FrancophonIA/ELRC3.0 huggingface dataset:
English: These observations support the conclusion that raloxifene has no intrinsic oestrogen agonist activity in breast tissue.
Croatian: Ta zapažanja idu u prilog zaključku da raloksifen nema intrinzično agonističko djelovanje estrogena u tkivu dojke.
English: When determining the choice of Optruma or other therapies, including oestrogens, for an individual postmenopausal woman, consideration should be given to menopausal symptoms, effects on uterine and breast tissues, and cardiovascular risks and benefits (see section 5.1).
Croatian: Prilikom odluke o izboru Optrume ili drugih terapija, uključujući i estrogensku terapiju, u pojedinih žena u postmenopauzi moraju se uzeti u obzir simptomi menopauze, učinci na tkivo maternice i dojke te srčano-krvožilni rizici i koristi (vidjeti dio 5.1).
English: • If you have liver disease (examples of liver disease include cirrhosis, mild hepatic impairment or cholestatic jaundice).
Croatian: • Ako imate bolest jetre (primjeri bolesti jetre uključuju cirozu, blago oštećenje jetre ili kolestatsku žuticu).
English: In the prevention trials, the percentage of subjects experiencing an increase or decrease in BMD during raloxifene therapy was: for the spine 37 % decreased and 63 % increased; and for the total hip 29 % decreased and 71 % increased.
Croatian: U ispitivanjima prevencije, postotak ispitanika u kojih se povećao ili smanjio BMD tijekom liječenja raloksifenom iznosio je: za kralježnicu 37 % smanjenje i 63 % povećanje te za kuk 29 % smanjenje i 71 % povećanje.
English: In a study comparing Optruma with oestrogen, bone from patients treated with either medicinal product was histologically normal, with no evidence of mineralisation defects, woven bone or marrow fibrosis.
Croatian: U ispitivanju u kojem se uspoređivala Optruma s estrogenom, kosti bolesnica koje su liječene jednim od lijekova bile su histološki uredne, bez dokaza poremećaja mineralizacije, iskrivljenja kostiju ili fibroze srži.
English: Raloxifene levels are maintained by enterohepatic recycling, giving a plasma half-life of 27.7 hours.
Croatian: Razine raloksifena održavaju se pomoću enterohepatičkog kruženja, zbog čega je njegov poluvijek u plazmi 27,7 sati.
English: Frequently co-administered medicinal products included: paracetamol, non-steroidal anti-inflammatory drugs (such as acetylsalicylic acid, ibuprofen, and naproxen), oral antibiotics, H1 antagonists, H2 antagonists, and benzodiazepines.
Croatian: paracetamol, nesteroidne protuupalne lijekove (kao što su acetilsalicilna kiselina, ibuprofen i naproksen), oralne antibiotike, H1-antagoniste, H2-antagoniste i benzodiazepine.
English: Compared to placebo, raloxifene was not associated with spotting or bleeding or endometrial hyperplasia.
Croatian: U usporedbi s placebom raloksifen nije bio povezan s pojavom probojnog ili drugog krvarenja ili hiperplazijom endometrija.
English: Raloxifene decreases resorption of bone; this effect on bone is manifested as reductions in the serum and urine levels of bone turnover markers, decreases in bone resorption based on radiocalcium kinetics studies, increases in BMD and decreases in the incidence of fractures.
Croatian: Raloksifen smanjuje resorpciju kosti; taj učinak na kosti iskazuje se smanjenjem razine biljega koštane pregradnje u serumu i urinu, smanjenjem resorpcije kosti na temelju ispitivanja kinetike radioaktivnoobilježenog kalcija, povećanjem BMD-a i smanjenjem incidencije prijeloma.
English: Raloxifene may cause foetal harm when administered to a pregnant woman.
Croatian: Raloksifen može uzrokovati oštećenje fetusa ako se primijeni kod trudnice.
English: • If you have severe kidney problems.
Croatian: • Ako imate teške probleme s bubrezima.
English: This finding should be considered when prescribing raloxifene for postmenopausal women with a history of stroke or other significant stroke risk factors, such as transient ischemic attack or atrial fibrillation.
Croatian: Taj nalaz treba uzeti u obzir prilikom propisivanja raloksifena ženama u postmenopauzi koje su imale moždani udar ili druge značajne čimbenike rizika za pojavu moždanog udara, kao što su tranzitorna ishemijska ataka ili fibrilacija atrija.
English: In the osteoporosis treatment study, significantly fewer Optruma-treated patients required initiation of hypolipidaemic therapy compared to placebo.
Croatian: U ispitivanju liječenja osteoporoze značajno manji broj bolesnica liječenih Optrumom zahtijevao je uvođenje hipolipemičke terapije u usporedbi sa skupinom koja je primala placebo.
English: • Decrease in the number of the platelets in the blood
Croatian: • smanjenje broja krvnih pločica (trombocita) u krvi
English: In a population pharmacokinetic study, a 47 % decrease in lean body mass adjusted creatinine clearance resulted in a 17 % decrease in raloxifene clearance and a 15 % decrease in the clearance of raloxifene conjugates.
Croatian: U populacijskom ispitivanju farmakokinetike, 47 % smanjenje klirensa kreatinina usklađenog s tjelesnom masom bez masnog tkiva prouzročilo je 17 % smanjenje klirensa raloksifena i 15 % smanjenje klirensa konjugata raloksifena.
English: Safety information following 3 years of raloxifene treatment suggests that raloxifene treatment does not increase pelvic floor relaxation and pelvic floor surgery.
Croatian: Podaci o sigurnosti primjene nakon 3 godine liječenja raloksifenom govore u prilog tome da liječenje raloksifenom ne uzrokuje povećanu relaksaciju dna zdjelice i potrebu za kirurškim zahvatom dna zdjelice.
English: e) Effects on cognitive function
Croatian: Učinci na kognitivne funkcije
English: It is unknown whether raloxifene/raloxifene metabolites are excreted in human milk.
Croatian: Nije poznato izlučuju li se raloksifen/metaboliti relaoksifena u majčino mlijeko.
English: Optruma should not be used in children of any age.
Croatian: Optrumu ne smiju uzimati djeca bilo koje dobi.
English: Raloxifene's biological actions, like those of oestrogen, are mediated through high affinity binding to oestrogen receptors and regulation of gene expression.
Croatian: Biološki učinci raloksifena, poput učinaka estrogena, posredovani su vezanjem velikim afinitetom za estrogenske receptore i regulacijom genske ekspresije.
English: Paediatric population:
Croatian: Pedijatrijska populacija
English: Based on these risk factors, prevention of osteoporosis with Optruma is indicated for women within ten years of menopause, with BMD of the spine between 1.0 and 2.5 SD below the mean value of a normal young population, taking into account their high lifetime risk for osteoporotic fractures.
Croatian: Na temelju navedenih rizičnih čimbenika prevencija osteoporoze Optrumom indicirana je u žena unutar deset godina od nastupa menopauze, s vrijednošću BMD-a kralježnice u rasponu od 1,0 do 2,5 SD ispod srednje vrijednosti zdrave mlade populacije, uzimajući u obzir visoki doživotni rizik od nastanka osteoporotičnih prijeloma.
English: Raloxifene is a potent antioestrogen in the rat uterus and prevented growth of oestrogen-dependent mammary tumours in rats and mice.
Croatian: Raloksifen ima snažno antiestrogensko djelovanje na maternice ženke štakora i sprječava rast estrogen-ovisnih tumora dojke u ženke štakora i miševa.
English: 14 film coated tablets 28 film coated tablets 84 film coated tablets
Croatian: OBLIK I SADRŽAJ 14 filmom obloženih tableta 28 filmom obloženih tableta 84 filmom obloženih tableta
English: c. Description of selected adverse reactions
Croatian: c. Opis odabranih nuspojava
English: Propylene glycol Indigo carmine (E 132)
Croatian: Tinta: šelak propilenglikol indigo karmin (E 132)
English: After 3 years of treatment, at least a 5 mm increase in endometrial thickness, assessed with transvaginal ultrasound, was observed in 1.9 % of the 211 women treated with raloxifene 60 mg/day compared to 1.8 % of the 219 women who received placebo.
Croatian: Nakon 3-godišnjeg liječenja, transvaginalnim ultrazvukom izmjereno je povećanje debljine endometrija od najmanje 5 mm u 1,9 % od 211 žena koje su liječene raloksifenom u dozi od 60 mg/dan u usporedbi s 1,8 % od 219 žena koje su dobivale placebo.
English: Optruma is not effective in reducing vasodilatation (hot flushes), or other symptoms of the menopause associated with oestrogen deficiency.
Croatian: Optruma nije učinkovita u smanjivanju vazodilatacije (navala crvenila uz osjećaj vrućine) niti drugih simptoma menopauze povezanih s manjkom estrogena.
English: In a 21-month carcinogenicity study in mice, there was an increased incidence of testicular interstitial cell tumours and prostatic adenomas and adenocarcinomas in males given 41 or 210 mg/kg, and prostatic leiomyoblastoma in males given 210 mg/kg.
Croatian: U 21-mjesečnom ispitivanju karcinogenosti u miševa postojala je veća incidencija tumora intersticijskih stanica testisa i adenoma i adenokarcinoma prostate u mužjaka koji su dobivali 41 ili 210 mg/kg i leiomioblastoma u mužjaka koji su dobivali 210 mg/kg.
English: A similar frequency of increases was noted among placebo patients.
Croatian: Slična učestalost porasta primijećena je u bolesnica na placebu.
English: Patients with this medical history should have serum triglycerides monitored when taking raloxifene.
Croatian: Bolesnicama s tom anamnezom treba pratiti vrijednosti serumskih triglicerida tijekom uzimanja raloksifena.
English: de la Industria 30, 28108 Alcobendas (Madrid), Spain.
Croatian: Lilly S.A., Avda. de la Industria 30, 28108 Alcobendas (Madrid), Španjolska.
English: The safety of Optruma in patients with breast cancer has not been adequately studied.
Croatian: Sigurnost primjene Optrume u bolesnica s karcinomom dojke nije dovoljno ispitivana.
English: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
Croatian: Nositelj odobrenja za stavljanje lijeka u promet Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, Nizozemska.
English: Other risk factors which may lead to the development of osteoporosis include early menopause; osteopenia (at least 1 SD below peak bone mass); thin body build; Caucasian or Asian ethnic origin; and a family history of osteoporosis.
Croatian: Drugi rizični čimbenici koji mogu izazvati razvoj osteoporoze uključuju ranu menopauzu, osteopeniju (najmanje 1 SD ispod vršne koštane mase), mršavu konstituciju, bjelačku ili azijsku rasnu pripadnost i osteoporozu u obiteljskoj anamnezi.
English: Likewise, Optruma is indicated for the treatment of osteoporosis or established osteoporosis in women with BMD of the spine 2.5 SD below the mean value of a normal young population and/or with vertebral fractures, irrespective of BMD.
Croatian: Također, Optruma je indicirana u liječenju osteoporoze ili utvrđene osteoporoze u žena s vrijednošću BMD kralježnice 2,5 SD ispod srednje vrijednosti zdrave mlade populacije i/ili s prijelomima kralježaka neovisno o BMD-u.
English: During an average follow-up of 5.6 years, 59 (1.2%) raloxifene-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women.
Croatian: Tijekom prosječnog praćenja od 5,6 godina 59 (1,2%) žena liječenih raloksifenom umrlo je uslijed moždanog udara u usporedbi s 39 (0,8%) žena koje su primale placebo.
English: In postmenopausal women with osteoporosis, Optruma reduces the incidence of vertebral fractures, preserves bone mass and increases bone mineral density (BMD).
Croatian: U žena u postmenopauzi koje boluju od osteoporoze Optruma smanjuje incidenciju prijeloma kralježaka, čuva koštanu masu i povećava mineralnu gustoću kostiju (BMD, bone mineral density).
English: • If you are allergic (hypersensitive) to raloxifene or any of the other ingredients of this medicine
Croatian: • Ako ste alergični (preosjetljivi) na raloksifen ili neki drugi sastojak ovog lijeka (naveden u dijelu 6).
English: However, since the overall extent of absorption and the elimination rate of raloxifene are not affected, raloxifene can be concurrently administered with ampicillin.
Croatian: Međutim, kako ukupni opseg apsorpcije i brzina eliminacije raloksifena ostaju nepromijenjeni, raloksifen se može istodobno primjenjivati s ampicilinom.
English: Must not be used in women with child bearing potential (see section 4.6).
Croatian: Ne smiju je uzimati žene u generativnoj dobi (vidjeti dio 4.6).
English: c) Effects on the endometrium and on the pelvic floor
Croatian: c) Učinci na endometrij i dno zdjelice
English: Optruma is only for use in postmenopausal women.
Croatian: Optruma je namijenjena samo za primjenu kod žena u postmenopauzi.
English: Therefore Optruma is not recommended to be used in patients with hepatic insufficiency.
Croatian: Stoga se primjena Optrume ne preporučuje u bolesnika s insuficijencijom jetre.
English: Its clinical use, therefore, cannot be recommended in breastfeeding women.
Croatian: Njegova se klinička primjena stoga ne može preporučiti dojiljama.
English: Raloxifene should not be co-administered with cholestyramine (or other anion exchange resins), which significantly reduces the absorption and enterohepatic cycling of raloxifene.
Croatian: Raloksifen se ne smije istodobno primjenjivati s kolestiraminom (ili s drugim anion izmjenjivačkim smolama), koji značajno smanjuje apsorpciju i enetrohepatično kruženje raloksifena.
English: Optruma has no effect on the risk of ER negative breast cancers.
Croatian: Optruma nema učinak na rizik od karcinoma dojke negativnog na ER.
English: Optruma contains lactose
Croatian: Optruma sadrži laktozu
English: The incidence of breast symptoms and uterine bleeding in raloxifene treated women was significantly lower than in women treated with either form of HRT.
Croatian: Incidencija simptoma što se tiče dojke i krvarenja iz maternice bila je značajno niža u skupini žena liječenih raloksifenom u usporedbi sa ženama liječenih bilo kojom vrstom HNT-e.
English: In vitro, raloxifene did not interact with the binding of warfarin, phenytoin, or tamoxifen.
Croatian: In vitro raloksifen ne pokazuje interakcije s vezanjem varfarina, fenitoina ili tamoksifena.
English: Optruma contains lactose.
Croatian: Optruma sadrži laktozu.
English: Optruma produced significant increases in bone density of hip and spine as well as total body mineral mass compared to placebo.
Croatian: Optruma je značajno povećala gustoću kosti kuka i kralježnice te cjelokupnu mineralnu masu tijela u usporedbi s placebo skupinom.
English: In female mice, an increased incidence of ovarian tumours in animals given 9 to 242 mg/kg (0.3 to 32 times the AUC in humans) included benign and malignant tumours of granulosa/theca cell origin and benign tumours of epithelial cell origin.
Croatian: Kod mišjih ženki povećana je incidencija tumora ovarija u životinja koje su dobivale od 9 do 242 mg/kg (0,3 do 32 puta AUC-a kod ljudi), uključujući benigne i maligne tumore ovarija porijeklom iz granuloznih i teka stanica i benigne tumore porijeklom iz epitelnih stanica.
English: Hepatic insufficiency - The pharmacokinetics of a single dose of raloxifene in patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) have been compared to that in healthy individuals.
Croatian: Hepatalna insuficijencija - farmakokinetika jednokratne doze raloksifena u bolesnica s cirozom i blagim oštećenjem jetre (stadij A prema Child-Pughu) uspoređena je sa zdravim pojedincima.
English: Raloxifene does not affect the steady-state AUC of digoxin.
Croatian: Raloksifen ne utječe na stanje dinamičke ravnoteže AUC-a digoksina.
English: Co-administration of raloxifene and warfarin does not alter the pharmacokinetics of either compound.
Croatian: Istodobna primjena raloksifena i varfarina ne mijenja farmakokinetičke osobine tih spojeva.
English: A significant reduction in the incidence of vertebral, but not hip fractures has been demonstrated.
Croatian: Dokazano je da značajno smanjuje incidenciju prijeloma kralježaka, ali ne i kuka.
English: There was no difference between Optruma and placebo treated women in the incidences of vaginal bleeding (spotting) or vaginal discharge.
Croatian: Nije postojala razlika između žena koje su liječene Optrumom u usporedbi s placebom u incidenciji vaginalnog krvarenja (probojnog krvarenja) ili vaginalnog iscjetka.
English: Raloxifene has no effect on the pharmacokinetics of methylprednisolone given as a single dose.
Croatian: Raloksifen ne utječe na farmakokinetiku metilprednizolona koji je jednokratno primjenjen.
English: Optruma lowers total cholesterol and LDL ("bad") cholesterol.
Croatian: Optruma snižava razinu ukupnog kolesterola i LDL („lošeg“) kolesterola.
English: i) Incidence of fractures.
Croatian: i) Incidencija prijeloma.
English: In the RUTH study, raloxifene did not affect the incidence of stroke, compared to placebo.
Croatian: U ispitivanju RUTH raloksifen nije utjecao na incidenciju moždanog udara u usporedbi s placebom.
English: Raloxifene undergoes extensive first pass metabolism to the glucuronide conjugates: raloxifene-4'glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4′-diglucuronide.
Croatian: Raloksifen je podvrgnut opsežnom metabolizmu prvog prolaza koji se odvija u jetri do glukuronidnih konjugata: raloksifen-4'-glukuronid, raloksifen-6-glukuronid i raloksifen-6,4'-diglukuronid.
English: • If you are receiving oral oestrogen therapy.
Croatian: • Ako primate estrogensku terapiju kroz usta.
English: Results from single oral doses of raloxifene predict multiple dose pharmacokinetics.
Croatian: Rezultati nakon jednokratnih peroralnih doza raloksifena predviđaju farmakokinetiku višekratne primjene.
English: Flu syndrome was reported by 16.2 % of Optruma treated patients and 14.0 % of placebo treated patients.
Croatian: Sindrom nalik gripi prijavljen je u 16,2 % bolesnica koje su liječene Optrumom i u 14,0 % bolesnica koje su dobivale placebo.
English: How to take Optruma
Croatian: Kako uzimati Optrumu
English: The decrease in oestrogen availability which occurs at menopause, leads to marked increases in bone resorption, bone loss and risk of fracture.
Croatian: Smanjenje raspoloživosti estrogena koje se javlja nakon menopauze dovodi do znatnog povećanja resorpcije kosti, gubitka kosti i rizika od nastanka prijeloma.
English: Talk to your doctor or pharmacist before you take Optruma.
Croatian: Upozorenja i mjere opreza Obratite se svom liječniku ili ljekarniku prije nego uzimete Optrumu.
English: Ink:
Croatian: SN:
English: In the RUTH study, venous thromboembolic events occurred at a frequency of approximately 2.0 % or 3.88 cases per 1,000 patient-years in the raloxifene group and 1.4 % or 2.70 cases per 1,000 patient-years in the placebo group.
Croatian: U ispitivanju RUTH venski tromboembolijski događaji javili su se s učestalošću od približno 2,0 % ili 3,88 slučajeva na 1000 bolesnika-godina u skupini koja je liječena raloksifenom i 1,4 % ili 2,70 slučajeva na 1000 bolesnika-godina u skupini koja je dobivala placebo.
English: In rabbits, abortion and a low rate of ventricular septal defects (≥ 0.1 mg/kg) and hydrocephaly (≥ 10 mg/kg) were seen.
Croatian: U kunića su opaženi pobačaji te mali postotak defekata ventrikularnog septuma (≥ 0,1 mg/kg) i hidrocefalija (≥ 10 mg/kg).
English: In the RUTH study, peripheral oedema occurred in 14.1 % of the raloxifene-treated patients and 11.7 % of the placebo-treated patients, which was statistically significant.
Croatian: U ispitivanju RUTH periferni edem pojavio se u 14,1 % bolesnica koje su liječene raloksifenom i 11,7 % bolesnica koje su dobivale placebo, što je bilo statistički značajno.
English: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Croatian: nedostatkom Lapp laktaze ili glukoza-galaktoza malapsorpcijom ne bi trebale uzimati ovaj lijek.
English: Compared with placebo-treated patients the occurrence of vasodilatation (hot flushes) was modestly increased in Optruma patients (clinical trials for the prevention of osteoporosis, 2 to 8 years postmenopausal, 24.3 % Optruma and 18.2 % placebo; clinical trials for the treatment of osteoporosis, mean age 66, 10.6 % for Optruma and 7.1 % placebo).
Croatian: Pojava vazodilatacije (navala crvenila uz osjećaj vrućine) umjereno je povećana u bolesnica koje su uzimale Optrumu u usporedbi s bolesnicama koje su uzimale placebo (klinička ispitivanja u prevenciji osteoporoze, 2 do 8 godina postmenopauzalno, 24,3 % Optruma i 18,2 % placebo; klinička ispitivanja u liječenju osteoporoze, srednja dob 66 godina, 10,6 % za Optrumu i 7,1 % placebo).
English: Raloxifene is absorbed rapidly after oral administration.
Croatian: Raloksifen se apsorbira brzo nakon peroralne primjene.
English: Hepatic impairment including cholestasis.
Croatian: Oštećenje jetre, uključujući kolestazu.
English: In postmenopausal women who received raloxifene treatment for 4 years, benign endometrial polyps were reported in 0.9 % compared to 0.3 % in women who received placebo treatment.
Croatian: U žena u postmenopauzi koje su liječene raloksifenom tijekom 4 godine benigni polipi endometrija javili su se u 0,9 % u usporedbi s 0,3 % žena koje su uzimale placebo.
English: How Optruma works
Croatian: Kako Optruma djeluje
English: If you wish you may take a glass of water with it. Do not break or crush the tablet before taking it. A broken or crushed tablet may taste bad and there is a possibility that you will receive an incorrect dose.
Croatian: Prelomljena ili zdrobljena tableta može imati neugodan okus i postoji mogućnost da ćete dobiti pogrešnu dozu.
English: Do not use after the expiry date which is stated on the pack after EXP.
Croatian: Ovaj lijek se ne smije upotrijebiti nakon isteka roka valjanosti navedenog na pakiranju iza oznake „Rok valjanosti“ ili „EXP“.
English: The most common side effects (affects more than 1 user in 10) are:
Croatian: Najčešće nuspojave (javljaju se u više od 1 na 10 korisnika):
English: Across all placebo-controlled trials, Optruma was indistinguishable from placebo with regard to frequency and severity of breast symptoms (no swelling, tenderness and breast pain).
Croatian: U svim placebom kontroliranim ispitivanjima nije se mogla uočiti razlika između Optrume i placeba u učestalosti pojave i težini simptoma dojke (bez edema, osjetljivosti i bolnih dojki).
English: Tablet coating: Titanium dioxide (E 171), polysorbate 80, hypromellose, macrogol 400, carnauba wax.
Croatian: Ovojnica tablete: titanijev dioksid (E171), polisorbat 80, hipromeloza, makrogol 400, karnauba vosak.
English: It is important that you continue taking Optruma for as long as your doctor prescribes the medicine, Optruma can treat or prevent your osteoporosis only if you continue to take the tablets.
Croatian: Optruma može liječiti Vašu osteoporozu ili ju spriječiti samo ako nastavite uzimati tablete.
English: Ink: Shellac, propylene glycol, indigo carmine (E 132).
Croatian: Tinta: šelak, propilenglikol, indigo karmin (E132).
English: Serum total bilirubin, gamma-glutamyl transferase, alkaline phosphatase, ALT and AST should be closely monitored during treatment if elevated values are observed.
Croatian: Tijekom terapije treba pažljivo pratiti vrijednosti serumskih koncentracija ukupnog bilirubina, gama glutamil transferaze, alkalne fosfataze, ALT i AST ako se uoče povišene vrijednosti.
English: During the whole length of the study concomitant use of other bone-active medications was permitted.
Croatian: Tijekom trajanja ispitivanja bilo je dopušteno istodobno uzimanje drugih lijekova koji djeluju na koštano tkivo.
English: Unexplained uterine bleeding.
Croatian: Neobjašnjivo krvarenje iz maternice.
English: The incidence of stroke mortality was 2.2 per 1000 women per year for raloxifene versus 1.5 per 1000 women per year for placebo (see section 4.8).
Croatian: Incidencija smrtnosti od moždanog udara bila je 2,2 od 1000 žena godišnje za raloksifen prema 1,5 od 1000 žena godišnje za placebo (vidjeti dio 4.8.).