qanastek/EMEA-V3 huggingface dataset:
3 Liver disorders During the phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (3.5%).
Disturbi fil- fwied Waqt studji kliniċi ta ’ fażi 3, kienu osservati anormalitajiet ħfief fit- test tal- funzjoni tal- fwied f’ pazjenti kkurati b’ febuxostat (3. 5%).
Liver function test is recommended prior to the initiation of therapy with febuxostat and periodically thereafter based on clinical judgement (see section 5.1).
Huwa rrakkomandat test tal- funzjoni tal- fwied qabel il- bidu tat - terapija b’ febuxostat u minn hemm ’ il quddiem kull tant żmien, ibbażat fuq ġudizzju kliniku (ara sezzjoni 5. 1).
Thyroid disorders Increased TSH values (> 5.5 µIU/ ml) were observed in patients on long-term treatment with febuxostat (5.0%) in the long term open label extension studies.
Disturbi fit- tirojde Fl- istudji ta ’ estensjoni, open label u fit- tul, kienet osservata żjieda fil- valuri ta ’ TSH (> 5. 5 µIU/ ml) f’ pazjenti fuq kura fit- tul b’ febuxostat (5. 0%).
Caution is required when febuxostat is used in patients with alteration of thyroid function (see section 5.1).
Attenzjoni hija meħtieġa meta febuxostat huwa wżat f’ pazjenti b’ bidla fil- funzjoni tat- tirojde (ara sezzjoni 5. 1).
Lactose Febuxostat tablets contain lactose.
3 Lactose Pilloli febuxostat fihom lactose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactase malabsorption should not take this medicine.
Pazjenti bi problemi ereditarji rari ta ’ intolleranza għal galactose, defiċjenza Lapp lactase, jew assorbiment ħażin ta ’ glucose- galactase, m’ għandhomx jieħdu din il - mediċina.
Mercaptopurine/ azathioprine Although interaction studies with febuxostat have not been performed, inhibition of xanthine oxidase (XO) is known to result in an increase in mercaptopurine or azathioprine levels.
Mercaptopurine/ azathioprine Għalkemm ma sarux studji ta ’ interazzjoni b’ febuxostat, inibizzjoni ta ’ xanthine oxidase (XO) hija magħrufa li twassal għal żjieda fil- livelli ta ’ mercaptopurine jew azathioprine.
On the basis of the mechanism of action of febuxostat on XO inhibition concomitant use is not recommended.
Fuq il- bażi tal - mekkaniżmu ta ’ azzjoni ta ’ febuxostat fuq l- inibizzjoni ta ’ XO, l- użu fl- istess waqt mhux irrakkomandat.
Drug interaction studies of febuxostat with cytotoxic chemotherapy have not been conducted.
Ma sarux studji ta ’ interazzjoni tal- mediċini dwar febuxostat ma ’ kimoterapija ċitotossika.
No data is available regarding the safety of febuxostat during cytotoxic therapy.
Mhux disponibbli tagħrif dwar is- sigurtà ta ’ febuxostat waqt terapija ċitotossika.
Theophylline Although interaction studies have not been performed with febuxostat, inhibition of XO may cause an increase in the theophylline level (inhibition of the metabolism of theophylline has been reported with other XO inhibitors).
Theophylline Għalkemm ma sarux studji ta ’ interazzjoni b’ febuxostat, inibizzjoni ta ’ XO tista ’ tikkawża żjieda fil - livell ta ’ theophylline (kienet irrapportata inibizzjoni tal- metaboliżmu ta ’ theophylline b’ inibituri ta ’ XO oħra).
Hence caution is advised if these active substances are given concomitantly, and theophylline levels should be monitored in patients starting febuxostat therapy.
Għalhekk attenzjoni hija rrakkomandata jekk dawn is- sustanzi attivi jingħataw fl- istess waqt, u l- livelli ta ’ theophylline għandhom jiġu sorveljati f’ pazjenti li bdew terapija b’ febuxostat.
Naproxen and other inhibitors of glucuronidation Febuxostat metabolism depends on UGT enzymes.
Naproxen u inibituri oħra tal- glukuronidazzjoni Il- metaboliżmu ta ’ febuxostat jiddependi fuq l- enżimi UGT.
Medicinal products that inhibit glucuronidation, such as NSAIDs and probenecid, could in theory affect the elimination of febuxostat.
Prodotti mediċinali li jinibixxu l - glukuronidazzjoni, bħal NSAIDs u probenecid, teoretikament jistgħu jaffettwaw l- eliminazzjoni ta ’ febuxostat.
In healthy subjects concomitant use of febuxostat and naproxen 250mg BID was associated with an increase in febuxostat exposure (Cmax 28%, AUC 41% and t1/ 2 26%).
F’ individwi b’ saħħithom l- użu fl- istess waqt ta ’ febuxostat u naproxen 250mg BID kien assoċjat ma ’ żjieda fl- esponiment ta ’ febuxostat (Cmax 28%, AUC 41% u t1/ 2 26%).
In clinical studies the use of naproxen or other NSAIDs/ Cox-2 inhibitors was not related to any clinically significant increase in adverse events.
Fi studji kliniċi l - użu ta ’ naproxen jew NSAIDs/ inibituri Cox- 2 oħra ma kien relatat ma ’ l- ebda żjieda ta ’ sinifikanza klinika fl- avvenimenti avversi.
Febuxostat can be co-administered with naproxen with no dose adjustment of febuxostat or naproxen being necessary.
Febuxostat jista ’ jingħata flimkien ma ’ naproxen bl- ebda ħtieġa ta ’ aġġustament fid- doża ta ’ febuxostat jew naproxen.
Inducers of glucuronidation Potent inducers of UGT enzymes might possibly lead to increased metabolism and decreased efficacy of febuxostat.
Indutturi tal- glukuronidazzjoni Hemm possibiltà li ndutturi qawwija ta ’ l- enżimi UGT iwasslu għal żjieda fil- metaboliżmu u tnaqqis fl- effikaċja ta ’ febuxostat.
Monitoring of serum uric acid is therefore recommended 1-2 weeks after start of treatment with a potent inducer of glucuronidation.
Għalhekk sorveljanza tal- uric acid fis- serum hija rrakkomandata ġimgħa sa ġimagħtejn wara l- bidu tal- kura b’ induttur qawwi tal- glukuronidazzjoni.
Conversely, cessation of treatment of an inducer might lead to increased plasma levels of febuxostat.
Bil- maqlub, waqfien tal- kura b’ induttur tista ’ twassal għal żjieda fil- livelli ta ’ febuxostat fil- plażma.
4 Colchicine/ indometacin/ hydrochlorothiazide/ warfarin Febuxostat can be co-administered with colchicine or indomethacin with no dose adjustment of febuxostat or the co-administered active substance being necessary.
Colchicine/ indometacin/ hydrochlorothiazide/ warfarin Febuxostat jista ’ jingħata flimkien ma ’ colchicine jew indomethacin bl’ ebda ħtieġa ta ’ aġġustament fid- doża ta ’ febuxostat jew tas- sustanza attiva li qed tingħata fl- istess waqt.
No dose adjustment is necessary for febuxostat when administered with hydrochlorothiazide.
L- ebda aġġustament fid- doża ta ’ febuxostat ma hija neċessarja meta jingħata ma ’ hydrochlorothiazide.
No dose adjustment is necessary for warfarin when administered with febuxostat.
L- ebda aġġustament fid- doża ta ’ warfarin ma hija neċessarja meta jingħata ma ’ febuxostat.
After initiation of febuxostat therapy, monitoring of anticoagulant activity should be considered in patients receiving warfarin or similar agents.
Wara l - bidu ta ’ terapija b’ febuxostat, għandha tiġi kkunsidrata sorveljanza ta ’ l- attività antikoagulanti f’ pazjenti li qed jirċievu warfarin jew sustanzi simili.
Desipramine/ CYP2D6 substrates.
Desipramine/ substrati ta ’ CYP2D6.
Febuxostat was shown to be a weak inhibitor of CYP2D6 in vitro.
Intwera li febuxostat huwa inibitur dgħajjef ta ’ CYP2D6 in vitro.
In a study in healthy subjects, 120 mg ADENURIC QD resulted in a mean 22% increase in AUC of desipramine, a CYP2D6 substrate indicating a potential weak inhibitory effect of febuxostat on the CYP2D6 enzyme in vivo.
Fi studju f’ individwi b’ saħħithom, 120 mg ADENURIC QD wassal għal żjieda medja ta ’ 22% fl- AUC ta ’ desipramine, substrat ta ’ CYP2D6 u dan jindika l- potenzjal ta ’ effett inibitorju dgħajjef ta ’ febuxostat fuq l- enżima CYP2D6 in vivo.
Thus, co-administration of febuxostat with other CYP2D6 substrates is not expected to require any dose adjustment for those compounds.
Għalhekk, l- għoti ta ’ febuxostat flimkien ma ’ substrati oħra ta ’ CYP2D6 mhux mistenni li jeħtieġ l- ebda aġġustament fid- doża għal dawn is- sustanzi.
Antacids Concomitant ingestion of an antacid containing magnesium hydroxide and aluminium hydroxide has been shown to delay absorption of febuxostat (approximately 1 hour) and to cause a 32% decrease in Cmax, but no significant change in AUC was observed.
4 Antaċidi It- teħid mill- ħalq fl- istess waqt ta ’ antaċidu li fih magnesium hydroxide u aluminium hydroxide intwera li jittardja l- assorbiment ta ’ febuxostat (madwar siegħa) u li jikkawża tnaqqis ta ’ 32% fis- Cmax, iżda ma kien osservat l- ebda tibdil sinifikanti fl- AUC.
Therefore, febuxostat may be taken without regard to antacid use.
Għalhekk, febuxostat jista ’ jittieħed mingħajr każ ta ’ l- użu ta ’ antaċidi.
Pregnancy Data on a very limited number of exposed pregnancies have not indicated any adverse effects of febuxostat on pregnancy or on the health of the foetus/ new born child.
Tqala Tagħrif minn numru limitat ħafna ta ’ użu waqt it- tqala juri li m’ hemm l- ebda effetti mhux mixtieqa ta ’ febuxostat fuq it- tqala jew fuq is- saħħa tal- fetu/ tarbija tat- twelid.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/ foetal development or parturition (see section 5.3).
Studji fuq il- bhejjem ma jurux effetti ħżiena diretti jew indiretti fuq it- tqala, fuq l- iżvilupp ta ’ l- embriju/ fetu, ħlas jew żvilupp wara t- twelid (ara sezzjoni 5. 3).
The potential risk for human is unknown.
Mhux magħruf ir- riskju potenzjali fuq in- nies.
Febuxostat should not be used during pregnancy.
Febuxostat m’ għandux jintuża waqt it- tqala.
Breast feeding It is unknown whether febuxostat is excreted in human breast milk.
Treddigħ Mhux magħruf jekk febuxostat jitneħħiex fil- ħalib tas- sider tal- bniedem.
Animal studies have shown excretion of this active substance in breast milk and an impaired development of suckling pups.
Studji fuq il- bhejjem urew tneħħija ta ’ din is- sustanza attiva fil- ħalib tas- sider u żvilupp imnaqqas tal- frieħ li qed jerdgħu.
A risk to a suckling infant cannot be excluded.
Riskju għal tarbija li qed titreddgħa ma jistax jiġi eskluż.
Febuxostat should not be used while breast-feeding.
Febuxostat m’ għandux jintuża waqt it- treddigħ.
As with other xanthine oxidase inhibitors adverse reactions such as somnolence, dizziness and paraesthesia have been reported.
Bħal b’ inibituri oħra ta ’ xanthine oxidase, ġew irrapportati reazzjonijiet avversi bħal ngħas, sturdament u parasteżija.
Patients should exercise caution before driving, using machinery or participating in dangerous activities until they are reasonably certain that ADENURIC does not adversely affect performance.
Pazjenti għandhom joqgħodu attenti qabel isuqu, iħaddmu magni jew jipparteċipaw f’ attivitajiet perikolużi sakemm ikunu ċerti biżżejjed li ADENURIC m’ għandux effett avvers fuq il- ħila.
A total of 2531 subjects received at least one dose of ADENURIC (10 mg – 300 mg) in clinical studies.
Total ta ’ 2531 individwu rċievew ta ’ l- inqas doża waħda ta ’ ADENURIC (10 mg – 300 mg) fl- istudji kliniċi.
Phase 3 randomised controlled studies 5 In randomised controlled phase 3 clinical studies, > ,1000 patients have been treated with the recommended doses of 80 mg or 120 mg (536 subjects enrolled in a 28 week study and 507 subjects enrolled in a 52 weeks study).
Studji randomised u kkontrollati ta ’ fażi 3 Fi studji kliniċi randomised u kkontrollati ta ’ fażi 3, > 1000 pazjent ġew kkurati bid- dożi rrakkomandati ta ’ 80 mg jew 120 mg (536 individwu daħlu fi studju ta ’ 28 ġimgħa u 507 individwu daħlu fi studju ta ’ 52 ġimgħa).
The treatment-related events (ADRs) were mostly mild or moderate in severity.
L- avvenimenti relatati mal- kura (ADRs) kienu fil- biċċa l- kbira ħfief jew moderati fis- severità.
The most commonly reported ADRs (investigator assessment) are liver function abnormalities (3.5%), diarrhoea (2.7%), headache (1.8%), nausea (1.7%), rash (1.5%).
L- aktar ADRs rrapportati b’ mod komuni (valutazzjoni ta ’ l- investigatur) huma anormalitajiet fil - funzjoni tal- fwied (3. 5%), dijarea (2. 7%), uġigħ ta ’ ras (1. 8%), tqalligħ (1. 7%), raxx (1. 5%).
A numerically greater incidence of investigator-reported cardiovascular events was observed in the febuxostat total group compared to the allopurinol group in the pivotal Phase III (1.3 vs 0.3 events per 100 PYs) and long-term extension studies (1.4 vs 0.7 events per 100 PYs), although no statistically significant differences were found and no causal relationship with febuxostat was established.
Kienet osservata inċidenza numerikament akbar ta ’ avvenimenti kardjovaskulari rrapportati mill - investigaturi fil- grupp totali ta ’ febuxostat meta mqabbel mal- grupp ta ’ allopurinol fl- istudji pivotali ta ’ Fażi III (1. 3 vs 0. 3 avvenimenti kull 100 PYs) u fl- istudji ta ’ estensjoni fit- tul (1. 4 vs 0. 7 avvenimenti kull 100 PYs), għalkemm ma nstabet l- ebda differenza statistikament sinifikanti u ma kienet stabbilita l- ebda relazzjoni kawżali b’ febuxostat.
Identified risk factors among these patients were a medical history of atherosclerotic disease and/ or myocardial infarction, or of congestive heart failure.
Fatturi ta ’ riskju identifikanti fost dawn il - pazjenti kienu passat mediku ta ’ mard aterosklerotiku u/ jew infart mijokardijaku, jew ta ’ insuffiċjenza tal- qalb konġestiva.
Common (≥ 1/ 100 to < 1/ 10), uncommon (≥ 1/ 1,000 to < 1/ 100) and rare (≥ 1/ 10,000 to < 1/ 1000) adverse reactions suspected (investigator assessment) to be drug related occurring in the 80 mg/ 120 mg treatment groups and reported more than once in the total febuxostat treatment group are listed below.
Reazzjonijiet avversi komuni (≥ 1/ 100 sa < 1/ 10), mhux komuni (≥ 1/ 1, 000 sa < 1/ 100) u rari (≥ 1/ 10, 000 sa < 1/ 1000) issuspettati (valutazzjoni ta ’ l- investigatur) li huma relatati mal- mediċina li seħħew fil- gruppi ta ’ kura ta ’ 80 mg/ 120 mg u li kienu rrapportati aktar minn darba waħda fil- grupp totali ta ’ kura b’ febuxostat huma mniżżla hawn taħt.
6 Table 1:
5 Tabella 1:
Treatment related adverse reactions in phase 3 randomized controlled studies Investigations
Reazzjonijiet avversi relatati mal- kura fi studji randomised u kkontrollati ta ’ Fazi 3 Investigazzjonijiet
Uncommon Blood amylase increase, platelet count decrease, blood creatinine increase, haemoglobin decrease, blood urea increase, LDH increase, triglycerides increase
Mhux komuni Żjieda ta ’ amylase fid- demm, tnaqqis fl- għadd ta ’ plejtlets, żjieda tal- krejatinina fid- demm, tnaqqis fl- emoglobina, żjieda tal- urea fid- demm, żjieda fl- LDH, żjieda fit- trigliserajds
Rare Palpitations
Rari Palpitazzjonijiet
Common Headache Uncommon Dizziness, paraesthesia, somnolence, altered taste
Komuni Uġigħ ta ’ ras Mhux komuni Sturdament, parasteżija, ngħas, bidla fit- togħma
Abdominal pain, gastro-oesophageal reflux disease, vomiting*, dry mouth, dyspepsia, constipation, frequent stools, flatulence, gastrointestinal discomfort,
Komuni Dijarea *, tqalligħ * Mhux komuni Uġigħ addominali, marda ta ’ rifluss gastro- esofagali, rimettar *, ħalq xott, dispepsja, stitikezza, purgar ta ’ spiss, gass, skomdu gastro- intestinali
Uncommon Nephrolithiasis, haematuria, pollakiuria Rare Renal insufficiency
Mhux komuni Nefrolitajasi, ematurja, pollakurja Rare Insuffiċjenza renali
Common Rash** Uncommon Dermatitis, urticaria, pruritus
Komuni Raxx ** Mhux komuni Dermatite, urtikarja, ħakk
Uncommon Arthralgia, arthritis, myalgia, muscle cramp, musculoskeletal pain
Mhux komuni Artralġja, artrite, mijalġja, bugħawwieġ, uġigħ muskolu- skeltrali
Metabolism and nutrition disorders Vascular disorders
Disturbi fil- metaboliżmu u n - nutrizzjoni Disturbi vaskulari
Uncommon Weight increase, increased appetite Uncommon Hypertension, flushing, hot flush,
Mhux komuni Żjieda fil- piż, żjieda fl- aptit Mhux komuni Pressjoni għolja, ħmura fil- wiċċ, fwawar ta ’ sħana
Uncommon Fatigue, oedema, influenza like symptoms Rare Asthenia, thirst
Mhux komuni
Hepato-biliary disorders
kondizzjonijiet ta 'mnejn jingħata Għeja, edima, sintomi bħal ta ’ l- influwenza Rari Astenja, għatx Disturbi fil- fwied u fil- marrara
Common LFT abnormalities
Komuni Anormalitajiet fl- LFT
Uncommon Libido decreased Rare Nervousness, Insomnia
Mhux komuni Tnaqqis fil- libido Rari Nervi, nuqqas ta ’ rqad
7 * Diarrhoea, nausea and vomiting are more frequent in patients concomitantly treated with colchicine ** No serious rashes or severe hypersensitivity reactions were noted in the clinical studies.
* Dijarea, tqalligħ u rimettar huma aktar frekwenti f’ pazjenti kkurati fl- istess waqt b’ colchicine ** Ma kienu nnutati l- ebda raxx serju jew reazzjonijiet severi ta ’ sensittività eċċessiva fl- istudji kliniċi.
Long-term open label extension studies In the long-term open label extension studies, the number of patients treated with febuxostat 80 mg/ 120 mg up to 1 year was 906, up to 2 years was 322, up to 3 years was 57, and up 4 years was 53.
Studji ta ’ estensjoni, open label u fit- tul Fl- istudji ta ’ estensjoni, open label u fit- tul, in- numru ta ’ pazjenti kkurati b’ febuxostat 80 mg/ 120 mg sa sena kien 906, sa sentejn kien 322, sa 3 snin kien 57, u sa 4 snin kien 53.
The treatment-related events reported during the long-term extension studies were similar to those reported in the Phase 3 studies (see Table 1).
L- avvenimenti relatati mal- kura rrapportati waqt l- istudji ta ’ estensjoni fit- tul kienu simili għal dawk irrapportati fl- istudji ta ’ Fażi 3 (ara Tabella 1).
The most commonly reported treatment-related events (investigator assessment) are: liver function abnormalities, diarrhoea, headache, rash, hypertension.
L- aktar avvenimenti relatati mal- kura rrapportati b’ mod komuni (valutazzjoni ta ’ l- investigatur) huma: anormalitajiet fil- funzjoni tal- fwied, dijarea, uġigħ ta ’ ras, raxx, pressjoni għolja.
The following treatment-related events were reported more than once in the total febuxostat treatment group and were reported as uncommon in subjects taking febuxostat 80 mg/ 120 mg in long-term extension studies (up to 4 years, > 1,900 Patient-years of exposure).
L- avvenimenti relatati mal- kura li ġejjin kienu irrapportati aktar minn darba waħda fil- grupp totali ta ’ kura b’ febuxostat u kienu rraportati bħala mhux komuni f’ individwi li kienu qed jieħdu febuxostat 80 mg/ 120 mg fl- istudji ta ’ estensjoni fit- tul (sa 4 snin, > 1, 900 snin tal- pazjent ta ’ esponiment).
These treatment-related events were either not reported or reported at a lower frequency for these doses, in the pivotal Phase 3 studies:
Dawn 6 l- avvenimenti relatati mal- kura ma kienux irrapportati jew irrapportati bi frekwenza aktar baxxa għal dawn id- dożi, fl- istudji pivotali ta ’ Fażi 3:
Diabetes, hyperlipidaemia, insomnia, hypoaesthesia, ECG abnormal, cough, dyspnoea, skin discolouration, skin lesion, bursitis, proteinuria, renal insufficiency, erectile dysfunction, blood potassium increase, blood TSH increase, lymphocyte count decreased, WBC decrease.
Dijabete, iperlipidimja, nuqqas ta ’ rqad, ipoesteżija, ECG mhux normali, sogħla, qtugħ ta ’ nifs, il- ġilda titlef il- kulur, feriti fil- ġilda, borżite, proteina fl- awrina, insuffiċjenza tal- kliewi, disfunzjoni erettili, żjieda tal- potassium fid- demm, żjieda ta ’ TSH fid- demm, tnaqqis ta ’ l- għadd ta ’ limfoċiti, tnaqqis ta ’ WBC.
Patients with an overdose should be managed by symptomatic and supportive care.
Pazjenti b’ doża eċċessiva għandhom jiġu mmaniġġjati b’ kura sintomatika u ta ’ support.
Preparations inhibiting uric acid production, ATC code:
Preparazzjonijiet li jinibixxu l- produzzjoni ta ’ uric acid, Kodiċi ATC:
Mechanism of action Uric acid is the end product of purine metabolism in humans and is generated in the cascade of hypoxanthine → xanthine → uric acid.
Mekkaniżmu ta ’ azzjoni Uric acid huwa l- prodott finali tal- metaboliżmu ta ’ purine fil- bnedmin u huwa ġenerat fil- kaskata ta ’ hypoxanthine → xanthine → uric acid.
Both steps in the above transformations are catalyzed by xanthine oxidase (XO).
Iż- żewġ passi fit- trasformazzjonijiet ta ’ hawn fuq huma katalizzati minn xanthine oxidase (XO).
Febuxostat is a 2-arylthiazole derivative that achieves its therapeutic effect of decreasing serum uric acid by selectively inhibiting XO.
Febuxostat huwa derivattiv ta ’ 2- arylthiazole li jilħaq l- effett terapewtiku tiegħu li jnaqqas il- uric acid fis- serum billi jinibixxi b’ mod selettiv lil XO.
Febuxostat is a potent, non-purine selective inhibitor of XO (NP-SIXO) with an in vitro inhibition Ki value less than one nanomolar.
Febuxostat huwa inibitur qawwi, mhux purine u selettiv ta ’ XO (NP- SIXO) b’ valur Ki ta ’ inibizzjoni in vitro inqas minn nanomolar wieħed.
Febuxostat has been shown to potently inhibit both the oxidized and reduced forms of XO.
Febuxostat intwera li jinibixxi b’ mod qawwi kemm il- forma ossidata kif ukoll dik ridotta ta ’ XO.
At therapeutic concentrations febuxostat does not inhibit other enzymes involved in purine or pyrimidine metabolism, namely, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase or purine nucleoside phosphorylase.
F’ konċentrazzjonijiet terapewtiċi febuxostat ma jinibixxix enżimi oħra involuti fil- metaboliżmu ta ’ purine jew ta ’ pyrimidine, jiġifieri, guanine deaminase, hypoxanthine guanine phosphoribosyltransferase, orotate phosphoribosyltransferase, orotidine monophosphate decarboxylase jew purine nucleoside phosphorylase.
Clinical studies results The efficacy of ADENURIC was demonstrated in two Phase 3 pivotal studies (APEX study and FACT study described below) that were conducted in 1832 patients with hyperuricemia and gout.
L- effikaċja ta ’ ADENURIC intweriet f’ żewġ studji pivotali ta ’ Fażi 3 (studju APEX u studju FACT deskritti hawn taħt) li twettqgħu f’ 1832 pazjent b’ iperuriċimja u gotta.
The primary efficacy endpoint
F’ kull studju pivotali ta ’ Fażi 3, ADENURIC wera ħila superjuri biex ibaxxi u jżomm il- livelli ta ’ uric acid fis- serum meta mqabbel ma ’ allopurinol.
8 in each study was the proportion of patients whose last 3 monthly serum uric acid levels were < 6.0 mg/ dl (357 µmol/ l).
L- mira primarja ta ’ l- effikaċja f’ kull studju kienet il- proporzjon ta ’ pazjenti li kellhom l- aħħar 3 livelli ta ’ kull xahar ta ’ uric acid fis- serum < 6. 0 mg/ dl (357 µmol/ l).
No patients with organ transplant have been included in these studies (see section 4.2).
F’ dawn l- istudji ma kienux inklużi pazjent bi trapjant ta ’ l- organi (ara sezzjoni 4. 2).
APEX Study:
Studju APEX:
The Allopurinol and Placebo-Controlled Efficacy Study of Febuxostat (APEX) was a Phase 3, randomized, double-blind, multicenter, 28-week study.
L- Istudju ta ’ l- Effikaċja Kkontrollat b’ Allopurinol u bil- Plaċebo ta ’ Febuxostat (APEX) kien studju ta ’ 28 ġimgħa, ta ’ Fażi 3, randomised, double- blind u multicenter.
One thousand and seventy-two (1072) patients were randomized: placebo (n=134), ADENURIC 80 mg QD (n=267), ADENURIC 120 mg QD (n=269), ADENURIC 240 mg QD (n=134) or allopurinol (300 mg QD [n=258] for patients with a baseline serum creatinine ≤ 1.5 mg/ dl or 100 mg QD [n=10] for patients with a baseline serum creatinine > 1.5 mg/ dl and ≤ 2.0 mg/ dl).
Elf u tnejn u sebgħin (1072) pazjent kienu randomised: plaċebo (n=134), ADENURIC 80 mg QD (n=267), ADENURIC 120 mg QD (n=269), ADENURIC 240 mg QD (n=134) jew allopurinol (300 mg QD [n=258] għall - pazjenti b’ linja bażi ta ’ krejatinina fis- serum ≤1. 5 mg/ dl jew 100 mg QD [n=10] għall- pazjenti b’ linja bażi ta ’ krejatinina fis- serum > 1. 5 mg/ dl u ≤2. 0 mg/ dl).
Two hundred and forty mg febuxostat (2 times the recommended highest dose) was used as a safety evaluation dose.
Mitejn u erbgħin mg ta ’ febuxostat (darbtejn l - ogħla doża rrakkomandata) intużat bħala doża ta ’ valutazzjoni tas- sigurtà.
The APEX study showed statistically significant superiority of both the ADENURIC 80 mg QD and the ADENURIC 120 mg QD treatment arms versus the conventionnally used doses of allopurinol 300mg (n = 258) / 100mg (n = 10) treatment arm in reducing the sUA below 6 mg/ dl (357 µmol/ l) (see Table 2 and Figure 1).
L- istudju APEX wera superjorità statistikament sinifikanti taż- żewġ gruppi ta ’ kura ta ’ ADENURIC 80 mg QD u ta ’ ADENURIC 120 mg QD versus il- grupp ta ’ kura ta ’ dożi konvenzjonali ta ’ allopurinol 300mg (n = 258) / 100mg (n = 10), biex inaqqsu l- sUA taħt 6 mg/ dl (357 µmol/ l) (ara Tabella 2 u Figura 1).
FACT Study:
Studju FACT:
The Febuxostat Allopurinol Controlled Trial (FACT) Study was a Phase 3, randomized, double-blind, multicenter, 52-week study.
L- Istudju Prova ta ’ Febuxostat Ikkontrollat b’ Allopurinol (FACT) kien studju ta ’ 52 ġimgħa, ta ’ Fażi 3, randomised, double- blind u multicenter.
Seven hundred sixty (760) patients were randomized:
Seba ’ mija u sittin (760) pazjent kienu
ADENURIC 80 mg QD (n=256), ADENURIC 120 mg QD (n=251), or allopurinol 300 mg QD (n=253).
ADENURIC 80 mg QD (n=256), ADENURIC 120 mg QD (n=251), jew allopurinol 300 mg QD (n=253).
The FACT study showed the statistically significant superiority of both ADENURIC 80 mg and ADENURIC 120 mg QD treatment arms versus the conventionally used dose of allopurinol 300 mg treatment arm in reducing and maintaining sUA below 6 mg/ dl (357 µmol/ l).
L- istudju FACT wera superjorità statistikament sinifikanti taż- żewġ gruppi ta ’ kura ta ’ ADENURIC 80 mg u ta ’ ADENURIC 120 mg QD versus il- grupp ta ’ kura ta ’ doża konvenzjonali ta ’ allopurinol 300 mg, biex inaqqsu u jżommu l- sUA taħt 6 mg/ dl (357 µmol/ l).
Table 2 summarises the primary efficacy endpoint results:
Tabella 2 tiġbor ir- riżultati tal- mira primarja ta ’ l- effikaċja:
Table 2 Proportion of Patients with Serum Uric Acid Levels < 6.0 mg/ dl (357µmol/ l) Last Three Monthly Visits
Tabella 2 Proporzjon ta ’ Pazjenti b’ Livelli ta ’ Uric Acid fis- Serum < 6. 0 mg/ dl (357µmol/ l) L- Aħħar Tliet Visti ta ’ Kull Xahar
ADENURIC 120 mg QD 65% *, #
Studju
100
100 mg QD1
(28 weeks) FACT (52 weeks) Combined Results
Kombinati
results from subjects receiving either 100 mg QD (n=10: patients with serum creatinine > 1.5 and ≤ 2.0 mg/ dl) or 300 mg QD (n=509) were pooled for analyses. * p < 0.001 vs allopurinol, # p < 0.001 vs 80 mg
riżultati minn individwi li rċievew 100 mg QD (n=10: pazjenti bi krejatinina fis- serum > 1. 5 u ≤2. 0 mg/ dl) jew 300 mg QD (n=509) inġabru għall- analiżi. * p < 0. 001 vs allopurinol, # p < 0. 001 vs 80 mg
The ability of ADENURIC to lower serum uric acid levels was prompt and persistent.
Il- ħila ta ’ ADENURIC biex ibaxxi l- livelli ta ’ uric acid fis- serum kienet immedjata u persistenti.
Reduction in serum uric acid level to < 6.0 mg/ dl (357 µmol/ l) was noted by the Week 2 visit and was maintained throughout treatment.
Tnaqqis fil- livell ta ’ uric acid fis- serum għal < 6. 0 mg/ dl (357 µmol/ l) kien innutat mal- vista ta ’ Ġimgħa 2 u kien miżmum tul il- kura.
The mean serum uric acid levels over time for each treatment group from the Phase 3 pivotal studies are shown in Figure 1.
Il- livelli medji ta ’ uric acid fis- serum tul iż- żmien għal kull grupp ta ’ kura mill- istudji pivotali ta ’ Fażi 3 huma murija f’ Figura 1.
9 Figure 1 Mean Serum Uric Acid Levels Combined Phase 3 Studies
Figura 1 Livelli Medji Kombinati ta ’ Uric Acid fis- Serum fl- Istudji ta ’ Fażi 3
11
11 Livell Medju (±SEM) ta ’ Uric Acid fis- Serum (mg/ dL)
10
) L 10
Mean (±SEM) Serum Uric Acid Level (mg/ dL) Placebo
Plaċebo
9
/ g m (9 l e v e L8 d i c A c7
8
Placebo
7
i r U m6 u r
6 ADENURIC 80 mg
ADENURIC 80 mg
5
n a e M3
4 ADENURIC 120 mg
2
3 ADENURIC 240 mg 2
ADENURIC 120 mg ADENURIC 240 mg
12 16 20 24
12 16 20
28 32 36 40 44 48 52 Week
24 28 32 36 40 44 Week Ġimgħa
BL=baseline
48 52
SEM=standard error of the mean
BL= linja bazi BL= linja bażi
Note:
8 Nota:
509 patients received allopurinol 300 mg QD; 10 patients with serum creatinine > 1.5 and < 2.0 mg/ dl were dosed with 100 mg QD.
509 pazjent irċievew allopurinol 300 mg QD; 10 pazjenti bi krejatinina fis- serum > 1. 5 u < 2. 0 mg/ dl kienu dożati b’ 100 mg QD.
(10 patients out of 268 in APEX study).
(10 pazjenti minn 268 fl- istudju APEX).
240 mg febuxostat was used to evaluate the safety of febuxostat at twice the recommended highest dose.
Intużat 240 mg febuxostat biex tiġi vvalutata s- sigurtà ta ’ febuxostat f’ doża id- doppju ta ’ l- ogħla doża rrakkomandata.
Primary endpoint in the sub-group of patients with renal impairment The APEX Study evaluated efficacy in 40 patients with renal impairment (i. e., baseline serum creatinine > 1.5 mg/ dl and < =2.0 mg/ dl).
Il- mira primarja fis- sottogrupp ta ’ pazjenti b’ indeboliment renali L- Istudju APEX ivvaluta l- effikaċja f’ 40 pazjent b’ indeboliment renali (i. e., linja bażi tal- krejatinina fis- serum > 1. 5 mg/ dl u < =2. 0 mg/ dl).
For renally impaired subjects who were randomized to allopurinol, the dose was capped at 100mg QD.
Għall- individwi b’ indeboliment renali li kienu randomised għal allopurinol, id- doża kienet mgħollija sa 100mg QD.
ADENURIC achieved the primary efficacy endpoint in 44% (80 mgQD), 45% (120 mg QD), and 60% (240 mg QD) of patients compared to 0% in the allopurinol 100 mg QD and placebo groups.
ADENURIC laħaq il- mira primarja ta ’ l- effikaċja f’ 44% (80 mgQD), 45% (120 mg QD), u 60% (240 mg QD) tal- pazjenti meta mqabbel ma ’ 0% fil - gruppi ta ’ allopurinol 100 mg QD u tal- plaċebo.
There were no clinically significant differences in the percent decrease in serum uric acid concentration in healthy subjects irrespective of their renal function (58% in the normal renal function group and 55% in the severe renal dysfunction group).
Ma kien hemm l- ebda differenza ta ’ sinifikanza klinika fil- persentaġġ ta ’ tnaqqis fil- konċentrazzjoni ta ’ uric acid fis- serum f’ individwi b’ saħħithom irrispettivament mill- funzjoni tal- kliewi tagħhom (58% fil- grupp b’ funzjoni tal- kliewi normali u 55% fil- grupp b’ indeboliment sever tal- funzjoni tal - kliewi).
Primary endpoint in the sub group of patients with sUA ≥ 10 mg/ dl Approximately 40% of patients (combined APEX and FACT) had a baseline sUA of ≥ 10 mg/ dl.
Il- mira primarja fis- sottogrupp ta ’ pazjenti b’ sUA ≥ 10 mg/ dl Madwar 40% tal- pazjenti (APEX u FACT kombinati) kellhom linja bażi ta ’ sUA ta ’ ≥ 10 mg/ dl.
In this subgroup ADENURIC achieved the primary efficacy endpoint in 41% (80 mg QD), 48% (120 mg QD), and 66% (240 mg QD) of patients compared to 9% in the allopurinol 300 mg/ 100 mg QD and 0% in the placebo groups.
F’ dan is- sottogrupp ADENURIC laħaq l- mira primarja ta ’ l- effikaċja f’ 41% (80 mg QD), 48% (120 mg QD), u 66% (240 mg QD) tal- pazjenti meta mqabbel ma ’ 9% fil- grupp ta ’ allopurinol 300 mg/ 100 mg QD u 0% fil- grupp tal- plaċebo.
Clinical Outcomes: proportion of patients requiring treatment for a gout flare and tophi size change The proportion of subjects requiring treatment for a gout flare (APEX and FACT Study) was numerically lower in the groups that achieved an average post-baseline serum urate level < 6.0 mg/ dl, < 5.0 mg/ dl, or < 4.0 mg/ dl compared to the group that achieved an average post- baseline serum urate level ≥ 6.0 mg/ dl during the last 32 weeks of the treatment period (Week 20-Week 24 to Week 48 - 52 intervals).
Riżultati Kliniċi: proporzjon ta ’ pazjenti li kellhom bżonn kura għall- irkadar tal- gotta u bidla fid- daqs tat- tofi Il- proporzjon ta ’ individwi li kellhom bżonn kura għall- irkadar tal- gotta (Studju APEX u FACT) kien numerikament aktar baxx fil- gruppi li laħqu livell medju ta ’ urate fis- serum wara l- linja bażi ta ’ < 6. 0 mg/ dl, < 5. 0 mg/ dl, jew < 4. 0 mg/ dl meta mqabbel mal- grupp li laħaq livell medju ta ’ urate fis- serum wara l- linja bażi ta ’ ≥6. 0 mg/ dl waqt l- aħħar 32 ġimgħa tal- perjodu ta ’ kura (intervalli Ġimgħa 20 - Ġimgħa 24 sa Ġimgħa 48 - 52).
10 Two years of data from the Phase 3 Open Label Extension study showed that the maintenance of serum urate levels < 6 mg/ dl (< 357 µmol/ l) resulted in a decrease in the incidence of gout flares with less than 3% of subjects requiring treatment for a flare (i. e. more than 97% of patients did not require treatment for a flare) at Month 16-24.
Sentejn ta ’ tagħrif mill- istudju ta ’ Estensjoni Open Label ta ’ Fażi 3 wera li manteniment ta ’ livelli ta ’ urate fis- serum ta ’ < 6 mg/ dl (< 357 µmol/ l) wassal għal tnaqqis fl- inċidenza ta ’ rkadar tal- gotta, b’ inqas minn 3% ta ’ l- individwi jinħtieġu kura għal rikaduta (i. e. aktar minn 97% tal- pazjenti ma kellhomx bżonn kura għal rikduta) f’ Xahar 16- 24.
This was associated with a reduction of tophus size leading to complete resolution in 54% of subjects at Month 24.
Dan kien assoċjat ma ’ tnaqqis fid- daqs tat- tofus li wassal għall- fejqan komplet f’ 54% ta ’ l- individwi f’ Xahar 24.
During the phase 3 clinical studies, mild liver function test abnormalities were observed in patients treated with febuxostat (3.5%).
Waqt l- istudji kliniċi ta ’ fażi 3, kienu osservati anormalitajiet ħfief fit- test tal- funzjoni tal- fwied f’ pazjenti kkurati b’ febuxostat (3. 5%).
These rates were similar to the rates reported on allopurinol (3.6%) (see section 4.4).
Dawn ir- rati kienu simili għar- rati rrapportati b’ allopurinol (3. 6%) (ara sezzjoni 4. 4).
Increased TSH values (> 5.5 µIU/ ml) were observed in patients on long-term treatment with febuxostat (5.0%) and patients with allopurinol (5.8%) in the long term open label extension studies (see section 4.4).
Kienu osservati valuri miżjuda ta ’ TSH (> 5. 5 µIU/ ml) f’ pazjenti fuq kura fit- tul b’ febuxostat (5. 0%) u f’ pazjenti b’ allopurinol (5. 8%) fl- istudji ta ’ estensjoni open label fit- tul (ara sezzjoni 4. 4).
The total exposure to ADENURIC in phase 3 pivotal studies and long-term extension studies is greater than 2700 patient-years.
L- esponiment totali għal ADENURIC fl- istudji pivotali ta ’ fażi 3 u fl- istudji ta ’ estensjoni fit- tul kien aktar minn 2700 sena ta ’ pazjent.
In healthy subjects, maximum plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) of febuxostat increased in a dose proportional manner following single and multiple doses of 10 mg to 120 mg.
F’ individwi b’ saħħithom, konċentrazzjonijiet massimi fil- plażma (Cmax) u l- erja taħt il- kurva tal - konċentrazzjoni fil- plażma u l- ħin (AUC) ta ’ febuxostat żdiedu f’ mod proporzjonali mad- doża wara doża waħda u dożi multipli ta ’ 10 mg sa 120 mg.
For doses between 120 mg and 300 mg, a greater than dose proportional increase in AUC is observed for febuxostat.
Għal dożi bejn 120 mg u 300 mg, kienet osservata żjieda fl- AUC iktar milli proporzjonali mad- doża għal febuxostat.
There is no appreciable accumulation when doses of 10 mg to 240 mg are administered every 24 hours.
M’ hemmx akkumulazzjoni apprezzabli meta dożi ta ’ 10 mg sa 240 mg jingħataw kull 24 siegħa.
Febuxostat has an apparent mean terminal elimination half-life (t1/ 2) of approximately 5 to 8 hours.
Febuxostat għandu medja tal - half- life terminali ta ’ l- eliminazzjoni (t1/ 2) ta ’ madwar 5 sa 8 sigħat.
Population pharmacokinetic/ pharmacodynamic analyses were conducted in 211 patients with hyperuricemia and gout, treated with ADENURIC 40-240 mg QD.
9 Saru analiżi tal- farmakokinetika/ farmakodinamika tal- popolazzjoni f’ 211- il pazjent b’ iperuriċimja u gotta, kkurati b’ ADENURIC 40- 240 mg QD.
In general, febuxostat pharmacokinetic parameters estimated by these analyses are consistent with those obtained from healthy subjects, indicating that healthy subjects are representative for pharmacokinetic/ pharmacodynamic assessment in the patient population with gout.
Ġeneralment, il- parametri farmakokinetiċi ta ’ febuxostat stmati minn dawn l- analiżi huma konsistenti ma ’ dawk miksuba minn individwi b’ saħħithom, u dan jindika li ndividwi b’ saħħithom huma rappreżentattivi għall- valutazzjoni farmakokinetika/ farmakodinamika fil- popolazzjoni ta ’ pazjenti bil- gotta.
Absorption Febuxostat is rapidly (tmax of 1.0-1.5 h) and well absorbed (at least 84%).
Assorbiment Febuxostat huwa assorbit malajr (tmax ta ’ 1. 0- 1. 5 h) u tajjeb (mill- inqas 84%).
After single or multiple oral 80 and 120 mg once daily doses, Cmax is approximately 2.8-3.2 µg/ ml, and 5.0- 5.3 µg/ ml, respectively.
Wara doża waħda jew dożi multipli orali kuljum ta ’ 80 u 120 mg, Cmax huwa madwar 2. 8- 3. 2 µg/ ml, u 5. 0- 5. 3 µg/ ml, rispettivament.
Absolute bioavailability of the febuxostat tablet formulation has not been studied.
Il- biodisponibiltà assoluta tal- formulazzjoni tal- pillola ta ’ febuxostat ma ġietx studjata.
Following multiple oral 80 mg once daily doses or a single 120 mg dose with a high fat meal, there was a 49% and 38% decrease in Cmax and a 18% and 16% decrease in AUC, respectively.
Wara dożi orali mutlipli ta ’ 80 mg darba kuljum jew doża waħda ta ’ 120 mg ma ’ ikla b’ ħafna xaħam, kien hemm tnaqqis ta ’ 49% u ta ’ 38% f’ Cmax u tnaqqis ta ’ 18% u 16% fl- AUC, rispettivament.
However, no clinically significant change in the percent decrease in serum uric acid concentration was observed where tested (80 mg multiple dose).
Iżda ma kienet osservata l- ebda bidla ta ’ sinifikanza klinika fil- persentaġġ ta ’ tnaqqis fl- konċentrazzjoni ta ’ uric acid fis- serum fejn ġie ttestjat (doża multipla ta ’ 80 mg).
Thus, ADENURIC may be taken without regard to food.
Għalhekk, ADENURIC jista ’ jittieħed mingħajr każ tal- ikel.
Distribution The apparent steady state volume of distribution (Vss/ F) of febuxostat ranges from 29 to 75 l after oral doses of 10-300 mg.
Distribuzzjoni Il- volum ta ’ distribuzzjoni apparenti fi stat stabbli (Vss/ F) ta ’ febuxostat ivarja minn 29 sa 75 l wara dożi orali ta ’ 10- 300 mg.
The plasma protein binding of febuxostat is approximately 99.2%, (primarily to albumin), and is constant over the concentration range achieved with 80 and 120 mg doses.
It- twaħħil mal- proteini fil- plażma ta ’ febuxostat huwa madwar 99. 2%, (primarjament ma ’ albumin), u huwa kostanti fuq il- firxa ta ’ konċentrazzjoni miksuba b’ dożi ta ’ 80 u 120 mg.
Plasma protein binding of the active metabolites ranges from about 82% to 91%.
It- twaħħil mal- proteini fil- plażma tal- metaboliti attivi jvarja minn madwar 82% sa 91%.
11 Metabolism Febuxostat is extensively metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UDPGT) enzyme system and oxidation via the cytochrome P450 (CYP) system.
Metaboliżmu Febuxostat huwa metabolizzat b’ mod estensiv permezz ta ’ konjugazzjoni permezz tas- sistema ta ’ l - enżima uridine diphosphate glucuronosyltransferase (UDPGT) u ta ’ ossidazzjoni permezz tas- sistema taċ- ċitokromju P450 (CYP).
Four pharmacologically active hydroxyl metabolites have been identified, of which three occur in plasma of humans.
Ġew identifikati erba ’ metaboliti hydroxyl farmakoloġikament attivi, li minnhom tlieta seħħu fil- plażma tal- bnedmin.
In vitro studies with human liver microsomes showed that those oxidative metabolites were formed primarily by CYP1A1, CYP1A2, CYP2C8 or CYP2C9 and febuxostat glucuronide was formed mainly by UGT 1A1, 1A8, and 1A9
Studji in vitro b’ mikrożomi tal- fwied uman urew li dawk il- metaboliti ossidattivi ġew iffurmati primarjament minn CYP1A1, CYP1A2, CYP2C8 jew CYP2C9 u febuxostat glucuronide kien iffurmat primarjament minn UGT 1A1, 1A8, u 1A9
Elimination Febuxostat is eliminated by both hepatic and renal pathways.
Eliminazzjoni Febuxostat huwa eliminat kemm mir- rotta epatika kif ukoll mir- rotta renali.
Following an 80 mg oral dose of 14 C-labeled febuxostat, approximately 49% of the dose was recovered in the urine as unchanged febuxostat (3%), the acyl glucuronide of the active substance (30%), its known oxidative metabolites and their conjugates (13%), and other unknown metabolites (3%).
Wara doża orali ta ’ 80 mg ta ’ febuxostat tikkettjat b’ 14C, madwar 49% tad- doża kienet irkuprata fl- awrina bħala febuxostat mhux mibdul (3%), l- acyl glucuronide tas- sustanza attiva (30%), il- metaboliti ossidattivi magħrufa tiegħu u l- konjugati tagħhom (13%), u metaboliti mhux magħrufa oħra (3%).
In addition to the urinary excretion, approximately 45% of the dose was recovered in the faeces as the unchanged febuxostat (12%), the acyl glucuronide of the active substance (1%), its known oxidative metabolites and their conjugates (25%), and other unknown metabolites (7%).
Barra mit- tneħħija fl- awrina, madwar 45% tad- doża kienet irkuprata fl- ippurgar bħala febuxostat mhux mibdul (12%), l- acyl glucuronide tas- sustanza attiva (1%), il- metaboliti ossidattivi magħrufa tiegħu u l- konjugati tagħhom (25%), u metaboliti mhux magħrufa oħra (7%).
Special populations Renal insufficiency Following multiple doses of 80 mg of ADENURIC in patients with mild, moderate or severe renal insufficiency, the Cmax of febuxostat did not change, relative to subjects with normal renal function.
Popolazzjonijiet speċjali Insuffiċjenza renali Wara dożi multipli ta ’ 80 mg ta ’ ADENURIC f’ pazjenti b’ insuffiċjenza renali ħafifa, moderata jew severa, Cmax ta ’ febuxostat ma nbidilx, relattivament għall- individwi b’ funzjoni renali normali.
The mean total AUC of febuxostat increased by approximately 1.8-fold from 7.5 μ g⋅ h/ ml in the normal renal function group to 13.2 μ g. h/ ml in the severe renal dysfunction group.
L- AUC totali medja ta ’ febuxostat żdiedet b’ madwar 1. 8 darbiet minn 7. 5 μg⋅h/ ml fil- grupp b’ funzjoni renali normali għal 13. 2 μg. h/ ml fil- grupp b’ indeboliment renali severi.
The Cmax and AUC of active metabolites increased up to 2- and 4-fold, respectively.
Cmax u l- AUC tal- metaboliti attivi żdiedu sa darbtejn u 4 darbiet, rispettivament.
However, no dose adjustment is necessary in patients with mild or moderate renal impairment.
Iżda, l- ebda aġġustament fid- doża ma huwa neċessarju f’ pazjenti b’ indeboliment renali ħafif jew moderat.
Hepatic impairment Following multiple doses of 80 mg of ADENURIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, the Cmax and AUC of febuxostat and its metabolites did not change significantly compared to subjects with normal hepatic function.
Indeboliment epatiku Wara dożi multipli ta ’ 80 mg ta ’ ADENURIC f’ pazjenti b’ indeboliment epatiku ħafif (Child- Pugh Klassi A) jew moderat (Child- Pugh Klassi B), Cmax u l- AUC ta ’ febuxostat u l- metaboliti tiegħu ma nbidlux b’ mod sinifikanti meta mqabbel ma ’ individwi b’ funzjoni epatika normali.
No studies have been conducted in patients with severe hepatic impairment (Child- Pugh Class C).
Ma twettqux studji f’ pazjenti b’ indeboliment epatiku sever (Child- Pugh Klassi Ċ).
Age There were no significant changes observed in AUC of febuxostat or its metabolites following multiple oral doses of ADENURIC in elderly as compared to younger healthy subjects.
10 Età Ma kienu osservati l- ebda tibdiliet sinifikanti fl- AUC ta ’ febuxostat jew tal- metaboliti tiegħu wara dożi orali multipli ta ’ ADENURIC fl- anzjani kif imqabbel ma ’ individwi b’ saħħithom iżgħar.
Gender Following multiple oral doses of ADENURIC, the Cmax and AUC were 24% and 12% higher in females than in males, respectively.
Sess Wara dożi orali multipli ta ’ ADENURIC, Cmax u l- AUC kienu 24% u 12% ogħla fin- nisa milli fl- irġiel, rispettivament.
However, weight-corrected Cmax and AUC were similar between the genders.
Madankollu, Cmax u l- AUC ikkoreġuti għall- piż kienu simili bejn is- sessi.
No dose adjustment is needed based on gender.
L- ebda aġġustament fid- doża ma huwa meħtieġ bbażat fuq is- sess.
Effects in non-clinical studies were generally observed at exposures in excess of the maximum human exposure.
Fi studji li m’ humiex kliniċi, effetti ġeneralment dehru f’ esponimenti aktar għolja mill- massimu ta ’ l - esponiment uman.
12 Carcinogenesis, mutagenesis, impairment of fertility In male rats, a statistically significant increase in urinary bladder tumours (transitional cell papilloma and carcinoma) was found only in association with xanthine calculi in the high dose group, at approximately 11 times human exposure.
Karċinoġeniċità, mutaġenesi, indeboliment fil- fertilità F’ firien maskili, żjieda statistikament sinifikanti fit- tumuri tal- bużżieqa ta ’ l- awrina (papilloma taċ - ċellula transitorja u karċinoma) nstabet biss f’ assoċjazzjoni ma ’ kalkuli ta ’ xanthine fil- grupp b’ doża għolja, ta ’ madwar 11- il darba l- esponiment uman.
There was no significant increase in any other tumour type in either male or female mice or rats.
Ma kienx hemm żjieda sinifikanti fl- ebda tip ta ’ tumur ieħor fil- ġrieden jew firien maskili jew femminili.
These findings are considered a consequence of species specific purine metabolism and urine composition and of no relevance to clinical use.
Dawn is- sejbiet huma kkunsidrati konsekwenza tal- metaboliżmu ta ’ purine u tal- kompożizzjoni ta ’ l- awrina speċifiċi għall- ispeċi u ta ’ l - ebda rilevanza għall- użu kliniku.
A standard battery of test for genotoxicity did not reveal any biologically relevant genotoxic effects for febuxostat.
Sensiela ta ’ testijiet stàndard għall- ġenotossiċità ma wrew l- ebda effetti ġenotossiċi rilevanti bioloġikament għal febuxostat.
Febuxostat at oral doses up to 48 mg/ kg/ day was found to have no effect on fertility and reproductive performance of male and female rats.
Febuxostat f’ dożi orali sa 48 mg/ kg/ kuljum instab li ma għandu l- ebda effett fuq il- fertilità u l- ħila riproduttiva ta ’ firien maskili u femminili.
There was no evidence of impaired fertility, teratogenic effects, or harm to the foetus due to febuxostat.
Ma kien hemm l- ebda evidenza ta ’ indeboliment fil- fertilità, effetti teratoġeniċi, jew ħsara lill- fetu minħabba febuxostat.
There was high dose maternal toxicity accompanied by a reduction in weaning index and reduced development of offspring in rats at approximately 4.3 times human exposure.
Kien hemm tossiċità fl- omm b’ doża għolja flimkien ma ’ tnaqqis fl- indiċi tal - ftim u żvilupp imnaqqas tal- frieħ fil- firien f’ madwar 4. 3 darbiet l- esponiment uman.
Teratology studies, performed in pregnant rats at approximately 4.3 times and pregnant rabbits at approximately 13 times human exposure did not reveal any teratogenic effects.
Studji teratoloġiċi, li twettqgħu f’ firien tqal f’ madwar 4. 3 darbiet u fi fniek tqal f’ madwar 13- il darba l - esponiment uman ma wrew l- ebda effetti teratoġeniċi.
Tablet core Lactose monohydrate Microcrystalline cellulose Magnesium stearate Hydroxypropylcellulose Croscarmellose sodium Silica, colloidal hydrated
Qalba tal- pillola Lactose monohydrate Microcrystalline cellulose Magnesium stearate Hydroxypropylcellulose Croscarmellose sodium Silica, colloidal hydrated
Tablet coating Opadry II, Yellow, 85F42129 containing:
Kisja tal- pillola Opadry II, Isfar, 85F42129 fih:
Polyvinyl alcohol Titanium dioxide (E171) Macrogols 3350 Talc Iron oxide yellow (E172)
Polyvinyl alcohol Titanium dioxide (E171) Macrogols 3350 Talc Iron oxide isfar (E172)
6.2 Incompatibilities
11 6. 2 Inkompatibilitajiet
This medicinal product does not require any special storage condition.
Din il- mediċina m’ għandhiex bżonn ħażna speċjali.
Clear (Aclar/ PVC/ Aluminium) blister of 14 tablets.
Folja ċara (Aclar/ PVC/ Aluminju) ta ’ 14- il pillola.
ADENURIC 80 mg is available in pack sizes of 28 and 84 film-coated tablets.
ADENURIC 80 mg huwa disponibbli f’ daqsijiet tal- pakkett ta ’ 28 u 84 pillola miksija b’ rita.
Beaufour Ipsen Pharma 24 rue Erlanger 75781 Paris Cedex 16 France
Beaufour Ipsen Pharma 24 rue Erlanger 75781 Paris Cedex 16 Franza
Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http: / /www. emea. europa. eu/
Informazzjoni dettaljata dwar dan il- prodott tinsab fuq il- website ta ’ l- Aġenzija Ewropeja dwar il- Mediċini (EMEA) http: // www. emea. europa. eu /.
ADENURIC 120 mg film-coated tablets
ADENURIC 120 mg pilloli miksija b’ rita
Each tablet contains 120 mg of febuxostat.
Kull pillola fiha 120 mg ta ’ febuxostat.
Each tablet contains 114.75mg of lactose monohydrate
Kull pillola fiha 114. 75mg ta ’ lactose monohydrate
Pale yellow to yellow, film-coated, capsule shaped tablets, engraved with “ 120 ” on one side
Pilloli forma ta ’ kapsula, sofor ċari sa sofor, miksija b’ rita, minquxa b ’ “ 120 ” fuq naħa waħda.
Limited information is available in patients with moderate hepatic impairment.
Huwa disponibbli tagħrif limitat f’ pazjenti b’ indeboliment epatiku moderat.
The efficacy and safety of febuxostat has not been studied in patients with severe hepatic impairment (Child Pugh Class C).
L- effikaċja u s- sigurtà ta ’ febuxostat ma ġewx studjati f’ pazjenti b’ indeboliment epatiku sever (Child Pugh Klassi Ċ).
15 Elderly No dose adjustment is required in the elderly (see section 5.2).
Anzjani L- ebda aġġustament fid- doża ma huwa meħtieġ fl- anzjani (ara sezzjoni 5. 2).