qanastek/EMEA-V3 huggingface dataset:
24 Adverse reactions based on experience from clinical trials and postmarketing experience are presented in the following table by system organ class and frequency of occurrence.
23 Reazzjonijiet avversi bażati fuq esperjenza minn provi kliniċi u esperjenza ta ’ wara t- tqegħid fis- suq huma preżentati fit- tabella li ġejja skont is- sistema tal- klassifika tal- organi u l- frekwenza ta ’ okkorrenza.
System Organ Class
Sistema tal- Klassifika tal- Organi Infezzjonijiet u
Hypersensitivity reactions, including anaphylactic/ anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis (see section 4.4)
Reazzjonijiet ta ’ sensittività eċċessiva, li jinkludu reazzjonijiet anafilattiċi / anafilattojdi, anġjoedema, dermatite eksfoljattiva, u vaskulitè ipersensittiva (ara sezzjoni 4. 4)
25 System Organ Class
24 Sistema tal- Klassifika tal- Organi Disturbi fil- qalb
Very common ( 1/ 10)
Komuni ħafna (≥1/ 10)
Common ( 1/ 100 to < 1/ 10)
Komuni (≥1/ 100 sa < 1/ 10) Takikardja
Uncommon ( 1/ 1000 to < 1/ 100)
Mhux komuni (≥1/ 1, 000 sa < 1/ 100) Effużjoni perikardjali (li tinkludi efużjonijiet emodinamikament sinifikanti fi tfal u adulti)
Metabolism and Hypokalaemia nutrition disorders
Disturbi vaskulari
Hypophosphataemia Hypercholesterolaemia Hyperglycaemia Hypertriglyceridaemia
Limfoċel
Nervous system disorders
Trombożi tal- vini
Headache
Disturbi
Cardiac disorders
Pressjoni għolja
Tachycardia
fondi Pnewmonite
Pericardial effusion (including haemodynamically significant effusions in children and adults)
Proteinosi
Vascular disorders Respiratory, thoracic, and mediastinal disorders
respiratorji, toraċiċi u medjastinali
Lymphocele Hypertension
Effużjoni plewrali Epistassi
Abdominal pain Diarrhoea Constipation Nausea
Disturbi muskolu — skeletrali u tal- connective tissue
Stomatitis
Artralġja
Pancreatitis
Osteonekrosi
Hepatobiliary disorders
Disturbi fil- kliewi u fis- sistema urinarja
Liver function tests abnormal
Sindromu nefrotiku (ara sezzjoni 4. 4)
Skin and subcutaneous tissue disorders
Disturbi ġenerali u
Acne
Edema periferali
Rash
Fejqan imdgħajjef
Musculoskeletal Arthralgia and connective tissue disorders
kundizzjonijiet ta ’ mnejn jingħata
Osteonecrosis
Deni Uġigħ
Proteinuria Impaired healing Oedema
Investigazzjonijiet
Nephrotic syndrome (see section 4.4)
Lactate dehydrogenase
Investigations Blood lactate dehydrogenase increased Blood creatinine increased
fid- demm mgħollija Żieda fil- krejatinina fid- demm
26 Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Rapamune.
Każijiet ta ’ nefropatija assoċjata ma ’ virus BK, kif ukoll każijiet ta ’ lewkoenċefalopatija multifokali progressiva (PML) assoċjata ma ’ virus JC, ġew irrappurtati f’ pazjenti trattati b’ immunosoppressanti, li jinkludu Rapamune.
Hepatoxicity has been reported.
Epatossiċità ġiet rapportata.
The risk may increase as the trough sirolimus level increases.
Ir- riskju jista ’ jiżdied kif il- livelli l- aktar baxxi ta ’ sirolimus jiżdiedu.
Rare reports of fatal hepatic necrosis have been reported with elevated trough sirolimus levels.
Rapporti rari ta ’ nekrożi epatika fatali ġew irrapportati ma’ żidiet fil- livelli l- aktar baxxi ta ’ sirolimus.
Impaired healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia, and anastomotic disruption (e. g. wound, vascular, airway, ureteral, biliary).
25 Fejqan imdgħajjef wara kirurġija ta ’ trapjant ġiet irrapportata, inklużi ftuħ tal- faxxa, ftuq inċiżjonali u sfaxxar tal- anastomożi (eż. ferita, vaskulari, passaġġi tal- arja, uretrali, biljari).
The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/ TTP/ TMA.
L- użu ta ’ sirolimus flimkien ma ’ impeditur ta ’ calcineurin jista ’ jżid ir- riskju ta ’ HUS/ TTP/ TMA imqanqlin minn impeditur ta ’ calcineurin.
Paediatric population Controlled clinical trials with posology comparable to that currently indicated for the use of Rapamune in adults — that is, use in combination with ciclosporin and corticosteroids for 2 to 3 months post-transplantation followed by withdrawal of ciclosporin thereafter— have not been conducted in children or adolescents ( 18 years of age).
Provi kliniċi b’ kontrolli b’ pożoloġija li tista ’ titqabbel ma ’ dik li attwalment hija indikata għall- użu ta ’ Rapamune fl- adulti — jiġifieri, l- użu flimkien ma ’ ciclosporin u kortikosterojdi għal minn xahrejn sa 3 xhur wara t- trapjant li jiġi segwit mit- tneħħija ta ’ ciclosporin wara dan— ma sarux fi tfal jew adolexxenti (li għandhom età ta ’ < 18- il sena).
Safety was assessed in a controlled clinical trial enrolling renal transplant patients  18 years of age considered of high-immunologic risk, defined as a history of one or more acute allograft rejection episodes and/ or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1).
Is- sigurtà ġiet analizzata fi prova klinika b’ kontrolli li fiha kienu rreġistrati pazjenti li kellhom trapjant tal- kliewi li kellhom < 18- il sena li huma kkunsidrati li għandhom riskju immunoloġiku għoli, definit bħala storja medika ta ’ episodju wieħed jew aktar ta ’ rifjut akuta u/ jew il- preżenza ta ’ nefropatija ta ’ allograft kronika meta ssir bijopsija tal- kliewi (ara sezzjoni 5. 1).
The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including but not limited to increased serum triglycerides and cholesterol), and urinary tract infections.
L- użu ta ’ Rapamune flimkien ma ’ impedituri ta ’ calcineurin u kortikosterojdi kien assoċjat ma ’ risku ogħla ta ’ deterjorament tal- funzjoni renali, abnormalitajiet tal- lipidi fis- serum (li jinkludu imma m’ humiex limitati għal żieda fit- trigliċeridi u l- kolesterol fis- serum), u infezzjonijiet fl- apparat urinarju.
The treatment regimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is not indicated for adult or paediatric patients (see section 4.1).
Il- kors tal- kura studjat (l - użu kontinwu ta ’ Rapamune flimkien ma ’ impeditur ta ’ calcineurin) mhuwiex indikat għal pazjenti adulti jew pedjatriċi (ara sezzjoni 4. 1).
In another study enrolling renal transplant patients  20 years of age that was intended to assess the safety of progressive corticosteroid withdrawal (beginning at six months post-transplantation) from an immunosuppressive regimen initiated at transplantation that included full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed post-transplant lymphoproliferative disorder (PTLD).
Fi studju ieħor li fih kienu rreġistrati pazjenti ta ’ ≤20 sena li kellhom trapjant tal- kliewi li kien maħsub biex jevalwa s- sigurtà ta ’ twaqqif progressiv tal- kortikosterojdi (li beda sitt xhur wara t- trapjant) minn kors immunosoppressiv li nbeda mat- trapjant, li kien jinkludi immunosoppressjoni b’ doża sħiħa kemm b’ Rapamune kif ukoll b’ impeditur ta ’ calcineurin flimkien ma ’ induzzjoni ta ’ basiliximab, mill- 274 pazjent li rreġistraw, 19 (6. 9%) kienu rrappurtati li żviluppaw disturb limfoproliferattiv ta ’ wara t - trapjant (PTLD).
27 Among 89 patients known to be EBV seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD.
Fost 89 pazjent magħruf li kienu seronegattivi għal EBV qabel it- trapjant, 13 (15. 6%) kienu rrappurtati li żviluppaw PTLD.
Sirolimus inhibits T cell activation induced by most stimuli, by blocking calcium dependent and calcium independent intracellular signal transduction.
Sirolimus jinibixxi l- attivazzjoni taċ- ċelluli T li s- soltu sseħħ permezz ta ’ ħafna stimuli, billi dan jimblokka t- transduzzjoni ta ’ messaġġi intraċellulari kemm dawk li huma u li mhumiex dependenti mill- kalċju.
The mean calculated glomerular filtration rate (GFR) at 12, 24, 36, 48 and 60 months was significantly higher for patients receiving Rapamune following ciclosporin elimination than for those in the Rapamune
Ir- rata medja kkalkulata ta ’ filtrazzjoni glomerulari (GFR) fi 12, 24, 36, 48 u 60 xahar kienet sinifikament ogħla għal pazjenti li jirċievu Rapamune wara l- eliminazzjoni ta ’ ciclosporin minn dawk fil- grupp tat- terapija ta ’ Rapamune ma ’ ciclosporin.
By 60 months, the incidence of non-skin malignancies was significantly higher in the cohort who continued ciclosporin as compared with the cohort who had ciclosporin withdrawn (8.4% vs.
Sa 60 xahar, l- inċidenza għal malinjitajiet li mhumiex tal- ġilda kienu sinifikament ogħla fil- koorti li kompla b’ ciclosporin meta mqabbel mal- koorti li kellu ciclosporin mneħħi (8. 4% vs 3. 8% rispettivamet).
Concomitant immunosuppressive agents included mycophenolate mofetil, azathioprine, and corticosteroids.
Sustanzi immunosoppressivi konkomitanti kienu jinkludu mycophenolate mofetil, azathioprine u
In the stratum with baseline calculated GFR > 40 mL/ min, the mean and median urinary protein to creatinine ratios were significantly higher in the Rapamune conversion group as compared to those of the calcineurin inhibitors continuation group at 24 months (see section 4.4).
Fl- istratum bil- GFR ikkalkulat fil- linja bażi > 40 ml/ min, il- proteina awrinarja medja u medjana għal proporzjonijiet ta ’ kreatinina kienu sinifikament ogħla fil- grupp ta ’ konverżjoni ta ’ Rapamune meta mqabbel ma ’ dawk fil- grupp li kompla fuq l- inibituri ta ’ calcineurin għal 24 xahar (ara sezzjoni 4. 4).
Rapamune was assessed in a 36-month controlled clinical trial enrolling renal transplant patients  18 years of age considered at high-immunologic risk, defined as having a history of one or more acute allograft rejection episodes and/ or the presence of chronic allograft nephropathy on a renal biopsy.
Rapamune kien evalwat fi prova klinika b’ kontrolli li damet 36 xahar li għaliha ġew irreġistrati pazjenti ta ’ < 18- il sena li kellhom trapjant tal- kliewi li kienu kkunsidrati li kienu f’ riskju immunoloġiku għoli, imfisser li pazjent ikollu storja medika ta ’ episodju wieħed jew aktar ta ’ rifjut ta ’ allograft akut u/ jew il- preżenza ta ’ nefropatija ta ’ allograft kronika meta ssir bijopsija tal- kliewi.
Subjects were to receive Rapamune (sirolimus target concentrations of 5 to 15 ng/ mL) in combination with a calcineurin inhibitor and corticosteroids or to receive calcineurin-inhibitor-based immunosuppression without Rapamune.
L - indvidwi kellhom jirċievu Rapamune (konċentrazzjonijiet fil- mira ta ’ sirolimus ta ’ bejn 5 sa 15 ng/ mL) flimkien ma ’ impeditur ta ’ calcineurin u kortikosterojdi jew inkella jirċievu immunosoppressjoni bbażata fuq impeditur ta ’ calcineurin mingħajr Rapamune.
The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including but not limited to increased serum triglycerides and total cholesterol), and urinary tract infections (see section 4.8).
L- użu ta ’ Rapamune li ngħata flimkien ma ’ impedituri ta ’ calcineurin u kortikosterojdi kien assoċjat ma ’ riskju ogħla ta ’ deterjorament tal- funzjoni renali, abnormalitajiet tal- lipidi fis- serum (li jinkludu, imma mhumiex limitati għal żieda ta ’ trigliċeridi u kolesterol totali fis- serum), u infezzjonijiet fis- sistema urinarju (ara sezzjoni 4. 8).
Information directly related to the tablet formulation is summarised specifically in the Oral Tablet section.
5. 2 Tagħrif farmakokinetiku
Oral solution Following administration of the oral solution, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses.
Soluzzjoni orali Wara t- teħid ta’ soluzzjoni orali, sirolimus jiġi assorbit malajr, biex jilħaq l- ogħla konċentrazzjoni tiegħu f’ ħin ta ’ siegħa f’ individwi b’ saħħithom li ngħataw dożi waħdanin u sagħtejn f’ pazjenti b’ allografts renali stabbli li ngħataw dożi multipli.
The systemic availability of sirolimus in combination with simultaneously administered ciclosporin (Sandimune) is approximately 14%.
Id- disponibilità sistematika ta ’ sirolimus f’ kumbinazzjoni ma ’ ciclosporin (Sandimune) mogħti fl- istess ħin hija ta ’ madwar 14%.
Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold.
Il- half life
The terminal half-life in stable renal transplant patients after multiple oral doses was 62  16 h.
28 terminali wara dożi orali multipli f’ pazjenti stabbli bi trapjant renali kienet ta ’ 62±16h.
The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days.
Madankollu, il- half- life effettiva hija iqsar u l- konċentrazzjonijiet ta ’ stat fiss medji kienu milħuqa wara 5 sa 7 ijiem.
Sirolimus trough concentration data in 35 renal transplant patients > 65 years of age were similar to those in the adult population (n = 822) from 18 to 65 years of age.
It- tagħrif dwar l- aktar konċentrazzjoni baxxa ta ’ sirolimus minn 35 pazjent bi trapjant renali li għandhom > 65 sena kienu simili għal dawk fil- popolazzjoni adulta (n=822) ta ’ bejn 18 sa 65 sena.
The target for trough concentrations was 10-20 ng/ mL.
Il- mira għall- konċentrazzjonijiet l- iktar baxxi kienu 10- 20 ng/ mL.
At steady state, 8 children aged 6-11 years received mean  SD doses of 1.75  0.71 mg/ day (0.064  0.018 mg/ kg, 1.65  0.43 mg/ m2) while 14 adolescents aged 12-18 years received mean  SD doses of 2.79  1.25 mg/ day (0.053  0.0150 mg/ kg, 1.86  0.61 mg/ m2).
Fl- istat fiss, 8 itfal ta ’ bejn l- etajiet ta ’ 6- 11- il sena rċevew dożi medji ± SD ta ’ 1. 75 ± 0. 71 mg/ kuljum (0. 064 ± 0. 018 mg/ kg, 1. 65 ± 0. 43 mg/ m2), filwaqt li 14- il adolexxent bejn l- etajiet ta ’ 12- 18- il sena rċevew dożi medji ± SD ta ’ 2. 79 ± 1. 25 mg/ kuljum (0. 053 ± 0. 0150 mg/ kg, 1. 86 ± 0. 61 mg/ m2).
These data indicate that younger children might require higher bodyweight-adjusted doses than adolescents and adults to achieve similar target concentrations.
Din id- dejta tindika li t- tfal iżgħar għandhom mnejn ikunu jeħtieġu dożi ogħla aġġustati għall- piż tal - ġisem milli għal adolexxenti u adulti sabiex jintlaħqu konċentrazzjonijiet fil- mira simili.
However, the development of such special dosing recommendations for children requires more data to be definitely confirmed.
Madanakollu, rakkomandazzjonijiet għall- iżvilupp ta ’ dożi speċjali bħal dawn għat- tfal jeħtieġu aktar dejta sabiex jiġu kkonfermati b’ mod definittiv.
In mild and moderate hepatically impaired patients (Child-Pugh classification A or B), mean values for sirolimus AUC and t1/ 2 were increased 61% and 43%, respectively, and CL/ F was decreased 33% compared to normal healthy subjects.
F’ pazjenti b’ indeboliment epatiku minn ħafif għal moderat (klassifikazzjoni Child- Pugh A jew B), il- valuri medji għal AUC u t1/ 2 ta ’ sirolimus żdiedu b’ 61% u b’ 43% rispettivament, u CL/ F kien imnaqqas b’ 33% meta mqabbel ma ’ individwi normali b’ saħħithom.
In severe hepatically impaired patients (Child-Pugh classification C), mean values for sirolimus AUC and t1/ 2 were increased 210% and 170% respectively, and CL/ F was decreased by 67% compared to normal healthy subjects.
F’ pazjenti b’ indeboliment epatiku sever (klassifikazzjoni Child- Pugh C), valuri medji għal AUC u t1/ 2 għal sirolimus żdiedu b’ 210% u 170% rispettivament, u CL/ F tnaqqas b’ 67% meta mqabbel ma ’ individwi b’ saħħithom normali.
30 Oral Tablet In healthy subjects, the mean extent of bioavailability of sirolimus after single-dose administration of the tablet formulation is about 27% higher relative to the oral solution.
Pilloli rali F’ individwi b’ saħħithom, il- medda medja ta ’ bijodisponibilità ta ’ sirolimus wara għoti ta ’ doża waħda tal- formulazzjoni tal- pillola hija madwar 27% ogħla relativa mas- soluzzjoni orali.
The mean Cmax was decreased by 35% and mean tmax increased by 82%.
Cmax medja tnaqqset b’ 35% u tmax medja żdied b’ 82%.
The difference in bioavailability was less marked upon steady-state administration to renal transplant recipients, and therapeutic equivalence has been demonstrated in randomised study of 477 patients.
Id- differenza fil- bijodisponibilità kienet anqas qawwija waqt l- għoti fi stat fiss lil reċipjenti ta ’ trapjanti renali, u ekivalenza terapewtika kienet murija fi studju każwali ta ’ 477 pazjent.
When switching patients between oral solution and tablet formulations, it is recommended to give the same dose and to verify the sirolimus trough concentration 1 to 2 weeks later to assure that it remains within recommended target ranges.
Meta pazjenti jkunu ser jinqalbu minn soluzzjoni orali jew formulazzjoni ta ’ pillola għall - oħra, hu rakkomandat li tingħata l- istess doża u li tivverifika l- konċentrazzjoni l- aktar baxxa ta ’ sirolimus ġimgħa sa ġimgħatejn wara biex tassigura li tibqa ’ fil- meded bersaljati.
Also when switching between different tablet strengths, verification of trough concentrations is recommended.
Verifikazzjoni ta ’ konċentrazzjonijiet l- aktar baxxi hija rakkomandata wkoll meta jkun hemm taqlib bejn qawwiet differenti tal- pilloli.
In 24 healthy volunteers receiving Rapamune tablets with a high-fat meal, Cmax, tmax and AUC showed increases of 65%, 32%, and 23%, respectively.
29 F’ 24 volontier b’ saħħtu li ħadu l- pilloli ta ’ Rapamune ma ’ ikla b’ kontenut għoli ta ’ xaħam, Cmax, tmax u AUC urew żidiet ta 65%, 32% u 23% rispettivament.
To minimise variability, Rapamune tablets should be taken consistently with or without food.
Sabiex titnaqqas il- varjabilità, il- pilloli ta ’ Rapamune għandhom jittieħdu konsistentament mal- ikel jew fuq stonku vojt.
Grapefruit juice affects CYP3A4-mediated metabolism and must, therefore, be avoided.
Il- meraq tal- grejpfrut jaffettwa l- metaboliżmu li jsir permezz ta ’ CYP3A4 u għalhekk għandu jkun evitat.
Sirolimus concentrations, following the administration of Rapamune tablets (5 mg) to healthy subjects as single doses are dose proportional between 5 and 40 mg.
Wara l- għoti ta ’ pilloli Rapamune (5 mg) lil individwi f’ saħħithom bħala dożi waħdanin, konċentrazzjonijiet ta ’ sirolimus huma proporzjonali għad- doża bejn 5 u 40 mg.
Initial Therapy (2 to 3 months post-transplant):
Terapija inizjali (2 sa 3 xhur wara t- trapjant):
In most patients receiving Rapamune tablets with a loading dose of 6 mg followed by an initial maintenance dose of 2 mg, whole blood sirolimus trough concentrations rapidly achieved steady-state concentrations within the recommended target range (4 to 12 ng/ ml, chromatographic assay).
F’ ħafna mill- pazjenti li jirċievu l- pilloli ta ’ Rapamune b’ doża inizjali ta ’ 6 mg segwita b’ doża inizjali ta ’ manteniment ta ’ 2 mg, il- konċentrazzjonijiet ta ’ sirolimus fid- demm sħiħ fl- iktar livell baxx, malajr laħqu l- konċentrazzjonijiet fissi fi ħdan il- livelli rakkomandati (4 sa 12 ng/ ml, assaġġ kromatografiku).
Sirolimus pharmacokinetic parameters following daily doses of 2 mg Rapamune tablets administered in combination with ciclosporin microemulsion (4 hours prior to Rapamune tablets) and corticosteroids in 13 renal transplant patients, based on data collected at months 1 and 3 after transplantation, were:
Il- parametri farmakokinetiċi ta ’ sirolimus b’ dożi ta ’ 2 mg kuljum ta ’ pilloli ta ’ Rapamune li ttieħdu ma mikroemulsjoni ta ’ ciclosporin (4 sigħat qabel il- pilloli ta ’ Rapamune) u kortikosterojdi f’ 13- il pazjent li kellhom trapjant renali, bbażata fuq dejta miġbura fiż- żmien xahar u tliet xhur wara t- trasplant kienu:
Cmin, ss, 7.39  2.18 ng/ ml; Cmax, ss, 15.0  4.9 ng/ ml; tmax, ss, 3.46  2.40 h; AUC, ss, 230  67 ng h/ ml; CL/ F/ WT, 139  63 ml/ h/ kg (parameters calculated from LC-MS/ MS assay results).
Cmin, ss, 7. 39 ± 2. 18 ng/ ml; Cmax, ss, 15. 0 ± 4. 9 ng/ ml; tmax, ss, 3. 46 ± 2. 40 h; AUCτ, ss, 230 ± 67 ng· h/ ml; CL/ F/ W, 139 ± 63 ml / siegħa / kg (parametri kkalkulati minn riżultati ta ’ testijiet LC- MS/ MS).
The corresponding results for the oral solution in the same clinical trial were Cmin, ss 5.40  2.50 ng/ ml, Cmax, ss 14.4  5.3 ng/ ml, tmax, ss 2.12  0.84 h, AUC, ss 194  78 ng h/ ml, CL/ F/ W 173  50 ml/ h/ kg.
Cmin, ss, 5. 40 ± 2. 50 ng/ ml; Cmax, ss, 14. 4 ± 5. 3 ng/ ml; tmax, ss, 2. 12 ± 0. 84 h; AUCτ, ss, 194 ± 78 ng· h/ ml; CL/ F/ W, 173 ± 50 ml/ siegħa/ kg.
Whole blood trough sirolimus concentrations, as measured by LC/ MS/ MS, were significantly correlated (r2 = 0.85) with AUC , ss.
Il- konċentrazzjonijiet ta ’ sirolimus fid- demm sħiħ fl- aktar livell baxx, kif mkejla LC/ MS/ MS, kienu korrelatati b’ mod sinifikattiv (r2 = 0. 85) ma ’ AUCτ, ss.
Based on monitoring in all patients during the period of concomitant therapy with ciclosporin, mean (10th, 90th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 8.6  3.0 ng/ ml (5.0 to 13 ng/ ml) and 2.1  0.70 mg (1.5 to 2.7 mg), respectively (see section 4.2).
Ibbażati fuq monitoraġġ fil- pazjenti kollha waqt il- perjodu tat- terapija konkomitanti b’ ciclosporin, konċentrazzjonijiet l- aktar baxxi (espressi bħala valuri ta ’ assaġġi kromatografiċi) medji (10, 90 percentili) u dożi meħuda kuljum kienu 8. 6 ± 3. 0 ng/ ml (5. 0 sa 13 ng/ ml) u 2. 1 ± 0. 70 mg (1. 5 sa 2. 7 mg), rispettivament (ara sezzjoni 4. 2).
From month 3 to month 12, following discontinuation of ciclosporin, mean (10th, 90th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 19  4.1 ng/ ml (14 to 24 ng/ mL) and 8.2  4.2 mg (3.6 to 13.6 mg), respectively (see section 4.2).
Wara t- twaqqif ta ’ ciclosporin, minn xahar 3 sa xahar 12, konċentrazzjonijiet l- aktar baxxi (espressi bħala valuri ta ’ assaġġi kromatografiċi) medji (10, 90 percentili) u dożi ta ’ kuljum kienu 19 ± 4. 1 ng/ ml (14 sa 24 ng/ ml) u 8. 2 ± 4. 2 mg (3. 6 sa 13. 6 mg), rispettivament (ara sezzjoni 4. 2).
Therefore, the sirolimus dose was approximately 4-fold higher to account for both the absence of the pharmacokinetic interaction with ciclosporin (2-fold increase) and the augmented immunosuppressive requirement in the absence of ciclosporin (2-fold increase).
Għalhekk, id- doża ta ’ sirolimus kienet madwar 4 darbiet ogħla biex tagħti kont kemm tan- nuqqas ta ’ interazzjoni farmakokinetika (żieda doppja) u l- ħtieġa immunosoppressiva awmentata fin- nuqqas ta ’ ciclosporin (żieda doppja).
Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese Hamster Ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.
Sirolimus ma kienx mutaġeniku fl- assaġġi in vitro ta ’ mutazzjonijiet batteriċi riversibbli, fl- assaġġ ta ’ aberrazzjoni kromosomali taċ- ċellula tal- ovarji tal- Ħamster Ċiniż, fl- assaġġ tal- mutazzjoni ’ il quddiem taċ- ċellula tal- limfoma tal- ġurdien, jew fl- assaġġ in vivo tal- mikronukleju tal- ġurdien.
31 Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse).
Studji dwar il- karċinoġeniċità magħmula fuq ġrieden u firien, urew żieda fl- inċidenza ta ’ limfomi (fi ġrieden irġiel u nisa), adenoma epatoċellulari u karċinoma (fi ġrieden irġiel) u lewkimja granuloċitika (fi ġrieden nisa).
Partly reversible reductions in sperm counts were reported in a 13-week rat study.
Tnaqqis fil- piż
Reductions in testicular weights and/ or histological lesions (e. g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study.
30 tat- testikoli u/ jew leżjonijiet istoloġiċi (eż. atrofija tubulari u ċelluli tubulari ġganti) kienu osservati fil- firien u fi studju fuq ix- xadini.
Lactose monohydrate Macrogol Magnesium stearate Talc.
Lactose monohydrate, Macrogol, Magnesium stearate, Talc.
Macrogol Glyceryl monooleate Pharmaceutical glaze Anhydrous calcium sulphate Microcrystalline cellulose Sucrose Titanium dioxide Poloxamer 188  -tocopherol Povidone Carnauba wax:
Macrogol, Glyceryl monooleate, Pharmaceutical glaze, Anhydrous calcium sulphate, Microcrystalline cellulose, Sucrose, Titanium dioxide, Poloxamer 188, α- tocopherol Povidone, Carnauba wax:
Red opacode S-1-15095 (shellac glaze ~45% in ethanol, red iron oxide (E172), isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, simethicone).
Red opacode S- 1- 15095 (shellac glaze ~45% f’ ethanol, red iron oxide (E172), isopropyl alcohol, n- butyl alcohol, propylene glycol, ammonium hydroxide, simethicone).
Keep the blister in the outer carton in order to protect from light.
Żomm il- folja fil- kartuna ta 'barra sabiex tilqa ’ mid- dawl.
32 6.5 Nature and contents of container
6. 5 In- natura tal- kontenitur u ta ’ dak li hemm ġo fih
Clear polyvinyl chloride (PVC)/ polyethylene (PE)/ polychlorotrifluoroethylene (Aclar) aluminium blister packages of 30 and 100 tablets.
Pakketti ta '30 u 100 pillola fil- folji tal- aluminju magħmulin minn polyvinyl chloride ċara (PVC) / polyethylene (PE) / polychlorotrifluoroethylene (Aclar).
Rapamune 2 mg coated tablets.
Rapamune 2 mg pilloli miksija.
Each tablet contains 2 mg sirolimus.
Kull pillola fiha 2 mg sirolimus.
Yellow to beige coloured, triangular-shaped coated tablet marked “ RAPAMUNE 2 mg ” on one side.
Pillola ta ’ kulur isfar fil- bex, f’ għamla trijangulari u mmarkata “ RAPAMUNE 2 mg ” fuq naħa waħda.
Ciclosporin should be progressively discontinued over 4 to 8 weeks and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/ ml
Ciclosporin għandu jitwaqqaf gradwalment fuq perjodu ta ’ minn 4 sa 8 ġimgħat u d- doża ta ’ Rapamune għandha tkun aġġustata biex tikseb l- inqas livell ta ’ 12 sa 20 ng/ ml fid- demm (assaġġ kromatografiku; ara Monitoraġġ tal– mediċina terapewtika).
Use in black recipients:
33 Użu f’ pazjenti ta ’ razza sewda:
Use in children and adolescents (< 18 years):
Użu fi tfal u fl- addolexxenti (< 18- il sena):
35 consequently, sirolimus levels will decrease when ciclosporin is discontinued unless the sirolimus dose is increased.
Bħala medja, id- doża ta ’ sirolimus għandha tkun 4 darbiet aktar ogħla
On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of ciclosporin (2-fold increase).
34 biex tpatti kemm għan- nuqqas tal- interazzjoni farmakokinetika (żieda doppja) kif ukoll l- ħtieġa immunosoppressiva awmentata fin- nuqqas ta ’ ciclosporin (żieda doppja).
The recommended ranges 24-hour trough concentration for sirolimus are based on chromatographic methods.
Il- firxiet irrakkomandati ta ’ konċentrazzjonijiet ta ’ 24 siegħa l- aktar baxxi għal sirolimus huma bbażati fuq metodi kromotografiċi.
36 In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely monitored.
35 F’ pazjenti b’ indeboliment epatiku, hu rakkomandat li l- livelli ta ’ konċentrazzjoni l- aktar baxxi ta ’ sirolimus fid- demm sħiħ ikunu mmonitorjati mill- qrib.
Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML).
Fost dawn il- kundizzjonijiet hemm nefropatija li hi assoċjata mal- virus BN u lewkoenċefalopatija multifokali progressiva (PML) li hi assoċjalta mal - virus JC.
These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
Dawn l- infezzjonijiet ta ’ spiss huma relatati ma ’ tagħbija immunosoppressiva totali għolja li tista ’ twassal għal kundizzjonijiet serji jew fatali li t- tobba għandhom jikkunsidraw fid- dijanjosi divrenzjali ta ’ pazjenti immunosoppressi b’ funzjoni renali li tkun sejra għall- agħar jew b’ sintomi newroloġiċi.
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.
Każijiet ta ’ ftuq fil- komunikazzjoni bejn it- tubi tal- bronki, ħafna minnhom fatali, kienu rrappurtati f” pazjenti li kellhom trapjant de novo tal- pulmun waqt li sirolimus kien użat bħala parti minn kors ta ’ kura mmirat biex inaqqas l- immunità.
37 Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.
36 Profilassi għal ċitomegalovirus (CMV) hu rakkomandat li jintuża għal 3 xhur wara t- trapjant, speċjalment minn pazjenti li għandhom riskju għoli għall- mard CMV.
38 telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels.
37 ketoconazole, voriconazole, itraconazole, telithromycin jew clarithromycin) inaqqsu l- metaboliżmu ta ’ sirolimus u jżidu l- livelli ta ’ sirolimus.
39 the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long term treatment with Rapamune.
38 interazzjoni farmakokinetika, ir- riżultati ma jeskludux il- possibilità ta ’ bidliet fil- farmakokinetiċi li jistgħu jaffettwaw l- effikaċja ta ’ kontraċettivi orali waqt trattament fuq tul taż- żmien b’ Rapamune.
Other possible interactions Moderate and weak inhibitorsof CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels (e. g. calcium channel blockers: nicardipine; antifungal agents: clotrimazole, fluconazole; antibiotics: troleandomycin; other substances: bromocriptine, cimetidine, danazol, protease inhibitors).
Interazzjonijiet oħra possibbli Inibituri moderati u dgħajfa ta ’ CYP3A4 jistgħu jnaqqsu l- metaboliżmu ta ’ sirolimus u jżidu l- livell ta ’ sirolimus fid- demm (eż. sustanzi li jimblukkaw il- kanali tal- kalċju: nicardipine; mediċini antifungali: clotrimazole, fluconazole; antibijotiċi: troleandomycin; sustanzi oħra: bromocriptine, cimetidine, danazol, inibituri ta ’ protease).
The most commonly reported adverse drug reactions (occurring in > 10% of patients) are thrombocytopenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH).
L- aktar reazzjonijiet avversi komuni rrapportati (li jiġru f ’ > 10% tal- pazjenti) huma tromboċitopenja, anemija, deni, pressjoni għolja, ipokalimja, ipofosfatemija, infezzjoni tal- passaġġi awrinarji, iperkolesterolemija, ipergliċemija, ipertrigliċeridemija, uġigħ addominali, limfosijl, edema periferali, artralġja, akne, dijarea, uġigħ, stitikezza, tqalligħ, uġigħ ta ’ ras, żieda ta ’ kreatinina fid- demm użieda fil- lactate dehydrogenase (LDH) fid- demm.
40 Adverse reactions based on experience from clinical trials and postmarketing experience are presented in the following table by system organ class and frequency of occurrence.
39 Reazzjonijiet avversi bażati fuq esperjenza minn provi kliniċi u esperjenza ta ’ wara t- tqegħid fis- suq huma preżentati fit- tabella li ġejja skont is- sistema tal- klassifika tal- organi u l- frekwenza ta ’ okkorrenza.
Blood and lymphatic system disorders
Tromboċitopenja
Thrombocytopenia Anaemia
Panċitopenija
Thrombotic thrombocytopenic purpura/ haemolytic uraemic syndrome Leukopenia Neutropenia
tad- demm u tas- sistema limfatika Disturbi fis- sistema immuni Disturbi fil- metaboliżmu u n- nutrizzjoni Disturbi fis- sistema nervuża
Pancytopenia
Anemija Ipokalemja Ipofosfatemija Iperkolesterolaemja Ipergliċemija Ipertrigliċeridemija Uġigħ ta ’ ras
41 System Organ Class
40 Sistema tal- Klassifika tal- Organi Disturbi fil- qalb
Headache
Emboliżmu
Cardiac disorders
Limfoedema
Tachycardia
Disturbi
Pericardial effusion (including haemodynamically significant effusions in children and adults)
Pressjoni għolja
Vascular disorders Respiratory, thoracic, and mediastinal disorders
fondi Pnewmonite
Lymphocele Hypertension
pulmonari Emorraġija
Deep vein thrombosis Pneumonitis Pleural effusion Epistaxis
respiratorji, toraċiċi u medjastinali
Pulmonary embolism Pulmonary haemorrhage
Effużjoni plewrali Epistassi
Lymphoedema Alveolar proteinosis
alveolari
Abdominal pain Diarrhoea Constipation Nausea
Uġigħ addominali, Dijarea Stitikezza Tqalligħ
Liver function tests abnormal
Testijiet tal- funzjoni tal- fwied b’ riżultat abnormali
Musculoskeletal Arthralgia and connective tissue disorders
Disturbi muskolu - skeletrali u tal- connective tissue
Osteonecrosis
Osteonekrosi
Renal and urinary disorders General Oedema peripheral disorders and Pyrexia administration Pain site conditions
Disturbi fil- kliewi u fis- sistema urinarja
Proteinuria Impaired healing Oedema
Sindromu nefrotiku (ara sezzjoni 4. 4)
Nephrotic syndrome (see section 4.4)
kundizzjonijiet ta ’ mnejn jingħata
Investigations Blood lactate dehydrogenase increased Blood creatinine increased
Lactate dehydrogenase
42 Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Rapamune.
Każijiet ta ’ nefropatija assoċjata ma ’ virus BK, kif ukoll każijiet ta ’ lewkoenċefalopatija multifokali progressiva (PML) assoċjata ma ’ virus JC, ġew irrappurtati f’ pazjenti trattati b’ immunosoppressanti, li jinkludu Rapamune.
Hepatotoxicity has been reported, the risk may increase as the trough sirolimus level increases.
Epatossiċità ġiet rapportata, ir- riskju jista ’ jiżdied kif il- livelli l- aktar baxxi ta ’ sirolimus jiżdiedu.
Impaired healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia, and anastomotic disruption (e. g. wound, vascular, airway, ureteral, biliary).
41 Fejqan imdgħajjef wara kirurġija ta ’ trapjant ġiet irrapportata, inklużi ftuħ tal- faxxa, ftuq inċiżjonali u sfaxxar tal- anastomożi (eż. ferita, vaskulari, passaġġi tal- arja, uretrali, biljari).
Paediatric population Controlled clinical trials with posology comparable to that currently indicated for the use of Rapamune in adults — that is, use in combination with ciclosporin and corticosteroids for 2 to 3 months post-transplantation followed by withdrawal of ciclosporin thereafter— have not been conducted in children or adolescents ( 18 years of age).
Provi kliniċi kkontrollati b’ pożoloġija li tista ’ titqabbel ma ’ dik li attwalment hija indikata għall- użu ta ’ Rapamune fl- adulti — jiġifieri, l- użu flimkien ma ’ ciclosporin u kortikosterojdi għal minn xahrejn sa 3 xhur wara t- trapjant li jiġi segwit mit- tneħħija ta ’ ciclosporin wara dan— ma sarux fi tfal jew adolexxenti (li għandhom età ta ’ < 18- il sena).
In another study enrolling renal transplant patients  20 years of age that was intended to assess the safety of progressive corticosteroid withdrawal (beginning at six months post-transplantation) from an immunosuppressive regimen initiated at transplantation that included full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed post-transplant lymphoproliferative disorder (PTLD).
Fi studju ieħor li fih kienu rreġistrati pazjenti ta ’ ≤20 sena li kellhom trapjant tal- kliewi li kien maħsub biex jevalwa s- sigurtà ta ’ twaqqif progressiv tal- kortikosterojdi (li beda sitt xhur wara t- trapjant) minn kors immunosoppressiv li nbeda mat- trapjant li kien jinkludi immunosoppressjoni b’ doża sħiħa kemm b’ Rapamune kif ukoll b’ impeditur ta ’ calcineurin flimkien ma ’ induzzjoni ta ’ basiliximab, mill- 274 pazjent li rreġistraw, 19 (6. 9%) kienu rrappurtati li żviluppaw disturb limfoproliferattiv ta ’ wara t - trapjant (PTLD).
43 Among 89 patients known to be EBV seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD.
Fost 89 pazjent magħruf li kienu seronegattivi għal EBV qabel it- trapjant, 13 (15. 6%) kienu rrappurtati li żviluppaw PTLD.
All patients who developed PTLD were aged  18 years.
Il- pazjenti kollha li żviluppaw PTLD kienu < 18 sena.
In the patient stratum with baseline calculated GFR > 40 mL/ min, renal function was not improved overall.
43 Fl- istratum tal- pazjenti bil- GFR ikkalkulat fil- linja bażi > 40 ml/ min, il- funzjoni renali ma kinetx mtejba globalment.
In two multi-centre clinical studies, de novo renal transplant patients treated with Rapamune, mycophenolate mofetil (MMF), corticosteroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with a calcineurin inhibitor, MMF, corticosteroids, and an IL-2 receptor antagonist (see section 4.4).
F’ żewġ studji kliniċi multi- ċentrali, pazjenti ta ’ trapjanti renali de novo trattati b’ Rapamune, mycophenolate mofetil (MMF), kortikosterojdi, u antagonista tar- riċettur IL- 2 kellhom rati ta ’ irroftar riġettazzjon akuta sinifikament ogħla u rati ta ’ mwiet numerikament ogħla meta mqabbla ma ’ pazjenti ttrattati b’ inibitur ta ’ calcineurin, MMF, kortikosterojdi u antagonista tar- riċettur IL- 2 (ara sezzjoni 4. 4).
Rapamune was assessed in a 36-month controlled clinical trial enrolling renal transplant patients  18 years of age considered at high-immunologic risk, defined as having a history of one or more acute allograft rejection episodes and/ or the presence of chronic allograft nephropathy on a renal biopsy.
Rapamune kien evalwat fi prova klinika kkontrollata li damet 36 xahar li għaliha ġew irreġistrati pazjenti ta ’ < 18- il sena li kellhom trapjant tal- kliewi li kienu kkunsidrati li kienu f’ riskju immunoloġiku għoli, imfisser bħala li pazjent ikollu storja medika ta ’ episodju wieħed jew aktar ta ’ rifjut ta ’ allograft akut u/ jew il- preżenza ta ’ nefropatija ta ’ allograft kronika meta ssir bijopsija tal - kliewi.
The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including but not limited to increased serum triglycerides and total cholesterol), and urinary tract infections (see section 4.8).
L- użu ta ’ Rapamune li ngħata flimkien ma ’ impedituri ta ’ calcineurin u kortikosterojdi kien assoċjat ma ’ riskju ogħla ta ’ deterjorament tal- funzjoni renali, abnormalitajiet tal- lipidi fis- serum (li jinkludu, imma mhumiex limitat għal żieda ta ’ trigliċeridi u kolesterol totali fis- serum), u infezzjonijiet fis- sistema urinarju (ara sezzjoni 4. 8).
45 Much of the general pharmacokinetic information was obtained using the oral solution, which is summarised first.
Ħafna mill- informazzjoni farmakokinetika ġenerali kienet miksuba permezz tas- soluzzjoni orali, li hija mogħtija fil- qosor l- ewwel.
Information directly related to the tablet formulation is summarised specifically in the Oral Tablet section.
Informazzjoni relatata direttament għal formulazzjoni tal- pillola hija miġbura fil- qosor taħt is- sezzjoni Pilloli orali.
Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold.
B’ għoti ripetut, il- konċentrazzjoni medja ta ’ sirolimus fid- demm tiżdied b’ madwar 3 darbiet.
The terminal half-life in stable renal transplant patients after multiple oral doses was 62  16 h.
Il- half life terminali wara dożi orali multipli f’ pazjenti stabbli bi trapjant renali kienet ta ’ 62±16h.
The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days.
Madankollu, il- half- life effettiva hija iqsar u l- konċentrazzjonijiet ta ’ stat fiss medji kienu milħuqa wara 5 sa 7
At steady state, 8 children aged 6-11 years received mean  SD doses of 1.75  0.71 mg/ day (0.064  0.018 mg/ kg, 1.65  0.43 mg/ m2) while 14 adolescents aged 12-18 years received mean  SD doses of 2.79  1.25 mg/ day (0.053  0.0150 mg/ kg, 1.86  0.61 mg/ m2).
Fl- istat fiss, 8 itfal ta ’ bejn l- etajiet ta ’ 6- 11- il sena irċevew dożi medji ± SD ta ’ 1. 75 ± 0. 71 mg/ kuljum (0. 064 ± 0. 018 mg/ kg, 1. 65 ± 0. 43 mg/ m2) filwaqt li 14- il adolexxent ta ’ bejn l- etajiet ta ’ 12- 18- il sena rċevew dożi medji ± SD ta ’ 2. 79 ± 1. 25 mg/ kuljum (0. 053 ± 0. 0150 mg/ kg, 1. 86 ± 0. 61 mg/ m2).
These data indicate that younger children might require higher bodyweight-adjusted doses than adolescents and adults to achieve similar target concentrations.
Din id- dejta tindika li t- tfal iżgħar għandhom mnejn ikunu jeħtieġu dożi ogħla aġġustati għall- piż tal- ġisemi ogħla milli għal adolexxenti u adulti sabiex jintlaħqu konċentrazzjonijiet fil- mira simili.
46 Oral Tablet In healthy subjects, the mean extent of bioavailability of sirolimus after single-dose administration of the tablet formulation is about 27% higher relative to the oral solution.
Pilloli orali F’ individwi b’ saħħithom, il- medda medja ta ’ bijodisponibilità ta ’ sirolimus wara għoti ta ’ doża waħda tal- formulazzjoni tal- pillola hija madwar 27% ogħla relativa mas- soluzzjoni orali.
In 24 healthy volunteers receiving Rapamune tablets with a high-fat meal, Cmax, tmax and AUC showed increases of 65%, 32%, and 23%, respectively.
45 F’ 24 volontier b’ saħħtu li ħadu l- pilloli ta ’ Rapamune ma ’ ikla b’ kontenut għoli ta ’ xaħam, Cmax, tmax u AUC urew żidiet ta 65%, 32% u 23% rispettivament.
Cmin, ss, 7.39  2.18 ng/ ml; Cmax, ss, 15.0  4.9 ng/ ml; tmax, ss, 3.46  2.40 h; AUC, ss, 230  67 ng h/ ml; CL/ F/ WT, 139  63 ml/ h/ kg (parameters calculated from LC-MS/ MS assay results).
Cmin, ss, 7. 39 ± 2. 18 ng/ ml; Cmax, ss, 15. 0 ± 4. 9 ng/ ml; tmax, ss, 3. 46 ± 2. 40 h; AUCτ, ss, 230 ± 67 ng· h/ ml; CL/ F/ W, 139 ± 63 ml/ siegħa/ kg (parametri kkalkulati minn riżultati ta ’ testijiet LC- MS/ MS).
From month 3 to month 12, following discontinuation of ciclosporin, mean (10th, 90th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 19  4.1 ng/ ml (14 to 24 ng/ ml) and 8.2  4.2 mg (3.6 to 13.6 mg), respectively (see section 4.2).
Wara t- twaqqif ta ’ ciclosporin, minn xahar 3 sa xahar 12, konċentrazzjonijiet l- aktar baxxi (espressi bħala valuri ta ’ assaġġi kromatografiċi) medji (10, 90 percentili) u dożi ta ’ kuljum kienu 19 ± 4. 1 ng/ ml (14 sa 24 ng/ ml) u 8. 2 ± 4. 2 mg (3. 6 sa 13. 6 mg), rispettivament (ara sezzjoni 4. 2).
Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.
Sirolimus ma kienx mutaġeniku fl- assaġġi in vitro ta ’ mutazzjonijiet batteriċi riversibbli, fl- assaġġ ta ’ aberrazzjoni kromosomali taċ- ċellula tal- ovarji tal- Ħamster Ċiniż, fl- assaġġ tal- mutazzjoni ’ il quddiem taċ- ċellula tal- limfoma tal- ġurdien, jew fl- assaġġ in vivo tal- mikronukleju tal- ġurdien.
47 Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse).
Studji dwar il- karċinoġeniċità magħmula fuq ġrieden u firien, urew żieda fl- inċidenza ta ’ limfomi (fi ġrieden irġiel u nisa), adenoma epatoċellulari u karċinoma (fi ġrieden irġiel) u lewkimja granuloċitika (fi ġrieden nisa).
Reductions in testicular weights and/ or histological lesions (e. g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study.
Tnaqqis fil- piż tat- testikoli u/ jew leżjonijiet istoloġiċi (eż. atrofija tubulari u ċelluli tubulari ġganti) kienu osservati 46 fil- firien u fi studju fuq ix- xadini.
Macrogol Glyceryl monooleate Pharmaceutical glaze Anhydrous calcium sulphate Microcrystalline cellulose Sucrose Titanium dioxide Brown iron oxide (E172) Yellow iron oxide (E172) Poloxamer 188  -tocopherol Povidone Carnauba wax Red opacode S-1-15095 (shellac glaze ~45% in ethanol, red iron oxide (E172), isopropyl alcohol, n-butyl alcohol, propylene glycol, ammonium hydroxide, simethicone).
Red opacode S- 1- 15095 (shellac glaze ~45% f’ ethanol, red iron oxide (E172), isopropyl alcohol, n- butyl alcohol, propylene glycol, ammonium hydroxide, simethicone).
23 months.
23 xahar
48 6.5 Nature and contents of container
6. 5 In- natura tal- kontenitur u ta ’ dak li hemm ġo fih
Any unused product or waste material would be disposed of in accordance with local requirements.
Kull fdal tal- prodott li ma jkunx intuża jew skart li jibqa ’ wara l- użu tal- prodott għandu jintrema kif jitolbu l- liġijiet lokali.
49 ANNEX II
48 ANNESS II
Kildare Ireland
Kildare l- Irlanda
Or
jew
Wyeth Pharmaceuticals New Lane, Havant, Hampshire, PO9 2NG United Kingdom
Wyeth Pharmaceuticals New Lane, Havant, Hampshire, PO9 2NG Ir- Renju Unit
The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch
Fuq il- fuljett ta ’ tagħrif tal- prodott mediċinali għandu jkun hemm l- isem u l- indirizz tal- manifattur responsabbli għal- ħruġ tal- lott konċernat
The Marketing Authorisation Holder will continue to submit annual PSURs.
Id- Detentur tal- Awtorizzazzjoni għat- Tqegħid fis- Suq ser jkompli jissottometti PSURs kull sena.
53 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING TEXT FOR 60 ml OUTER CARTON (CONTAINING SYRINGES/ BOTTLE IN CARTON)
52 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA U L- PAKKETT LI JMISS MAL- PRODOTT TEST GĦALL- PAKKETT TA ’ BARRA 60 ml (PAKKETT FIH SIRINGI/ FLIXKUN)
Rapamune 1 mg/ ml oral solution Sirolimus
Rapamune 1 mg/ ml soluzzjoni orali Sirolimus
Each ml of Rapamune contains 1 mg sirolimus.
Kull ml ta ’ Rapamune fih 1 mg sirolimus.
Also contains: ethanol (1.5% to 2.5%), propylene glycol, soya fatty acids.
Fih ukoll: ethanol (1. 5% sa 2. 5%), propylene glycol, soya fatty acids.
60 ml oral solution 30 dosing syringes 1 syringe adapter 1 carrying case
60 ml soluzzjoni orali 30 siringi tad- dożaġġ 1 adapter tas- siringi 1 but li ġġorru miegħek
The bottle containing Rapamune can be removed from the carton and stored directly in the refrigerator.
Il- flixkun li fih Rapamune jista ’ jitneħħa mill- kartuna u jinħażen direttament fi friġġ.
Use within 30 days after opening bottle.
Uża fi żmien 30 jum wara li tiftaħ il- flixkun.
Wyeth Europa Ltd Huntercombe Lane South Taplow, Maidenhead, Berkshire, SL6 0PH United Kingdom
Wyeth Europa Ltd Huntercombe Lane South Taplow, Maidenhead, Berkshire, SL6 0PH Ir- Renju Unit
55 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING TEXT FOR RAPAMUNE INTERMEDIATE CARTON:
54 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA U L- PAKKETT LI JMISS MAL- PRODOTT TEST GĦALL- PAKKETT TAN- NOFS, RAPAMUNE:
60 ml BOTTLE
FLIXKUN 60 ml
60 ml oral solution
60 ml soluzzjoni orali
57 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING TEXT FOR RAPAMUNE FIX-A-FORM BOTTLE LABEL:
56 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA U L- PAKKETT LI JMISS MAL- PRODOTT TEST GĦAT- TIKKETTA MWAĦĦALA MAL- FLIXKUN RAPAMUNE:
Oral use.
Użu orali
Peel back for further information
Qaxxar wara għal aktar informazzjoni
Date opened
Data meta ġie miftuħ
59 PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING CARTONS – PACK SIZES 30 AND 100 TABLETS
58 TAGĦRIF LI GĦANDU JIDHER FUQ IL- PAKKETT TA ’ BARRA U L- PAKKETT LI JMISS MAL- PRODOTT KARTUN – PAKKETTI TA ’ QISIEN TA ’ 30 U 100 PILLOLA
Rapamune 1 mg coated tablets Sirolimus
Rapamune 1 mg pilloli miksija Sirolimus
Each Rapamune tablet contains 1 mg sirolimus
Kull pillola ta ’ Rapamune fiha 1 mg sirolimus.
Also contains: lactose monohydrate, sucrose
Fih ukoll: lactose monohydrate, sucrose
30 coated tablets 30 x 1 mg 100 coated tablets 100 x 1 mg
30 pillola miksija 30 x 1 mg 100 pillola miksija 100 x 1 mg
Oral use Read the package leaflet before use
Aqra l- fuljett ta ’ tagħrif qabel l- użu.
Keep the blister in the outer carton in order to protect from light.
Żomm il- folja fil- kartuna ta ’ barra sabiex tilqa ’ mid- dawl.
EU/ 1/ 01/ 171/ 007 30 tablets EU/ 1/ 01/ 171/ 008 100 tablets
EU/ 1/ 01/ 171/ 007 30 pillola EU/ 1/ 01/ 171/ 008 100 pillola
Rapamune 1 mg tablets Sirolimus
Rapamune 1 mg pilloli Sirolimus