natgillin/translations-raw huggingface dataset:
In 50% of the cases, a neuropathy was also reported.
V 50 % primerov so poročali tudi o nevropatiji.
Data from clinical trials
Podatki iz kliničnih preskušanj
In addition, France had concerns with regards to the benefit of almitrine in its approved indications.
Poleg tega je imela Francija pomisleke glede koristi almitrina pri odobrenih indikacijah.
• Respiratory events, mainly due to awareness of respiratory movements
• dogodki na dihalih, zlasti zaradi zavedanja dihalnih gibov;
The mean time to onset for the cases reported was 5 months but time to onset was variable ranging from 15 days to 2,5 years.
Povprečen čas do pojava neželenih učinkov pri zabeleženih primerih je bil 5 mesecev, vendar pa je bil čas spremenljiv in je znašal od 15 dni do 2,5 leta.
Weight loss observed in patients with respiratory insufficiency is progressive.
Zmanjšanje telesne mase, ki ga opažajo pri bolnikih z dihalno insuficienco, je progresivno.
Scientific conclusions and grounds for the revocation of the marketing authorisations
Znanstveni zaključki in podlaga za odvzem dovoljenj za promet z zdravili
Grounds for PRAC recommendation
Podlaga za priporočilo PRAC
Almitrine containing medicinal products for oral use are currently authorised in 3 European Member States (France, Poland and Portugal) and only marketed in France and Poland (see Annex I for the list of almitrine containing medicinal products for oral use authorised in the EU).
Zdravila za peroralno uporabo, ki vsebujejo almitrin, so trenutno odobrena v 3 evropskih državah članicah (v Franciji, na Poljskem in Portugalskem), tržijo pa se samo v Franciji in na Poljskem (za seznam zdravil za peroralno uporabo, ki vsebujejo almitrin in so odobrena za uporabo v EU, glejte Prilogo I).
In November 2012 the French National Competent Authority considered that the above-mentioned major safety concerns were not fully controlled in clinical practice despite the risk minimisation measures in place.
Novembra 2012 je francoski pristojni nacionalni organ ugotovil, da zgoraj omenjeni veliki zadržki v zvezi z varnostjo kljub izvajanju ukrepov za zmanjšanje tveganja v klinični praksi niso dovolj nadzorovani.
No effect was nor observed on pulmonary functional status.
Prav tako niso opazili učinka na funkcionalno stanje pljuč.
In the view of the negative benefit risk balance, patients will need to be switched to alternative therapies.
Zaradi negativnega razmerja med tveganji in koristmi bodo morali bolniki poseči po alternativnih oblikah zdravljenja.
Globally, an important proportion of cases had an outcome reported as not recovered or recovered with sequelae (489 cases out of the 2304 reported, i.e. 21.2%).
Skupno so pri velikem odstotku primerov poročali o tem, da se bolezen ni popravila ali da je pustila posledice (489 od 2 304 primerov, tj. 21,2 %).
Regarding weight loss, 795 cases were reported since launch, some of them severe.
V zvezi z zmanjšanjem telesne mase so od začetka trženja poročali o 795 primerih, med katerimi so bili tudi resni primeri.
Besides, the PRAC also noted that the knowledge in physiopatholigical mechanism and management of COPD (including life expectancy in COPD) has been considerably improved.
Poleg tega je PRAC upošteval tudi, da sta se znanje o fiziopatološkem mehanizmu in zdravljenje KOPB (vključno s pričakovano življenjsko dobo pri KOPB) znatno izboljšala.
In view of the 11 above mentioned published clinical studies, it is acknowledged that efficacy results among clinical studies are contradictory and extrapolations not feasible.
V zvezi z zgoraj omenjenimi 11 objavljenimi kliničnimi študijami je bilo ugotovljeno, da so si rezultati o učinkovitosti iz kliničnih študij nasprotujoči, zato ekstrapolacije niso mogoče.
Almitrine for oral use was studied in several clinical studies.
Almitrin za peroralno uporabo so raziskali v več kliničnih študijah.
The MAH has never performed trials or investigations to document/establish the mechanism of action of these adverse effects.
Imetnik dovoljenja za promet z zdravilom ni izvedel nobenih preskušanj ali raziskav, s katerimi bi dokumentiral/ugotovil mehanizem delovanja teh neželenih učinkov.
Spontaneous reports of peripheral neuropathies persist even after the introduction of sequential administration scheme.
Spontana poročila o periferni nevropatiji beležijo tudi po uvedbi sekvenčne sheme odmerjanja.
During the period September 2003 to December 2012, 20 cases of peripheral neuropathies were reported, suggesting that the risk minimisation measures are not able to prevent the occurrence of these reactions.
V obdobju med septembrom 2003 in decembrom 2012 so poročali o 20 primerih periferne nevropatije, kar kaže na to, da ukrepi za zmanjšanje tveganja niso preprečili pojavljanja teh neželenih učinkov.
Consideration that long-term oxygen therapy can be discontinued, delayed or even avoided with almitrine is not based on scientific or clinical evidence.
Trditev, da je z almitrinom mogoče prekiniti, odložiti ali celo preprečiti trajno zdravljenje s kisikom, ni utemeljena z znanstvenimi ali kliničnimi dokazi.
The decrease in reporting of peripheral neuropathy mentioned by the MAH, is probably mainly related to the decrease in sales over the last 10 years.
Zmanjšanje števila poročil o periferni nevropatiji, ki ga je izpostavil imetnik dovoljenja za promet, je verjetno povezano predvsem z upadom prodaje v zadnjih 10 letih.
The PRAC considered that many of the publications reported that a clinical benefit of oral almitrine could not be seen in terms of exacerbations or hospitalisation, exercise capacity, clinical outcome, survival, or quality of life.
PRAC je upošteval, da številne publikacije navajajo, da almitrin za peroralno uporabo ni izkazal kliničnih koristi v smislu eksacerbacij ali hospitalizacije, telesne zmogljivosti, kliničnega izida, preživetja ali kakovosti življenja.
The NCAs should undertake timely actions allowing an appropriate switching of patients to other therapeutic alternatives.
Pristojne nacionalne agencije morajo nemudoma ukrepati in omogočiti bolnikom, da preidejo na druge oblike zdravljenja.
This adverse effect was also clearly recognised in the trials comparing almitrine at high doses to placebo.
Ta neželeni učinek so jasno prepoznali tudi v preskušanjih, v katerih so almitrin pri visokih odmerkih primerjali s placebom.
In France, almitrine containing medicinal products for oral use have been under close monitoring due to serious adverse reaction .
V Franciji so zdravila za peroralno uporabo, ki vsebujejo almitrin, podrobno spremljali zaradi resnih neželenih učinkov.
Finally the PRAC noted that the current international consensus for the management of COPD and chronic hypoxemia (Global Initiative for Obstructive Lung Disease (GOLD) and other practical recommendation) does no longer refer to the use of almitrine.
Prav tako je PRAC upošteval, da trenutne mednarodne smernice za zdravljenje KOPB in kronične hipoksemije (Globalna iniciativa za obstruktivno pljučno bolezen (Global Initiative for Obstructive Lung Disease - GOLD) in druga praktična priporočila) za uporabo almitrina ne veljajo več.
Risk minimisation measures (reduction of the dose and implementation of a sequential treatment scheme ) were implemented since the initial marketing authorisation.
Ukrepi za zmanjšanje tveganja (zmanjšanje odmerka in uvedba sekvenčne sheme zdravljenja) se izvajajo od odobritve prvega dovoljenja za promet z zdravilom.
The doses of 100-200 mg of almitrine continuously were associated with a higher incidence of adverse effects and withdrawals compared to placebo.
Neprekinjeno dajanje odmerkov od 100-200 mg almitrina je bilo povezano z večjo pojavnostjo neželenih učinkov in prekinitev zdravljenja v primerjavi s placebom.
In published clinical studies with continuous administration1234567, peripheral neuropathies and weight loss were encountered when the study duration was longer than 3 months, indicating that the duration of continuous exposure have played a role in their development.
V objavljenih kliničnih študijah z neprekinjenim zdravljenjem 1234567 so periferno nevropatijo in zmanjšanje telesne mase opazili, kadar je zdravljenje trajalo več kot 3 mesece, kar kaže na to, da je imelo trajanje neprekinjene izpostavljenosti pomembno vlogo pri njunem razvoju.
Therefore, in accordance with Articles 31 and 32 of Directive 2001/83/EC, the PRAC recommends the revocation of the marketing authorisations of the marketing authorisations for all medicinal products referred to in Annex I.
Zato je PRAC v skladu s členoma 31 in 32 Direktive 2001/83/ES priporočil odvzem dovoljenj za promet z vsemi zdravili, navedenimi v Prilogi I.
PRAC noted that in the clinical trials with results in favour of almitrine, effect of almitrine could have been overestimated as a high rate of patients withdrew predominantly in the almitrine group as compared to placebo (Voisin and al, 1987 and in most of all the clinical trials).
PRAC je ugotovil, da bi lahko bil učinek almitrina v kliničnih preskušanjih z rezultati v korist almitrina precenjen, saj je v skupini z almitrinom velik delež bolnikov predčasno prekinil zdravljenje v primerjavi s skupino s placebom (Voisin et al., 1987 ter v večini kliničnih preskušanj).
The last trials, conducted with sequential treatment and following a double blind placebo controlled design, account for 366 patients.
V zadnjih preskušanjih, izvedenih s sekvenčnim zdravljenjem, ki so bila dvojno slepa in nadzorovana s placebom, je sodelovalo 366 bolnikov.
An important proportion of cases seems to have been reported with an outcome as not recovered during the period from September 2003 to December 2012 (5 cases of the 7 reported).
Med septembrom 2003 in decembrom 2012 so zabeležili znaten delež primerov, ko si bolniki niso opomogli (5 primerov od 7, o katerih so poročali).
A total of 11 published clinical studies which became available after the initial Marketing Authorisation were reviewed.
Skupno so pregledali 11 kliničnih študij, ki so jih objavili po odobritvi prvega dovoljenja za promet z zdravilom.
Overall summary of the scientific evaluation of Almitrine containing medicinal products for oral use by PRAC
Splošni povzetek znanstvenega vrednotenja zdravil za peroralno uporabo, ki vsebujejo almitrin
One of the proposed further risk minimisation measures by the MAH was a restricted indication in patients with PaO2 between 55 mmHg and 65 mmHg or as adjuvant treatment to Long Term Oxygen Therapy (LTOT).
Eden od ukrepov za zmanjšanje tveganja, ki jih predlagal imetnik dovoljenja za promet z zdravilom, je bila omejena indikacija pri bolnikih s PaO2 med 55 mmHg in 65 mmHg ali indikacija adjuvantnega zdravljenja k trajnemu zdravljenju s kisikom (TZK).
• Digestive events (nausea, burning sensation and sensation of epigastric heaviness, dyspepsia),
• prebavni dogodki (navzeja, pekoč občutek in občutek teže v epigastrični regiji, dispepsija),
The PRAC is of the opinion that almitrine cannot be considered as an alternative to LTOT for which reduction in mortality has been achieved.
PRAC meni, da almitrin ne more biti alternativa trajnemu zdravljenju s kisikom, s katerim so dosegli zmanjšanje umrljivosti.
This included data from the Member States and published literature data which became available since the original marketing authorisations and the MAH's response.
Med njimi so bili podatki, ki so jih predložile države članice, in podatki iz literature, ki so bili objavljeni po odobritvi prvih dovoljenj za promet, ter odgovori imetnika dovoljenja za promet;
The uncertainties relating to the mechanisms of action implying the vasoconstriction of pulmonary vasculature (which is inverse to the beneficial effect of LTOT on pulmonary arterial pressure) was noted by the PRAC.
PRAC je upošteval negotovosti v zvezi z mehanizmom delovanja, ki bi morda lahko povzročil vazokonstrikcijo pljučnega žilja (kar je ravno nasprotno koristnemu učinku TZK na pljučni arterijski tlak).
The CMDh, having considered the PRAC recommendation dated 16 May 2013 with regards to the Almitrine containing medicinal products for oral use, agrees with the recommendation therein as stated below:
CMDh se je po proučitvi priporočila, ki ga je za zdravila za peroralno uporabo, ki vsebujejo almitrin, dne 16. maja 2013 izdal PRAC, strinjala s priporočilom, ki je navedeno v nadaljevanju:
Moreover, no data is available to support any benefit of almitrine in the restrictive indication proposed by the MAH (patient with PaO2: 55 mmHg< PaO2< 65 mmHg).
Poleg tega ni na voljo nobenih podatkov, ki bi dokazovali koristi almitrina pri omejeni indikaciji, ki jo je predlagal imetnik dovoljenja za promet z zdravilom (bolniki s PaO2: 55 mmHg < PaO2 < 65 mmHg).
Concerns have also been raised with regards to the potential risks of hepatobilary disorders, skin disorders and cytopenia with the use of oral almitrine.
Zadržki so se pojavili tudi v zvezi z možnimi tveganji za bolezni jeter, žolčnika in žolčevodov, bolezni kože in citopenijo, povezanimi z almitrinom za peroralno uporabo.
Taken together, these clinical trials enrolled 2036 patients (1380 under almitrine, 656 under placebo).
Skupno je bilo v teh kliničnih preskušanjih zdravljenih 2 036 bolnikov (1 380 z almitrinom, 656 pa s placebom).
The PRAC noted that most cases of peripheral neuropathies reported from September 2003 to December 2012 were not recovered or recovered with sequelae.
PRAC je upošteval, da se pri večini primerov, o katerih so poročali med septembrom 2003 in decembrom 2012, periferna nevropatija ni popravila ali pa je pustila posledice.
Among the clinical studies in Chronic Obstructive Pulmonary Disease (COPD) patients, only those with more than 30 patients treated with therapeutic doses of almitrine for at least 3-month were selected for an efficacy and safety overview.
Od vseh kliničnih preskušanj z bolniki s kronično obstruktivno pljučno boleznijo (KOPB) so za pregled učinkovitosti in varnosti izbrali samo tiste, v katerih je sodelovalo več kot 30 bolnikov, ki so bili najmanj 3 mesece zdravljeni s terapevtskimi odmerki almitrina.
Even if occurrence of peripheral neuropathy in COPD patients with associated conditions could be considered as a confounding factor, the occurrence of cases with positive rechallenge with almitrine during the post-marketing experience is strongly in favour of a causal relationship between almitrine and peripheral neuropathies.
Četudi bi lahko bila pojavnost periferne nevropatije pri bolnikih s KOPB in povezanimi bolezenskimi stanji obravnavana kot sočasen dejavnik, pojavnost primerov s ponovnim nastopom simptomov po ponovni uporabi almitrina v obdobju trženja močno kaže na vzročno razmerje med almitrinom in perifernimi nevropatijami.
The first trials, conducted with non-sequential treatment, account for 1670 patients (1006 following a double blind, placebo controlled design).
V prvih preskušanjih, izvedenih z nesekvenčnim zdravljenjem, je sodelovalo 1 670 bolnikov (1 006 v dvojno slepih, s placebom nadzorovanih preskušanjih).
The CMDh, having considered the PRAC recommendation dated 16 May 2013 pursuant to Article 107k(1) and (2) of Directive 2001/83/EC, reached an agreement on the revocation of the marketing authorisations of almitrine containing products for oral use.
CMDh se je po proučitvi priporočila, ki ga je dne 16. maja 2013 v skladu s členoma 107k(1) in (2) Direktive 2001/83/ES podal PRAC, strinjala z odvzemom dovoljenj za promet z zdravili za peroralno uporabo, ki vsebujejo almitrin.
On 27 November 2012 France informed the European Medicines Agency, pursuant to Article 31 of Directive 2001/83/EC, of their consideration to review the benefit risk balance of almitrine for oral use in the treatment of chronic respiratory diseases resulting from the evaluation of data relating to pharmacovigilance.
27. novembra 2012 je Francija v skladu s členom 31 Direktive 2001/83/ES obvestila Evropsko agencijo za zdravila, da namerava na podlagi ocene podatkov iz dejavnosti farmakovigilance ponovno proučiti razmerje med tveganji in koristmi almitrina za peroralno uporabo pri zdravljenju kroničnih bolezni dihal.
In addition to publications of clinical studies, the PRAC reviewed post marketing data provided by the MAH.
Poleg objavljenih kliničnih študij je PRAC pregledal tudi podatke iz obdobja trženja, ki jih je predložil imetnik dovoljenja za promet.
• The PRAC therefore concluded, in view of the available data, that the risks of serious peripheral neuropathy and weight loss adverse reactions associated with the use of almitrine-containing medicinal products for oral administration in the treatment of respiratory failure with hypoxemia related to obstructive bronchitis outweigh the limited benefits.
• PRAC je na podlagi vseh razpoložljivih podatkov zaključil, da so tveganja za resna neželena učinka periferno nevropatijo in zmanjšanje telesne mase, povezana z uporabo zdravil za peroralno uporabo, ki vsebujejo almitrin, pri zdravljenju odpovedi dihal s hipoksemijo, povezano z obstruktivnim bronhitisom, večja od omejenih koristi zdravila.
The PRAC noted that weight loss reported led to almitrine discontinuation in 90,9% of the cases.
PRAC je upošteval, da je zmanjšanje telesne mase v 90,9 % primerov privedlo do prekinitve zdravljenja z almitrinom.
Hypoxemia alone is not sufficient to explain severe weight loss reported with almitrine.
Hipoksemija sama ne more pojasniti hudega zmanjšanja telesne mase, opaženega pri uporabi almitrina.
• The PRAC considered, based on the assessment of the impact of risk minimisation measures already implemented (reduction of the dose and implementation of a sequential treatment scheme) and on the published literature, that the additional risk minimisation measures proposed by the Marketing Authorisation Holder and discussed during the assessment would not be able to adequately reduce the risks of serious adverse reactions to a clinically acceptable level.
• PRAC je na podlagi ocene učinkovitosti že obstoječih ukrepov za zmanjšanje tveganja (zmanjšanje odmerka in uvedba sekvenčne sheme zdravljenja) in objavljene literature menil, da z dodatnimi ukrepi za zmanjšanje tveganja, ki jih je predlagal imetnik dovoljenja za promet z zdravilom in so jih obravnavali med postopkom, ne bi bilo mogoče zmanjšati tveganja za resne neželene učinke na klinično sprejemljivo raven;
• The PRAC considered that the available efficacy data, including data which became available since the initial marketing authorisation, showed only very limited clinical efficacy of almitrine in its approved indications.
• PRAC je menil, da razpoložljivi podatki o učinkovitosti, vključno s podatki, ki so postali na voljo po odobritvi prvega dovoljenja za promet z zdravilom, kažejo na zelo majhno klinično učinkovitost almitrina pri odobrenih indikacijah;
However, the PRAC noted that weight loss reported with almitrine could occur faster and be more severe than what is commonly observed in chronic respiratory insufficiency.
Vendar pa je PRAC ugotovil, da se lahko zmanjšanje telesne mase pojavi hitreje in v hujši obliki, kot je sicer običajno pri kronični dihalni insuficienci.
Overall, a significant number of cases with outcomes reported as not recovered or recovered with sequelae is not acceptable to the PRAC.
Na splošno je PRAC menil, da veliko število primerov, pri katerih so poročali o tem, da se bolezen ni popravila ali pa je pustila posledice, ni sprejemljivo.
• The PRAC considered the procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data, for almitrine containing products for oral administration (see Annex I).
• PRAC je obravnaval napotitev po členu 31 Direktive 2001/83/ES, ki je bila na podlagi farmakovigilančnih podatkov sprožena za zdravila za peroralno uporabo, ki vsebujejo almitrin (glejte Prilogo I);
Based on the data from clinical studies and post-marketing experience, the two main safety concerns with almitrine are peripheral neuropathy and weight loss.
Glede na podatke iz kliničnih študij in izkušnje v obdobju trženja sta glavna zadržka glede varnosti almitrina periferna nevropatija in zmanjšanje telesne mase.
Further risk minimisation measures, as proposed by the MAH, such as additional amendments to the product information (restriction of the indication and contra-indications), communication material (dear Health Care Professional Communication) and restricted prescription (restriction to one month for pneumologists and hospital's use) were also considered during the discussions.
Med razpravo so obravnavali tudi dodatne ukrepe za zmanjšanje tveganja, ki jih je predlagal imetnik dovoljenja za promet z zdravilom, na primer dodatne spremembe informacij o zdravilu (omejitev indikacije in kontraindikacije), gradivo za obveščanje (obvestilo zdravstvenim delavcem) in omejeno predpisovanje (omejitev na en mesec za uporabo s strani pnevmologov in bolnišnično uporabo).
The reported reactions consisted mainly of peripheral neuropathy and weight loss.
Neželeni učinki, o katerih so poročali, so večinoma vključevali periferno nevropatijo in zmanjšanje telesne mase.
Long-term use of almitrine bismesylate is currently recommended at a dose level of 50 to 100 mg per day with limitation of the dose at 50 mg per day in patients with body weight less than 50 kg. After 3-month treatment, maintenance therapy of the sequential type is recommended: a 1-month interval for every 2 months treatment.
Priporočeni odmerek pri dolgoročni uporabi almitrin bismesilata je trenutno od 50 do 100 mg na dan, pri čemer je pri bolnikih s telesno maso manj kot 50 kg omejen na 50 mg na dan.
Almitrine bismesylate is indicated in patients with respiratory failure with hypoxemia related to obstructive bronchitis.
Almitrin bismesilat je indiciran pri bolnikih z odpovedjo dihal s hipoksemijo, povezano z obstruktivnim bronhitisom.
This was supported by the fact that cases of peripheral neuropathy continued to be reported from September 2003 to November 2012 despite the implemented minimisation measures (recommendation for a sequential scheme of administration and dose adjustment initially, followed by contra-indications and warnings).
To so utemeljili z dejstvom, da so med septembrom 2003 in novembrom 2012 kljub izvajanju ukrepov za zmanjšanje tveganja (najprej so priporočili sekvenčno shemo odmerjanja in prilagoditev odmerka, nato so sledile kontraindikacije in opozorila) še naprej poročali o primerih periferne nevropatije.
Further risk minimisation measures such as additional amendments to the product information (restriction of the indication and contra-indications), communication material (dear Health Care Professional Communication) and restricted prescription were also considered during the discussions.
Med razpravo so obravnavali tudi dodatne ukrepe za zmanjšanje tveganja, na primer dodatne spremembe informacij o zdravilu (omejitev indikacije in kontraindikacije), gradivo za obveščanje (obvestilo zdravstvenim delavcem) in omejeno predpisovanje.
The PRAC, as a consequence, concluded that pursuant to Article 116 of Directive 2001/83/EC the risk-benefit balance for almitrine containing products for oral administration is not favourable.
Posledično je PRAC zaključil, da v skladu s členom 116 Direktive 2001/83/ES razmerje med tveganji in koristmi za zdravila za peroralno uporabo, ki vsebujejo almitrin, ni ugodno.
During the assessment, the MAH confirmed that all the available data have been provided and that they will not be able to provide any further data to demonstrate the clinical benefit of oral almitrine in in the management of chronic hypoxemia in COPD.
Med postopkom ocenjevanja je imetnik dovoljenja za promet z zdravilom potrdil, da je predložil vse razpoložljive podatke in da ne more predložiti nobenih dodatnih podatkov, ki bi dokazovali klinično korist almitrina za peroralno uporabo pri zdravljenju kronične hipoksemije pri KOPB.
• The PRAC considered the totality of the data available for almitrine containing products for oral administration in relation to the risk of peripheral neuropathy and weight loss.
• PRAC je upošteval vse razpoložljive podatke za zdravila za peroralno uporabo, ki vsebujejo almitrin, v zvezi s tveganjem za periferno nevropatijo in zmanjšanje telesne mase.