in the AWMF guideline on the histopathology of non-alcoholic and alcoholic fatty liver disease; German Society of Pathology, 2009), the natural course of hepatic steatosis/non-alcoholic fatty liver disease (NAFLD) in individual patients is not predictable; it is indicated that steatosis may progress to steatohepatitis/NASH in about 10-20% of cases, and of these less than 5% ultimately develop cirrhosis.
Po podatkih iz literature (npr. kot je povzeto v smernicah AWMF za histopatologijo nealkoholne in alkoholne zamaščenosti jeter; Nemško združenje za patologijo, 2009) naravnega poteka jetrne steatoze/nealkoholne zamaščenosti jeter (NAFLD) pri posameznih bolnikih ni mogoče predvideti; podatki kažejo, da bi lahko steatoza napredovala v steatohepatitis/nealkoholni steatohepatitis pri približno 10-20 % bolnikov, od katerih naj bi jih 5 % na koncu zbolelo za cirozo.
At the time of opinion, there are no outstanding issues on the quality of the active substance or the medicinal product.
Ob sprejetju mnenja ni bilo odprtih vprašanj glede kakovosti zdravilne učinkovine ali samega zdravila.
In the Open-Label Extention study, patients showed ALT increases (18%), AST increases (16%), hepatic enzyme increases (3%), abnormal liver function tests (2%), and transaminases increases (0.7%).
V odprti podaljšani študiji so pri bolnikih opazili povišanje ravni ALT (18 %), povišanje ravni AST (16 %), povišanje jetrnih encimov (3 %), nenormalne teste delovanja jeter (2 %) in porast transaminaz (0,7 %).
Mipomersen treatment can cause liver enzyme elevations and hepatic steatosis and this may induce steatohepatitis.
Zdravljenje z mipomersenom lahko povzroči povišanje jetrnih encimov in jetrno steatozo ter posledično steatohepatitis.
Furthermore, the CHMP considered the input from the expert group meeting and noted that there was an agreement amongst the experts that the tolerability of mipomersen treatment was poor.
CHMP je preučil tudi mnenja s sestanka strokovne skupine in upošteval, da so se strokovnjaki strinjali, da bolniki slabo prenašajo zdravljenje z mipomersenom.
Otherwise, additional studies to clarify the drug effect on these parameters are mandatory.” The issue of prospective planning for CVS safety outcome is even more specifically addressed in the recent Draft Guideline on Clinical Investigation of Medicinal Products in the Treatment of Lipid Disorders (EMA/CHMP/718840/2012).
Vprašanje vnaprejšnjega načrtovanja spremljanja kardiovaskularne varnosti je še podrobneje obravnavano v osnutku smernic za klinične preiskave zdravil za zdravljenje motenj lipidov (EMA/CHMP/718840/2012).
Mipomersen is also associated with a high incidence of flu-like symptoms, effect on inflammatory markers and decrease on complement component C3.
Mipomersen je povezan tudi z visoko pojavnostjo simptomov, podobnih gripi, vplivom na označevalce vnetja in zmanjšanjem koncentracije komponente komplementa C3.
Though considerable uncertainty remains, overall the analyses suggest an unfavourable effect of mipomersen treatment on several CVS risk factors.
Čeprav ostaja veliko nejasnosti, na splošno analize kažejo na možnost neugodnih učinkov mipomersena na več kardiovaskularnih dejavnikov tveganja.
To conclude on ground 2, the discussion provided by the applicant for the reexamination of Kynamro does not provide a new insight to the former CHMP assessment on mipomersen treatment and CVS risk.
Zaključek glede razloga 2 je, da razprava predlagatelja za ponovni pregled mnenja o zdravilu Kynamro ni prinesla novih spoznanj, ki bi vplivala na predhodno oceno mipomersena in kardiovaskularnega tveganja, ki jo je podal odbor CHMP.
Despite the fact that CVS events analyses were performed post hoc, the imbalance observed in the pivotal trials is worrisome.
Kljub dejstvu, da so bile opravljene naknadne analize kardiovaskularnih dogodkov, je neravnovesje, ki so ga opazili v ključnih študijah, zaskrbljujoče.
The following issues were addressed by the applicant;
Predlagatelj je obravnaval naslednja vprašanja:
The studies proposed are poorly defined and it is questioned that these can solve the concerns of particular interest like CVS events/hepatic toxicity.
Predlagane študije so slabo opredeljene, zato je vprašanje, ali bi lahko pomagale odpraviti pomisleke, povezane predvsem s kardiovaskularnimi dogodki/toksičnostjo za jetra.
Furthermore, there is a potential risk of irreversibility of liver disease even if mipomersen-treatment is stopped.
Prav tako obstaja tveganje za trajno okvaro jeter, četudi se zdravljenje z mipomersenom prekine.
Following discussions at the Scientific Advisory Group (SAG) meeting in September 2012, the applicant restricted the indication to HoFH patients only, in which the lifetime exposure to extremely high low density lipoprotein cholesterol (LDL-C) levels is responsible for CVS morbidity and early age mortality.
Po razpravi na sestanku Znanstvene svetovalne skupine (SAG) septembra 2012 je predlagatelj indikacijo omejil na bolnike s homozigotno družinsko hiperholesterolemijo, ki so zaradi vseživljenjske izpostavljenosti izjemno visokim ravnem holesterola v lipoproteinih majhne gostote (LDL) podvrženi kardiovaskularni obolevnosti in zgodnji umrljivosti.
This was not considered applicable either, even if possible within the scope of Article 2 of Commission Regulation (EC) No. 507/2006, as the requirements as defined in Article 4 of the said Regulation were not met, in particular the demonstration by the applicant of a positive risk-benefit balance of the medicinal product and the likelihood to provide comprehensive clinical data by way of specific obligations.
Zaključil je, da tudi tovrstna odobritev ni mogoča, četudi jo dopušča člen 2 Uredbe Komisije (ES) št. 507/2006, saj niso bile izpolnjene zahteve iz člena 4 iste uredbe, zlasti da bi moral predlagatelj dokazati, da je razmerje med tveganji in koristmi pozitivno, in da je verjetno, da bo predložil izčrpne klinične podatke v skladu s posebnimi pogoji.
Indeed, an annual event rate of 6% has been described for a composite endpoint of non-fatal MI and cardiac death in a comparable population (Scandinavian-Simvastatin Survival Study Group, 1995, Lancet).
Dejansko so pri primerljivi populaciji za sestavljeni opazovani dogodek (srčni infarkt brez smrtnega izida in srčna smrt) zabeležili letno stopnjo 6 % (ScandinavianSimvastatin Survival Study Group, 1995, Lancet).
There is no proven relationship between mipomersen treatment and the occurrence of neoplasm, mainly due to the low incidence rate, lack of systematic evaluation during the studies, and the short timing after start of mipomersen, but uncertainties about the clinical relevance of these findings remain.
Povezava med zdravljenjem z mipomersenom in pojavom novotvorb ni dokazana, predvsem zaradi nizke stopnje pojavnosti, pomanjkljivega sistematičnega vrednotenja med študijami in kratkega časa spremljanja po začetku zdravljenja z mipomersenom, vendar pa ostajajo odprta vprašanja o klinični pomembnosti omenjenega odkritja.
Thus, the CHMP concluded that with respect to mipomersen´s hepatotoxicity, no aspects other than the ones already assessed in the initial procedure, which could lead to different conclusions, were presented by the applicant.
Zato je CHMP zaključil, da predlagatelj v zvezi s hepatotoksičnostjo mipomersena ni predstavil nobenih utemeljitev, ki ne bi bili obravnavani že med prvim postopkom in na podlagi katerih bi bilo mogoče podati drugačne zaključke.
The applicant argues that the degree of LDL reduction observed with mipomersen treatment is expected to result in a potential reduction in coronary heart disease risk greater than 50%, which is based on meta-analyses of data from multiple studies (Baigent, 2010, the Lancet).
Predlagatelj trdi, da bi lahko stopnja znižanja holesterola LDL, opažena pri zdravljenju z mipomersenom, prispevala k več kot 50-odstotnemu zmanjšanju tveganja za koronarno bolezen srca, na kar nakazujejo metaanalize podatkov iz različnih študij (Baigent, 2010, the Lancet).
Focusing on the targeted HoFH population, the CHMP noted that the withdrawal rate for HoFH patients who had been enrolled in the pivotal 6 months DB study CS5 and consented to further participate in the OL extension study CS6 (for one or two years, including the time in CS5), was approximately 60% (23/38) within the first two years.
CHMP je upošteval, da je bila stopnja prekinitve zdravljenja pri ciljni populaciji bolnikov s homozigotno družinsko hiperholesterolemijo, ki so bili vključeni v ključno dvojno slepo 6-mesečno študijo CS5 in so privolili tudi v sodelovanje v odprti podaljšani študiji CS6 (za eno ali dve leti, vključno s časom študije CS5), približno 60 % (23/38) v prvih dveh letih.
As liver biopsy was not performed on a regular basis in the mipomersen study programme, it is not clear whether a small or a significant proportion of patients with mipomersen-induced steatosis also had inflammatory changes and fibrosis, i.e. might develop steatohepatitis, which may not be reversible after stopping the treatment.
Ker v študijah uporabe mipomersena niso redno opravljali biopsije jeter, ni jasno, ali so se pri majhnem ali velikem deležu bolnikov s steatozo, ki je posledica uporabe mipomersena, pojavile tudi vnetne spremembe in fibroza, tj. možnost za razvoj steatohepatitisa, ki ga ni mogoče odpraviti po prekinitvi zdravljenja.