FrancophonIA/ELRC3.0 huggingface dataset:
English: - if you have had a heart attack within the last 3 months or if you have other severe problems with your heart which cause daily symptoms
Croatian: - ako ste u prethodna 3 mjeseca imali srčani udar ili ako imate druge teške probleme sa srcem koji uzrokuju svakodnevne simptome
English: • You can take Rizmoic at any time of the day, with food or between meals.
Croatian: • Rizmoic možete uzeti u bilo koje doba dana, s hranom ili između obroka.
English: However, once you start taking the medicine, take it at around the same time each day.
Croatian: Međutim, kad ga jednom počnete uzimati, uzimajte ga svakog dana u približno isto vrijeme.
English: Do not take this medicine if any of the above applies to you.
Croatian: Nemojte uzimati ovaj lijek ako se nešto od gore navedenog odnosi na Vas.
English: AT, BE, BG, CY, CZ, DK, EE, IE, EL, FI, FR, HR, HU, IE, IS, LT, LU, LV, MT, , NO, PL, PT, RO, SE, SI, SK
Croatian: AT, BE, BG, CY, CZ, DK, EE, IE, EL, FI, FR, HR, HU, IE, IS, LT, LU, LV, MT, NO, PT, RO, SE, SI, SK Shionogi B.V.
English: However if it is less than 12 hours until your next dose, skip the missed dose, and wait until it is time to take your next tablet.
Croatian: Međutim, ako je preostalo manje od 12 sati do sljedeće doze, preskočite dozu koju ste propustili i pričekajte dok ne bude vrijeme za uzimanje sljedeće tablete.
English: This medicine is not for children or adolescents under the age of 18 years because the effects of the medicine in children and adolescents are not known.
Croatian: Ovaj lijek nije namijenjen djeci ili adolescentima mlađima od 18 godina zato što nisu poznati učinci lijeka u djece i adolescenata.
English: A risk to the suckling child cannot be excluded.
Croatian: Rizik za dojenče ne može se isključiti.
English: There is no clinically significant food effect.
Croatian: Hrana nema klinički značajan učinak.
English: Not Known (frequency cannot be estimated from the available data)
Croatian: Nepoznato (ne može se procijeniti iz dostupnih podataka):
English: The safety and efficacy of naldemedine in children and adolescents aged below 18 years have not yet been established.
Croatian: Sigurnost i djelotvornost naldemedina u djece i adolescenata u dobi do 18 godina nisu još ustanovljene.
English: Age, gender, body weight and race
Croatian: Dob, spol, tjelesna težina i etnička pripadnost
English: Kingsfordweg 151 1043GR Amsterdam The Netherlands
Croatian: Kingsfordweg 151 1043GR Amsterdam Nizozemska
English: What Rizmoic is and what it is used for
Croatian: Što je Rizmoic i za što se koristi
English: The symptoms resolved.
Croatian: Simptomi su se povukli.
English: Rizmoic should be taken once daily, with or without food (see section 5.2).
Croatian: Rizmoic se uzima jedanput dnevno, s hranom ili bez nje (vidjeti dio 5.2).
English: Pharmacokinetics in subpopulations
Croatian: Farmakokinetika u podpopulacijama
English: The absolute bioavailability of naldemedine is estimated to be in the range of 20% to 56%.
Croatian: Procjenjuje se da je apsolutna bioraspoloživost naldemedina u rasponu od 20% do 56%.
English: Patients with evidence of significant structural abnormalities of the gastrointestinal tract were not enrolled in these studies.
Croatian: Bolesnici s dokazanim značajnim strukturnim abnormalnostima gastrointestinalnog trakta nisu bili uključeni u ta ispitivanja.
English: Your doctor will advise you about whether you can use Rizmoic if you are pregnant.
Croatian: Liječnik će Vam savjetovati smijete li uzimati Rizmoic ako ste trudni.
English: You should not drink large amounts of grapefruit juice whilst taking Rizmoic.
Croatian: Ne smijete piti velike količine soka od grejpa dok uzimate Rizmoic.
English: Approximately 20% of the naldemedine dose is excreted unchanged in urine.
Croatian: Približno 20% doze naldemedina izluči se nepromijenjeno u mokraći.
English: If you miss a tablet of Rizmoic, take it as soon as you remember.
Croatian: Ako propustite uzeti tabletu lijeka Rizmoic, uzmite je čim se sjetite.
English: Rizmoic with drink
Croatian: Rizmoic s pićem
English: See 'Other medicines and Rizmoic'.
Croatian: Pogledajte „Drugi lijekovi i Rizmoic“.
English: Shionogi B.V. Tel/Tel./Teл./Tlf/Tél/Puh/Sími/Τηλ:
Croatian: Tel/Tel./Teл./Tlf/Tél/Puh/Sími/Τηλ:
English: Opioid withdrawal syndrome typically develops within minutes to several days following administration of an opioid antagonist.
Croatian: Sindrom ustezanja od opioida obično se razvija u roku od nekoliko minuta do nekoliko dana nakon primjene nekog antagonista opioida.
English: - if you are allergic to naldemedine or any of the other ingredients of this medicine (listed in section 6).
Croatian: - ako ste alergični na naldemedin ili neki drugi sastojak ovog lijeka (naveden u dijelu 6).
English: • sweating
Croatian: • znojenje
English: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and embryo-fetal development.
Croatian: Neklinički podaci ne ukazuju na poseban rizik za ljude na temelju konvencionalnih ispitivanja sigurnosne farmakologije, toksičnosti ponovljenih doza, genotoksičnosti, kancerogenog potencijala i embriofetalnog razvoja.
English: You will be monitored for opioid withdrawal symptoms (see section 2, under ‘Warnings and Precautions', and section 4).
Croatian: Nadzirat će Vas zbog simptoma ustezanja od opioida (pogledajte dio 2 pod naslovom „Upozorenja i mjere opreza“ i dio 4).
English: What Rizmoic is and what it is used for What you need to know before you take Rizmoic How to take Rizmoic
Croatian: Što je Rizmoic i za što se koristi Što morate znati prije nego počnete uzimati Rizmoic Kako uzimati Rizmoic
English: Two of the nine cases have been classified as cases of interest by the MAH, one of which they consider ‘possibly related' and other ‘probably related'.
Croatian: Od tih devet slučajeva nositelj odobrenja izdvojio je dva kao slučajeve od interesa; jedan se slučaj smatra „moguće povezanim“, a drugi „vjerojatno povezanim“.
English: If you have these conditions and develop opioid withdrawal symptoms (see section 4) or if the opioid medicine no longer controls your pain, contact your doctor immediately.
Croatian: Ako bolujete od ovih bolesti i razvijete simptome ustezanja od opioida (pogledajte dio 4) ili Vam opioidni lijek više ne može kontrolirati bol, odmah se obratite liječniku.
English: The effect on oestrous cycle is not considered clinically relevant at the proposed therapeutic dose.
Croatian: Smatra se da učinak na ciklus estrusa nije klinički važan u predloženoj terapijskoj dozi.
English: - if you have cancer of the brain or central nervous system, multiple sclerosis, or Alzheimer's disease.
Croatian: - ako imate rak mozga ili središnjeg živčanog sustava, multiplu sklerozu ili Alzheimerovu bolest.
English: • feeling depressed
Croatian: • osjećaj potištenosti
English: - if you have severe diarrhoea or stomach ache, tell your doctor, so that the doctor can monitor you and treat you with rehydration and appropriate medicines if needed.
Croatian: - ako imate jaki proljev ili bol u trbuhu, obavijestite liječnika, tako da Vas mogu nadzirati i po potrebi liječiti rehidracijom i odgovarajućim lijekovima.
English: Whilst the more limited information provided in these five cases is acknowledged the assessor considers that the potential role of Naldemedine cannot be excluded in all of these.
Croatian: Iako je prihvaćeno da su u tih pet slučajeva informacije ograničene, ocjenjitelj smatra da se ni u jednom od njih ne može isključiti moguća uloga naldemedina.
English: Prior to enrollment, patients had been using their current opioid for an average of 5 years.
Croatian: Prije uključenja bolesnici su uzimali tadašnji opioid u prosjeku 5 godina.
English: If you have taken more Rizmoic than you should, talk to your doctor or go to the hospital.
Croatian: Ako ste uzeli više lijeka Rizmoic nego što ste trebali, obratite se liječniku ili otiđite u bolnicu.
English: - if you are taking certain medicines such as itraconazole to treat fungal infections, or an antibiotic called rifampicin to treat tuberculosis and other infections.
Croatian: - ako uzimate određene lijekove poput itrakonazola za liječenje gljivičnih infekcija ili antibiotik pod nazivom rifampicin za liječenje tuberkuloze i drugih infekcija.
English: In Study V9235, patients on a stable laxative regimen at screening (52.4%) were allowed to continue using that same regimen without change throughout the study duration.
Croatian: U ispitivanju V9235, bolesnicima na stabilnom režimu laksativima (52,4%) na probiru bilo je dopušteno da nastave uzimati taj isti režim bez promjene tijekom cijelog trajanja ispitivanja.
English: Treatment difference
Croatian: Terapijska razlika
English: What Rizmoic looks like and contents of the pack
Croatian: Kako Rizmoic izgleda i sadržaj pakiranja
English: 7 film-coated tablets 10 film-coated tablets 28 film-coated tablets 30 film-coated tablets 84 film-coated tablets 100 film-coated tablets
Croatian: 7 filmom obloženih tableta 10 filmom obloženih tableta 28 filmom obloženih tableta 30 filmom obloženih tableta 84 filmom obložene tablete 100 filmom obloženih tableta
English: Patients with cardiovascular conditions
Croatian: Bolesnici s kardiovaskularnim bolestima
English: It is therefore considered that the presented cases are sufficient to support an update to the product information to both section 4.4 and 4.8.
Croatian: Stoga se smatra da su prikazani slučajevi dovoljni da podupru potrebu za ažuriranjem informacija o lijeku u dijelu 4.4 i u dijelu 4.8.
English: Stop taking Rizmoic and contact your doctor if you get a combination of 3 or more of the following symptoms of opioid withdrawal on the same day:
Croatian: Prestanite uzimati Rizmoic i obratite se svom liječniku ako razvijete kombinaciju od 3 ili više sljedećih simptoma ustezanja od opioida istog dana:
English: What you need to know before you take Rizmoic Do not take Rizmoic:
Croatian: Što morate znati prije nego počnete uzimati Rizmoic Nemojte uzimati Rizmoic:
English: Patients responding, n (%) p value* *Statistically significant: p-values based on the Chi-square test.
Croatian: Bolesnici s terapijskim odgovorom, n (%) p vrijednost* *Statistički značajno: p-vrijednosti na temelju hi-kvadrat testa.
English: Pharmacotherapeutic group: Drugs for constipation, peripheral opioid receptor antagonists, ATC code: A06AH05.
Croatian: Farmakoterapijska skupina: lijekovi za konstipaciju, antagonisti perifernih opioidnih receptora, ATK oznaka: A06AH05.
English: Due to the limited therapeutic experience in patients 75 years old and older, naldemedine therapy should be initiated with caution in this age group.
Croatian: Zbog ograničenog terapijskog iskustva u bolesnika u dobi od 75 godina i starijih, terapiju naldemedinom u ove dobne skupine treba započeti s oprezom.
English: If you are being treated with an opioid medicine for cancer.
Croatian: Ako se liječite opioidnim lijekom zbog raka.
English: In vitro data also showed that naldemedine is not a direct inhibitor of OATP1B1, OATP1B3, OAT1 and OAT3 transporters.
Croatian: In vitro podaci također su pokazali da naldemedin nije izravni inhibitor prijenosnika OATP1B1, OATP1B3, OAT1 i OAT3.
English: The frequency categories are defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
Croatian: Kategorije učestalosti definirane su prema sljedećoj konvenciji: vrlo često (≥1/10); često (≥1/100 i <1/10); manje često (≥1/1000 i <1/100); rijetko (≥1/10 000 i <1/1000);
English: If you take more Rizmoic than you should
Croatian: Ako uzmete više lijeka Rizmoic nego što ste trebali
English: The apparent terminal elimination half-life of naldemedine is approximately 11 hours, and the apparent total clearance (CL/F) of naldemedine is 8.4 L/h.
Croatian: Prividno terminalno poluvrijeme eliminacije naldemedina iznosi približno 11 sati, a prividni ukupni klirens (CL/F) naldemedina iznosi 8,4 l/h.
English: The European Medicines Agency has deferred the obligation to submit the results of studies with Rizmoic in one or more subsets of the paediatric population in the treatment of opioid-induced constipation (see section 4.2 for information on paediatric use).
Croatian: Europska agencija za lijekove odgodila je obvezu podnošenja rezultata ispitivanja lijeka Rizmoic u jednoj ili više podskupina pedijatrijske populacije u liječenju konstipacije uzrokovane opioidima (vidjeti dio 4.2 za informacije o pedijatrijskoj primjeni).
English: Aluminium/aluminium blister containing 7, 10 or 14 film-coated tablets.
Croatian: Aluminij/aluminij blister koji sadrži 7, 10 ili 14 filmom obloženih tableta.
English: • The recommended dose is one 200 microgram tablet once daily.
Croatian: • Preporučena doza je jedna tableta od 200 mikrograma jedanput dnevno.
English: • an enlarged colon due to a condition known as Ogilvie's syndrome;
Croatian: • prošireno debelo crijevo zbog stanja koje se naziva Ogilviejev sindrom
English: The effects of the medicine in pregnant women are not known.
Croatian: Nisu poznati učinci ovog lijeka u trudnica.
English: These patients should be clinically monitored when taking Rizmoic.
Croatian: Te je bolesnike potrebno klinički pratiti dok uzimaju Rizmoic.
English: Naldemedine should not be used during pregnancy unless the clinical condition of the woman requires treatment with naldemedine.
Croatian: Naldemedin se ne smije primjenjivati tijekom trudnoće osim ako kliničko stanje žene ne zahtijeva liječenje naldemedinom.
English: The following side effects may happen with this medicine:
Croatian: Uz ovaj se lijek mogu pojaviti sljedeće nuspojave:
English: Other medicines and Rizmoic
Croatian: Drugi lijekovi i Rizmoic
English: Do not use this medicine after the expiry date which is stated on the carton and blisters after EXP.
Croatian: Ovaj lijek se ne smije upotrijebiti nakon isteka roka valjanosti navedenog na kutiji i blisterima iza oznake „EXP“.
English: Pack sizes of 7, 10, 28, 30, 84 or 100 tablets.
Croatian: Veličine pakiranja od 7, 10, 28, 30, 84 ili 100 tablete.
English: • a disease causing severe inflammation of the digestive tract such as Crohn's disease .
Croatian: • bolest koja uzrokuje jaku upalu probavnog sustava, kao što je Crohnova bolest.
English: Therefore, treatment with naldemedine is not expected to alter the pharmacokinetics of co-administered medicines that are substrates of these enzymes and transporters.
Croatian: Stoga se ne očekuje da će liječenje naldemedinom mijenjati farmakokinetiku istodobno primijenjenih lijekova koji su supstrati ovih enzima i prijenosnika.
English: Detailed information on this medicine is available on the European Medicines Agency web site: http://www.ema.europa.eu.
Croatian: Detaljnije informacije o ovom lijeku dostupne su na internetskoj stranici Europske agencije za lijekove: http://www.ema.europa.eu
English: None of the identified cases are without significant confounding factors and the difficulties in definitively determining causality are acknowledged.
Croatian: U svim utvrđenim slučajevima postoje značajni zbunjujući čimbenici i potvrđene su teškoće u konačnom određivanju uzročno-posljedične povezanosti.
English: The efficacy and safety were also assessed in the laxative inadequate responders (LIR) and non-LIR subgroups.
Croatian: Djelotvornost i sigurnost bile su procijenjene i u podskupini bolesnika s neadekvatnim odgovorom na laksative (podskupina LIR prema engl. laxative inadequate responders) i podskupini ne-LIR.
English: Subjects were required to be treated with opioids for ≥14 days prior to Screening and had to be receiving a stable dose.
Croatian: Ispitanici su morali biti liječeni opioidima tijekom ≥14 dana prije probira i morali su dobivati stabilnu dozu.
English: If you are not sure, talk to your doctor or pharmacist before taking Rizmoic.
Croatian: Ako niste sigurni, obratite se liječniku ili ljekarniku prije nego što uzmete Rizmoic.
English: Talk to your doctor or pharmacist before taking Rizmoic: - if you suffer from a disease which may affect your bowel wall such as:
Croatian: Obratite se svom liječniku ili ljekarniku prije nego što uzmete Rizmoic: - ako bolujete od bolesti koja može zahvatiti stijenku crijeva kao što je:
English: Nevertheless, given the times to onset and the mechanism of action of Naldemedine which leads to an increase in the propulsive contractions of the intestinal muscle it is considered that Naldemedine could plausibly have contributed to perforation events in these patients who were already at increased risk due to the presence of additional risk factors including underlying disease and concomitant treatments.
Croatian: Ipak, s obzirom na vrijeme do nastupa nuspojava i mehanizam djelovanja naldemedina koji dovodi do povećanja propulzivnih kontrakcija intestinalnih mišića, smatra se uvjerljivim da je naldemedin mogao pridonijeti događajima perforacije u onih bolesnika koji su već bili pod povećanim rizikom zbog prisutnosti dodatnih čimbenika rizika, uključujući osnovnu bolest i istodobne terapije.
English: EU/1/18/1291/001 7 film-coated tablets EU/1/18/1291/002 28 film-coated tablets EU/1/18/1291/003 84 film-coated tablets EU/1/18/1291/004 10 film-coated tablets EU/1/18/1291/005 30 film-coated tablets EU/1/18/1291/006 100 film-coated tablets
Croatian: EU/1/18/1291/001 7 filmom obloženih tableta EU/1/18/1291/002 28 filmom obloženih tableta EU/1/18/1291/003 84 filmom obložene tablete EU/1/18/1291/004 10 filmom obloženih tableta EU/1/18/1291/005 30 filmom obloženih tableta EU/1/18/1291/006 100 filmom obloženih tableta
English: At therapeutic doses, most opioids (e.g morphine, meperidine, methadone) are excreted into breast milk in minimal amounts.
Croatian: Pri terapijskim dozama većina se opioida (npr. morfij, meperidin, metadon) izlučuje u mlijeko u minimalnim količinama.
English: - if you have severe liver disease such as alcoholic liver disease, viral liver infection or impaired liver function.
Croatian: - ako imate tešku bolest jetre poput bolesti jetre uzrokovane alkoholom, virusne infekcije jetre ili oštećene funkcije jetre
English: In the event of an overdose, patients should be closely monitored for potential signs and symptoms of opioid withdrawal syndrome (see section 4.4) and provided with appropriate supportive care.
Croatian: U slučaju predoziranja, bolesnike je potrebno pažljivo pratiti zbog mogućih znakova i simptoma sindroma ustezanja od opioida (vidjeti dio 4.4) te im treba osigurati odgovarajuću potpornu skrb.
English: Gastrointestinal perforation is added a new adverse reaction with a frequency “Not known”.
Croatian: Gastrointestinalna perforacija dodana je kao nova nuspojava, s učestalošću „nepoznato“.
English: No dose adjustment is required in patients older than 65 years of age (see section 5.2).
Croatian: Nije potrebna prilagodba doze u bolesnika starijih od 65 godina (vidjeti dio 5.2).
English: A QTc study performed with naldemedine in healthy volunteers did not indicate any prolongation of the QT interval.
Croatian: Ispitivanje utjecaja naldemedina na QTc interval u zdravih dobrovoljaca nije pokazalo produljenje QTc intervala.
English: The MAH identified nine cases of gastrointestinal perforation in their global database.
Croatian: Nositelj odobrenja utvrdio je u svojoj globalnoj bazi podataka devet slučajeva gastrointestinalne perforacije.
English: The studies included a 2-week Screening Period, 2-week Treatment Period and 4-week Follow-up Period.
Croatian: Ispitivanja su se sastojala od dvotjednog razdoblja probira, dvotjednog razdoblja liječenja i četverotjednog razdoblja praćenja.
English: • You can take Rizmoic with or without laxatives.
Croatian: • Rizmoic možete uzimati s laksativima ili bez njih.
English: Interaction with strong P-gp inhibitors
Croatian: Interakcija s jakim inhibitorima P-gp-a
English: In juvenile toxicity studies in rats, at the same dose levels, exposure in juvenile animals (PND 10) was increased compared to adult animals (2.3 to 7.4-fold).
Croatian: U ispitivanjima toksičnosti u mladunčadi štakora, izloženost mladih životinja (PND 10) pri dozama iste razine bila je veća od one u odraslih životinja (2,3 do 7,4 puta).
English: Patients were allowed to receive rescue laxative(s) as needed regardless of being on a stable laxative regimen at baseline (apart from within 24 hours of the start of the Treatment Period).
Croatian: Bolesnici su smjeli primati laksativ(e) za hitno olakšanje tegoba po potrebi, bez obzira na to jesu li bili na stabilnom režimu laksativima na početku ispitivanja (osim tijekom 24 sata od početka razdoblja liječenja).
English: The absolute bioavailability of naldemedine has not been established.
Croatian: Apsolutna bioraspoloživost naldemedina nije ustanovljena.
English: The use of naldemedine during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier.
Croatian: Primjena naldemedina tijekom trudnoće može izazvati ustezanje od opioida u fetusa zbog nezrelosti fetalne krvno-moždane barijere.
English: Based on these data, naldemedine can be taken with or without food (see section 4.2).
Croatian: S obzirom na ove podatke, naldemedin se može uzimati s hranom ili bez nje (vidjeti dio 4.2).
English: The medicine is available in aluminium blisters, containing 7,10 or 14 tablets.
Croatian: Ovaj je lijek dostupan u aluminijskim blisterima koji sadrže 7, 10 ili 14 tableta.
English: Film coating: hypromellose , talc and yellow iron oxide (E172).
Croatian: Film-ovojnica: hipromeloza, talk i žuti željezov oksid (E172).
English: The peak plasma concentration was reduced by 35% and time to achieve peak plasma concentration was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, whereas no significant difference was observed in the area under the plasma concentration-time curve by food intake.
Croatian: Vršna koncentracija u plazmi bila je snižena za 35%, a vrijeme do postizanja vršne koncentracije u plazmi produljeno s 0,75 sati u stanju natašte na 2,5 sati u sitom stanju, dok u površini ispod krivulje plazmatska koncentracija-vrijeme nije bila opažena nikakva značajna razlika kod uzimanja hrane.
English: The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naldemedine was not evaluated.
Croatian: Učinak teškog oštećenja funkcije jetre (Child-Pugh stadij C) na farmakokinetiku naldemedina nije procijenjen.
English: Do not breast-feed during treatment with Rizmoic as it is not known if naldemedine passes into breast milk.
Croatian: Nemojte dojiti tijekom liječenja lijekom Rizmoic jer nije poznato prelazi li naldemedin u majčino mlijeko.
English: There is no experience in patients treated for constipation induced by partial opioid mu-agonists (e.g. buprenorphine).
Croatian: Ne postoji iskustvo u bolesnika liječenih zbog konstipacije izazvane parcijalnim opioidnim agonistima μ-receptora (npr. buprenorfinom).
English: NL-8465 RX Oudehaske
Croatian: NL-8465 RX Oudehaske 8465 RX Oudehaske
English: There is no specific antidote for naldemedine.
Croatian: Ne postoji specifičan antidot za naldemedin.
English: Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids without reversing the central nervous system (CNS)-mediated opioid effects.
Croatian: Naldemedin funkcionira kao antagonist mi-opioidnih receptora s perifernim djelovanjem u tkivima kao što je gastrointestinalni trakt pa tako smanjuje konstipacijske učinke opioida bez poništavanja njihovih opioidnih učinaka posredovanih središnjim živčanim sustavom (SŽS).
English: If any of the above apply to you, or you are not sure, talk to your doctor or pharmacist before taking Rizmoic.
Croatian: Ako se nešto od gore navedenog odnosi na Vas ili niste sigurni, obratite se svom liječniku ili ljekarniku prije nego što uzmete Rizmoic.
English: Patients should be advised to report severe, persistent or worsening symptoms to their physician.
Croatian: Bolesnicima treba savjetovati da svom liječniku prijave jake simptome ili simptome koji su perzistirajući ili se pogoršavaju.