natgillin/translations-raw huggingface dataset:
• 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).
Even though the primary endpoint of that study (PFS) did not reveal a clear delay in the tumour progression for the experimental arm, the longer survival associated with the olaratumab combination treatment supported the granting of a conditional marketing authorisation. 
Čeprav primarni opazovani dogodek pri tej študiji (PFS) ni jasno pokazal poznejšega napredovanja tumorja pri preiskovani skupini, je daljše preživetje, povezano s kombiniranim zdravljenjem z olaratumabom, podprlo izdajo pogojnega dovoljenja za promet z zdravilom.
No new safety concerns arose from the ANNOUNCE study. 
V študiji ANNOUNCE niso opazili novih pomislekov glede varnosti.
Doxorubicin was administered for a maximum of 8 cycles every 3 weeks, along with olaratumab/placebo which was continued after 8 cycles until PD, unacceptable toxicity, death, or other withdrawal criteria. 
Doksorubicin so dajali največ osem ciklov vsake tri tedne v kombinaciji z olaratumabom/placebom, ki so ga dajali po osmih ciklih do napredovanja bolezni, nesprejemljive toksičnosti, smrti ali drugih odtegnitvenih meril.
A total of 170 (66.1%) vs 158 (63.5%) of patients died in the investigational vs control arm, respectively, mostly attributed to study disease (63.4% vs 61%). 
V preiskovani in kontrolni skupini je umrlo skupno 170 (66,1 %) oziroma 158 (63,5 %) bolnikov, kar so večinoma pripisali proučevani bolezni (63,4 % oziroma 61 %).
The rate of potential immediate (i.e. occurring on the day of infusion) hypersensitivity reactions was higher in the investigational arm for all grade events (11.7% vs. 7.2%) and Grade ≥3 events (2.3% vs 0.8%) but no fatal events were reported. 
Delež morebitnih takojšnjih (tj. na dan infuzije) preobčutljivostnih reakcij je bil večji pri preiskovani skupini pri dogodkih vseh stopenj (11,7 % v primerjavi s 7,2 %) in dogodkih stopnje ≥ 3 (2,3 % v primerjavi z 0,8 %), vendar pa niso poročali o nobenem smrtnem dogodku.
The analyses of ANNOUNCE study showed that PDGFR-α status did not have any predictive role of the response to olaratumab in terms of OS or PFS, and that PDGFR-α was a poor prognostic factor, consistently with literature data. 
Analize študije ANNOUNCE so pokazale, da status PDGFR-α ni imel nobene napovedne vrednosti glede odziva na olaratumab v smislu skupnega preživetja ali preživetja brez napredovanja bolezni in da je bil PDGFR-α slab prognostični dejavnik, kar se sklada s podatki iz literature.
The study gave rise to concerns about lack of efficacy, because it did not meet the primary objective to prolong survival in the overall population or in the leiomyosarcoma sub-population. 
Študija je vzbudila pomisleke o pomanjkanju učinkovitosti, ker niti v splošni populaciji niti v podpopulaciji z leiomiosarkomom ni bil dosežen primarni cilj podaljšanja preživetja.
Compared to the currently recommended posology of olaratumab (15 mg/kg on days 1 and 8 of each 3 week cycle), a loading cycle of 20 mg/kg on day 1 and day 8 of cycle 1 was used, to minimize the number of patients exposed to sub-therapeutic olaratumab serum levels without an increased risk of toxicity, based on PK and matched case-control analysis by exposure quartiles results. 
V primerjavi s trenutno priporočenim odmerjanjem olaratumaba (15 mg/kg 1. in 8. dan vsakega tritedenskega cikla) so uporabili obremenitveni cikel 20 mg/kg 1. in 8. dan 1. cikla, da bi zmanjšali število bolnikov, izpostavljenih podterapevtskim serumskim ravnem olaratumaba brez povečanega tveganja za toksičnost, na podlagi farmakokinetike in analize ujemajočih se primerov in kontrol s kvartilnimi rezultati izpostavljenosti.
The latter showed an unexpected survival gain in patients with advanced/metastatic STS recruited in the United States. 
V njej so ugotovili nepričakovano podaljšanje preživetja pri bolnikih z napredovalim/metastatskim sarkomom mehkih tkiv, ki so bili v študijo vključeni v Združenih državah.
No data on AE adjusted by exposure are available. 
Podatki o neželenih dogodkih, prilagojenih po izpostavitvi, niso na voljo.
Consequently, as the ANNOUNCE study was imposed as a specific obligation to confirm the efficacy and safety of olaratumab in the authorised indication, the conditional marketing authorisation for Lartruvo should be revoked. 
Ker je bila študija ANNOUNCE odrejena kot posebna zahteva za potrditev učinkovitosti in varnosti olaratumaba pri odobreni indikaciji, je treba pogojno dovoljenje za promet z zdravilom Lartruvo preklicati.
Of those, 2 TEAE leading to deaths were considered related to study treatment in the investigational arm (pneumonia and aspiration) vs none in the control arm. 
Od teh sta se pri preiskovani skupini za povezana s študijskim zdravilom štela dva neželena dogodka zaradi zdravljenja, ki sta vodila v smrt (pljučnica in aspiracija), pri kontrolni skupini pa nobeden.
Death due to AEs on therapy or within 30 days from the last dose of study drug were 5 (1.9%) vs 3 (1.2%) (investigational arm: pulmonary embolism in 2 subjects, acute respiratory failure, aspiration and pneumonia in one patient each; control arm: cerebrovascular accident, ischemic stroke and sepsis, each in one patient). 
Smrti zaradi neželenih dogodkov ob zdravljenju ali v 30 dneh po zadnjem odmerku proučevanega zdravila je bilo 5 (1,9 %) oziroma 3 (1,2 %) (preiskovana skupina: pljučna embolija pri dveh preskušancih, akutna respiratorna insuficienca, aspiracija in pljučnica, vsaka od teh pri enem bolniku; kontrolna skupina: cerebrovaskularni insult, ishemična možganska kap in sepsa, vsak od teh pri enem bolniku).
The rate of TEAE was overall similar in both treatment arms (98.1% vs 99.2%). 
Delež neželenih dogodkov zaradi zdravljenja je bil na splošno podoben pri obeh zdravljenih skupinah (98,1 % v primerjavi z 99,2 %).
In order to confirm the efficacy and safety of olaratumab, the marketing authorisation holder was required to submit as specific obligation, by January 2020, the clinical study report of a phase III randomised double-blind confirmatory study comparing doxorubicin plus olaratumab versus doxorubicin in patients with advanced or metastatic soft tissue sarcoma (Study I5B-MCJGDJ [JGDJ]; ANNOUNCE), including exploratory biomarker data. 
Da bi potrdili učinkovitost in varnost olaratumaba, je moral imetnik dovoljenja za promet z zdravilom do januarja 2020 v okviru posebne zahteve predložiti poročilo o kliničnem preskušanju za randomizirano, dvojno slepo potrditveno študijo III. faze, v kateri so doksorubicin in olaratumab primerjali z doksorubicinom pri bolnikih z napredovalim ali metastatskim sarkomom mehkih tkiv (študija I5B-MCJGDJ [JGDJ]; ANNOUNCE), vključno z raziskovalnimi podatki o bioloških označevalcih.
ANNOUNCE as the confirmatory trial was specifically designed to show differences in OS. 
Študija ANNOUNCE je bila kot potrditveno preskušanje posebej zasnovana za to, da bi pokazala razliko v skupnem preživetju.
In the LMS population, ORR was in favour of the control arm (no statistical significance) and DCR was statistically significant in favour of the control arm. 
Pri populaciji z LMS je bila skupna stopnja odziva v korist kontrolne skupine (brez statistične razlike), stopnja obvladovanja bolezni pa je bila statistično pomembna v korist kontrolne skupine.
The incidence for all grades of events in the cardiac dysfunction AESI category was 18.3% in the investigational arm and 13.7% in the control arm, the majority being events of peripheral oedema (13.2 vs 9.2%) and oedema (1.2% vs 0%). 
Incidenca vseh stopenj dogodkov v kategoriji srčne disfunkcije kot neželenega dogodka posebnega pomena je bila 18,3 % pri preiskovani skupini in 13,7 % pri kontrolni skupini, pri čemer je večina dogodkov vključevala periferni edem (13,2 % oziroma 9,2 %) in edem (1,2 % oziroma 0 %).
Cardiac arrhythmia events were more commonly reported in the investigational arm (any grade 12.8% vs 9.6%; grade >=3 2.7% vs 0.8%). 
O srčnih aritmijah so pogosteje poročali v preiskovani skupini (katera koli stopnja 12,8 % v primerjavi z 9,6 %; stopnja >= 3 2,7 % v primerjavi z 0,8 %).
The primary endpoint for this study was OS in the ITT population and in the LMS population. 
Primarni opazovani dogodek pri tej študiji je bilo skupno preživetje pri populaciji z namenom zdravljenja in populaciji z LMS.
Lartruvo was authorised based on a single open-label, randomised phase 1b/2 clinical trial which enrolled doxorubicin-naïve subjects with advanced soft tissue sarcoma not amenable to treatment with surgery and radiotherapy (study JGDG). 
Zdravilo Lartruvo je bilo odobreno na podlagi enkratnega odprtega, randomiziranega kliničnega preskušanja faze 1b/2, ki je vključevalo z doksorubicinom še nezdravljene preskušance z napredovalim sarkomom mehkih tkiv, ki jih ni bilo mogoče zdraviti z operacijo in radioterapijo (študija JGDG).
In this trial, treatment with olaratumab in combination with doxorubicin resulted in an improvement in progression-free survival (PFS) (8.2 vs. 4.4 months according to independent assessment; 6.6 vs. 4.1 months, hazard ratio (HR) 0.672 [95% CI: 0.442, 1.021], p = 0.0615 according to investigator assessment) and overall survival (OS) (26.5 months vs. 14.7 months, HR = 0.463; p = 0.0003). 
Pri tem preskušanju je zdravljenje z olaratumabom v kombinaciji z doksorubicinom privedlo do podaljšanja preživetja brez napredovanja bolezni (PFS) (8,2 meseca v primerjavi s 4,4 meseca po neodvisni oceni; 6,6 meseca v primerjavi s 4,1 meseca, razmerje obetov (HR) 0,672 [95-odstotni interval zaupanja: 0,442, 1,021], p = 0,0615 po oceni raziskovalca) in skupnega preživetja (OS) (26,5 meseca v primerjavi s 14,7 meseca, HR = 0,463; p = 0,0003).
In total, 509 patients were randomised to treatment either with Lartruvo + doxorubicin (followed by Lartruvo monotherapy until progression) or with placebo + doxorubicin (followed by placebo monotherapy until progression). 
Skupno je bilo 509 bolnikov razporejenih bodisi na zdravljenje s kombinacijo zdravila Lartruvo in doksorubicina (čemur je sledila monoterapija z zdravilom Lartruvo do napredovanja) bodisi s kombinacijo placeba in doksorubicina (čemur je sledila monoterapija s placebom do napredovanja bolezni).
Overall, 509 adult patients with advanced or metastatic soft tissue sarcoma not amenable to treatment with surgery or radiotherapy with curative intent (of those 234 were leiomiosarcoma, LMS) were randomized 1:1, stratified by number of prior systemic therapies for advanced/metastatic disease, histological tumour type, and ECOG PS, to the investigational arm (n=258; LMS n=119) with olaratumab plus doxorubicin or the control arm (n=251; LMS n=114) with placebo plus doxorubicin. 
Skupno so 509 odraslih bolnikov z napredovalim ali metastatskim sarkomom mehkih tkiv, ki jih ni bilo mogoče zdraviti z operacijo ali radioterapijo z namenom ozdravitve (od tega jih je 234 imelo leiomiosarkom, LMS), randomizirali v razmerju 1 : 1, stratificirano po številu predhodnih sistemskih zdravljenj za napredovalo/metastatsko bolezen, histološki vrsti tumorja in oceni zmogljivosti po ECOG, v preiskovano skupino (n = 258; LMS, n = 119), ki je prejemala olaratumab in doksorubicin, ali kontrolno skupino (n = 251; LMS, n = 114), ki je prejemala placebo in doksorubicin.
Even though no new safety concerns arose from the ANNOUNCE study, any safety concerns associated with olaratumab render the benefit-risk balance of Lartruvo negative in view of the lack of therapeutic efficacy observed in the study. 
Čeprav v študiji ANNOUNCE niso bili zaznani novi pomisleki glede varnosti, pomeni ob pomanjkanju terapevtske učinkovitosti, ugotovljene v študiji, vsak pomislek glede varnosti, povezan z olaratumabom, negativno razmerje med tveganji in koristmi pri zdravilu Lartruvo.
The median PFS was 5.42 months in the investigational arm and 6.77 months in the control arm (HR=1.231 [95% CI: 1.009, 1.502]; p=0.042). 
Mediana preživetja brez napredovanja bolezni je bila 5,42 meseca pri preiskovani skupini in 6,77 meseca pri kontrolni skupini (HR = 1,231 [95-odstotni interval zaupanja: 1,009, 1,502]; p = 0,042).
It is plausible that a different rate of several histologies between the two studies could have had an impact in the dissimilar efficacy observed. 
Verjetno je, da bi bil lahko razlog za ugotovljeno razliko v učinkovitosti različen delež posameznih histologij v obeh študijah.
• The Committee noted that no benefit was observed from adding Lartruvo to doxorubicin in the treatment of patients with advanced soft tissue sarcoma, when compared to doxorubicin alone. 
• odbor je ugotovil, da pri zdravljenju bolnikov z napredovalim sarkomom mehkih tkiv ob dodajanju zdravila Lartruvo doksorubicinu niso ugotovili nobene koristi v primerjavi z doksorubicinom samim;
No difference was observed in any of the other secondary endpoints analysed in the ITT population. 
Pri populaciji z namenom zdravljenja niso opazili nobene razlike pri nobenem drugem analiziranem sekundarnem opazovanem dogodku.
Neither the exploratory analysis of PDGFR-α expression nor the immunogenicity appear to explain the absence of benefit. 
Zdi se, da odsotnosti koristi ni mogoče razložiti niti z raziskovalno analizo izražanja PDGFR-α niti z imunogenostjo.
ANNOUNCE (I5B-MC-JGDJ) was a randomized, double-blind, placebo-controlled, phase 3 trial of olaratumab plus doxorubicin versus placebo plus doxorubicin in patients with locally advanced or metastatic soft tissue sarcoma. 
Študija ANNOUNCE (I5B-MC-JGDJ) je bilo randomizirano, dvojno slepo, s placebom nadzorovano preskušanje III. faze, v katerem so pri bolnikih z lokalno napredovalim ali metastatskim sarkomom mehkih tkiv primerjali kombinacijo olaratumaba in doksorubicina s kombinacijo placeba in doksorubicina.
In the ITT population, the median OS was 20.37 months in the investigational arm and 19.75 months in the control arm (HR=1.047 [95% CI: 0.841, 1.303]; p=0.69), and the OS KM curves are completely overlapping, indicating that adding Lartruvo to doxorubicin had no favourable effect on OS. Further OS analyses showed that in most subgroups HR estimates ranged from 0.9 to 1.1, consistent with the overall OS results. 
Pri populaciji z namenom zdravljenja je bila mediana skupnega preživetja 20,37 meseca pri preiskovani skupini in 19,75 meseca pri kontrolni skupini (HR = 1,047 [95-odstotni interval zaupanja: 0,841, 1,303]; p = 0,69), Kaplan-Meierjevi krivulji skupnega preživetja pa se popolnoma prekrivata, kar kaže, da dodatek zdravila Lartruvo k doksorubicinu ni ugodno vplival na skupno preživetje.
These data seem to suggest a different tolerability to doxorubicin depending on the group, which appears to be different from that observed in the previous phase II trial, where the exposure to doxorubicin was higher for patients in the investigational group as compared to the control group (7 vs 4). 
Ti podatki naj bi kazali na razliko v toleranci za doksorubicin med skupinama, ki se zdi drugačna, kot so jo ugotovili v predhodnem preskušanju II.
Overall, 6 patients in the investigational vs none in the control arm developed an anaphylactic reaction. 
Skupno se je anafilaktična reakcija pojavila pri šestih bolnikih v preiskovani skupini in nobenem v kontrolni skupini.
The Kaplan-Meier curves for OS are overlapping. 
KaplanMeierjevi krivulji skupnega preživetja se prekrivata.
The only significant difference found in PFS was in the ITT population, but in favour of the control arm. 
Edino pomembno razliko v zvezi s preživetjem brez napredovanja bolezni so ugotovili v populaciji z namenom zdravljenja, vendar v korist kontrolne skupine.
No statistically significant difference in ORR or DCR in the ITT population was observed between the investigational arm and control arms, and both rates favoured the control arm. 
Med preiskovano skupino in kontrolno skupino niso opazili nobene statistično pomembne razlike v skupni stopnji odziva ali stopnji obvladovanja bolezni v populaciji z namenom zdravljenja, obe stopnji pa sta bili v korist kontrolne skupine.
With regard to PDGFR-β, no significant association was found between PDGFR-β status and response to olaratumab in terms of OS or PFS. PDGFR-β did not seem to have a clear prognostic role in STS either. 
Glede PDGFR-β niso ugotovili nobene pomembne povezave med statusom PDGFRβ in odzivom na olaratumab v smislu skupnega preživetja ali preživetja brez napredovanja bolezni.
Nausea, neutropenia and fatigue were the most frequently reported TEAEs. 
Neželeni dogodki zaradi zdravljenja, o katerih so poročali najpogosteje, so bili slabost, nevtropenija in utrujenost.
The sample size, conduct of the study, endpoints, statistical methods or randomisation do not seem to explain the discrepancy between ANNOUNCE and the phase II JGDG. 
faze JGDG ni mogoče razložiti z velikostjo vzorca, izvedbo študije, opazovanimi dogodki, statističnimi metodami ali randomizacijo.
No significant difference in PFS between the treatment arms in the LMS population was found. 
Pri populaciji z LMS niso ugotovili nobene pomembne razlike v preživetju brez napredovanja bolezni med zdravljenimi skupinami.
In summary, no benefit of adding Lartruvo to doxorubicin in patients with advanced STS was observed in the ANNOUNCE study. 
Če povzamemo, v študiji ANNOUNCE pri bolnikih z napredovalim sarkomom mehkih tkiv niso opazili koristi dodajanja zdravila Lartruvo doksorubicinu.
The different exposure to doxorubicin between investigational arm and the control group was noted. 
Med preiskovano in kontrolno skupino so ugotovili razliko v izpostavljenosti doksorubicinu.
It seems no single reason can explain the discrepancy in results between phase II JGDG and phase III ANNOUNCE studies. 
faze JGDG in študije III. faze ANNOUNCE ni mogoče razložiti z nobenim posameznim vzrokom.
Few more SAE (38.9% vs 34.9%) occurred in the investigational arm than in the control arm. Febrile neutropenia was the most frequently SAE occurring with similar frequency in both arms (12.8% vs 13.3%). 
Najpogostejši hudi neželeni dogodek je bila febrilna nevtropenija, ki se je s podobno pogostostjo pojavila v obeh skupinah (12,8 % oziroma 13,3 %).
There was a significant difference in PFS in the ITT population based on investigator assessment, but in favour of the control arm. 
Na podlagi ocene preiskovalca se je močno razlikovalo preživetje brez napredovanja bolezni pri populaciji z namenom zdravljenja, vendar v korist kontrolne skupine.
Evidence in support of efficacy 
Dokazi v podporo učinkovitosti
Consequently the matter was referred to the CVMP. 
Zadeva je bila zato napotena na odbor CVMP.
Target animal safety 
Varnost za ciljne živalske vrste
CVMP conclusions after the re-examination 
Zaključki odbora CVMP po ponovnem pregledu
National Competent Authorities, coordinated by the reference Member State, shall ensure that the following condition is fulfilled by the marketing authorisation holder: 
Pristojni nacionalni organi, ki jih usklajuje referenčna država članica, morajo zagotoviti, da imetnik dovoljenja za promet z zdravilom izpolni naslednji pogoj:
The presentations for use in dogs have already been authorised in the reference Member State, the Czech Republic, since December 2011 and the cat product was more recently authorised there in May 2012. 
Različice zdravila za uporabo pri psih so bile v referenčni državi članici Češki republiki že odobrene decembra 2011, različico za mačke pa so odobrili kasneje, in sicer maja 2012.
The condition for lifting the suspension of the marketing authorisations is described in Annex III. 
Pogoj za preklic začasnega umika dovoljenj za promet z zdravilom je opredeljen v Prilogi III.
The MAH highlighted paragraph 3.5 of Title III of Directive 2009/9/EC which states that: “Post-marketing experience with other products containing the same constituents is of particular importance and applicants shall put a special emphasis on this issue.” 
Imetnik dovoljenja za promet z zdravilom je izpostavil odstavek 3.5 Naslova III Direktive 2009/9/ES, ki navaja: „Izkušnje z drugimi zdravili po dajanju na trg, ki vsebujejo enake sestavine, so zlasti pomembne, zato vlagatelji to še posebej poudarijo.“
Applications for marketing authorisation were submitted to the concerned Member States using the mutual recognition procedure. 
Vloge za pridobitev dovoljenja za promet z zdravilom so bile zadevnim državam članicam predložene po postopku z medsebojnim priznavanjem.
related to the legal requirements for a well-established use application. 
in so bili povezani z zakonskimi pogoji za vlogo, ki temelji na dobro uveljavljeni uporabi.
The quality and safety (apart from target animal safety) of Fiprex were not assessed in this referral procedure. 
Kakovosti in varnosti (razen varnosti pri ciljnih živalskih vrstah) zdravila Fiprex v tem napotitvenem postopku niso obravnavali.
The CVMP assessed the detailed grounds for re-examination presented by Vet-Agro Trading Sp. z o.o. 
Odbor CVMP je proučil podrobne razloge za ponoven pregled, ki jih je predstavila družba Vet-Agro Trading Sp. z o.o.
These differences may at least partly be attributable to the effect of the formulation on the rate and/or extent of dermal absorption and distribution of fipronil. 
Te razlike je vsaj delno mogoče pripisati vplivu formulacije na hitrost in/ali obseg kožne absorpcije ter porazdelitve fipronila.
INN Strength Pharmaceutical form 
Jakost Farmacevtska oblika
allowed for the establishment of a 4-week period of acaricidal activity. 
mogoče potrditi 4-tedensko akaricidno delovanje.
In relation to clinical efficacy, the published literature demonstrates that even minor differences in formulation can significantly affect the duration of product efficacy. 
Kar zadeva klinično učinkovitost, objavljena literatura kaže, da lahko že manjše razlike v formulaciji znatno vplivajo na trajanje učinkovitosti zdravila.