qanastek/EMEA-V3 huggingface dataset:
There is insufficient experience to recommend the use of Rapamune in children and adolescents (see section 4.2).
M’ hemmx biżżejjed esperjenza sabiex l- użu ta ’ Rapamune jiġi rakkomandat fi tfal u adolexxenti (ara sezzjoni 4. 2).
11 4.9 Overdose
4. 9 Doża eċċessiva
At present, there is minimal experience with overdose.
Attwalment hemm esperjenza minima f’ doża eċċessiva.
One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of Rapamune.
Pazjent wieħed kellu esperjenza ta ’ episodju ta ’ fibrillazjoni atrijali wara li ħa doża ta ’ 150 mg ta ’ Rapamune.
In general, the adverse effects of overdose are consistent with those listed in section 4.8.
Ġeneralment l- effetti avversi ta ’ doża eċċessiva huma konsistenti ma ’ dawk elenkati f’ sezzjoni 4. 8.
General supportive measures should be initiated in all cases of overdose.
Għandhom jittieħdu miżuri ġenerali ta ’ appoġġ fil- każijiet kollha ta ’ doża eċċessiva.
Based on the poor aqueous solubility and high erythrocyte and plasma protein binding of Rapamune, it is anticipated that Rapamune will not be dialysable to any significant extent.
Huwa antiċipat li Rapamune ma jkunx dijalizzabbli b’ mod sinifikattiv, minħabba li ma jitħallatx malajr fl- ilma u r- rabta għolja mal- eritroċiti u l- proteini fil- plażma.
Pharmacotherapeutic group: selective immunosuppressant agents.
Kategorija farmakoterapewtika: mediċini immunosoppressivi selettivi.
Sirolimus inhibits T cell activation induced by most stimuli, by blocking calcium dependent and calcium independent intracellular signal transduction.
11 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.
Studies demonstrated that its effects are mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other immunosuppressive agents.
Studji wrew li l- effetti tiegħu jsiru permezz ta ’ mekkaniżmu li hu differenti minn dak ta ’ cyclosprin, tacrolimus, u mediċini immunosoppressivi oħra.
Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12 and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression.
Evidenza mill- esperimenti turi li sirolimus jintrabat ma ’ proteina ċitosolika speċifika FKPB- 12 u li l- kumpless FKPB 12- sirolimus jinibixxi l- attivazzjoni ta ’ bersall mammiferu ta ’ Rapamycin (mTOR), kinase kritiku għal progressjoni taċ- ċiklu ċellulari.
The inhibition of mTOR results in blockage of several specific signal transduction pathways.
L- inibizzjoni ta ’ mTOR tirriżulta fl- ostruzzjoni ta ’ diversi mogħdijiet speċifiċi tas- sinjal tat- transduzzjoni.
The net result is the inhibition of lymphocyte activation, which results in immunosuppression.
Ir- riżultat kollu hu t- twaqqif tal- inibizzjoni tal- attivazzjoni tal- limfoċita, li tirriżulta f’ immunosoppressjoni.
In animals, sirolimus has a direct effect on T and B cell activation suppressing immune mediated reactions such as allograft rejection.
Fl- annimali, sirolimus għandu effett dirett fuq l- attivazzjoni taċ- ċelluli T u B li jrażżan reazzjonijiet immunitarji bħal ma huma r- riġettazzjoni tal- allograft.
Clinical Trials Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin elimination-Rapamune maintenance trial, which included patients receiving a renal allograft from a cadaveric or living donor.
Provi Kliniċi Pazjenti b’ riskju immunologiku minn baxx sa moderat kienu mistħarrġa fi prova ta ’ fażi 3 dwar l- eliminazzjoni ta ’ ciclosporin- manteniment ta ’ Rapamune, li kienet tinkludi pazjenti li ngħataw allograft renali minn donatur kadaveriku jew ħaj.
In addition, re-transplant recipients whose previous grafts survived for at least 6 months after transplantation were included.
Barra dan, kienu inklużi wkoll reċipjenti ta ’ trapjanti ġodda li l- grafts li kellhom baqgħu jgħixu għal tal- inqas 6 xhur minn wara li sar it- trapjant.
Ciclosporin was not withdrawn in patients experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum creatinine > 400  mol/ l, or who had inadequate renal function to support ciclosporin withdrawal.
Ciclosporin ma kienx imwaqqaf f’ pazjenti li esperjenzaw episodji ta ’ riġettazzjoni akuta Banff Grad 3, li kienu dipendenti mid- dijalisi, li kellhom kreatinina fis- serum > 400 μmol/ l, jew li kellhom il- funzjoni renali inadegwata sabiex tiflaħ għat- twaqqif ta ’ ciclosporin.
Patients at high immunological risk of graft loss were not studied in sufficient number in the ciclosporin elimination- Rapamune maintenance trials and are not recommended for this treatment regimen.
Pazjenti li kienu f’ riskju immunoloġiku għoli li jitilfu t- tessuti tat- trapjant ma kinux mistħarrġa f’ numru suffiċjenti fil- proċessi ta ’ provi dwar l- eliminazzjoni ta ’ ciclosporin- manteniment ta ’ Rapamune u mhumiex rakkomandati għal dan ir- reġimen ta ’ fejqan.
At 12, 24 and 36 months, graft and patient survival were similar for both groups.
Fit- 12, 24 u 36 xahar, is- sopravivenza tal- graft u tal- pazjent kienu l- istess għaż- żewġ gruppi.
At 48 months, there was a statistically significant difference in graft survival in favour of the Rapamune following ciclosporin elimination group compared to the Rapamune with ciclosporin therapy group (including and excluding loss to follow-up).
Fit- 48 xahar, kien hemm differenza statistikament sinifikattiva fis- sopravivenza tal- graft a favur tal- grupp li rċieva Rapamune wara l- eliminazzjoni ta ’ ciclosporin, meta kkumparat mal- grupp li rċieva Rapamune flimkien mat- terapija b’ ciclosporin (li tinkludi u teskludi t- telf mal- follow up).
There was a significantly higher rate of first biopsy-proven rejection in the ciclosporin elimination group compared to the ciclosporin maintenance group during the period post-randomisation to 12 months (9.8% vs.
Kien hemm rata sinifikament ogħla tal- ewwel riġettazzjoni pprovata b’ bijopsija fil- grupp tal- eliminazzjoni ta ’ ciclosporin meta mqabbel mal- grupp ta ’ manteniment ta ’ ciclosporin wara l- perjodu ta ’ wara r- randomizzazzjoni għal 12- il xahar (9. 8% vs.
4.2%, respectively).
4. 2% rispettivament).
Thereafter, the difference between the two groups was not significant.
Minn hemm ’ il quddiem id- differenza bejn iż- żewġ gruppi ma kinetx sinifikanti.
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 with ciclosporin therapy group.
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.
Based upon the analysis of data from 36 months and beyond, which showed a growing difference in graft survival and renal function, as well as significantly lower blood pressure in the ciclosporin elimination group, it was decided to discontinue subjects from the Rapamune with ciclosporin group.
Abbażi tal- analiżi tad- dejta minn 36 xahar ’ il quddiem, li wriet differenza dejjem tikber fis- sopravivenza tal- graft u tal- funzjoni renali, kif ukoll pressjoni tad- demm sinifikattivament iktar baxxa fil- grupp ta ’ eliminazzjoni ta ’ ciclosporin, ġie deċiż li l- pazjenti ma jitħallewx ikomplu fil- grupp ta ’ Rapamune flimkien 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
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).
For skin carcinoma, the median time to first occurrence was significantly delayed.
Għal karċinoma tal- ġilda, il- ħin medjan għall- ewwel okkorenza kien sinifikament ittardjat.
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients (6-120 months after transplantation) was assessed in a randomised, multicentre, controlled trial, stratified by calculated GFR at baseline (20-40 mL/ min vs > 40 mL/ min).
Is- sigurtà u l- effikaċja tal- konverżjoni minn inibituri ta ’ calcineurin għal Rapamune f’ pazjenti bi trapjanti renali mantenuti (6- 120 xahar wara t- trapjant) kienu assessjati fi prova kkontrollata, każwali, multiċentrali, stratifikata skont il- GFR ikkalkulat fil- linja bażi (20- 40 ml/ min kontra > 40 ml/ min).
Concomitant immunosuppressive agents included mycophenolate mofetil, azathioprine, and corticosteroids.
Sustanzi immunosoppressivi konkomitanti kienu jinkludu mycophenolate mofetil, azathioprine u kortikosterojdi.
Enrollment in the patient stratum with baseline calculated GFR < 40 mL/ min was discontinued due to an imbalance in safety events (see section 4.8).
Ir- reklutaġġ fl- istratum tal- pazjenti bil- GFR ikkalkulat fil- linja bażi < 40 ml/ min ġie mwaqqaf minħabba żbilanċ f’ okkorenzi ta ’ sigurtà (ara sezzjoni 4. 8).
In the patient stratum with baseline calculated GFR > 40 mL/ min, renal function was not improved overall.
Fl- istratum tal- pazjenti bil- GFR ikkalkulat fil- linja bażi > 40 ml/ min, il- funzjoni renali ma kinetx mtejba globalment.
The rates of acute rejection, graft loss, and death were similar at 1 and 2 years.
Ir- rati ta ’ riġettazzjoni akuta, telf ta ’ graft u mewt kienu simili fl- 1 u t- 2 sena.
Treatment emergent adverse events occurred more frequently during the first 6 months after Rapamune conversion.
Każijiet emerġenti ta ’ trattament avvers seħħew bi frekwenza akbar matul l- ewwel sitt xhur wara konverżjoni għal Rapamune.
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
New onset nephrosis (nephrotic syndrome) was also reported (see section 4.8).
Il- ħruġ ta ’ nefrożi ġdida (sindromu nefrotiku) kien ukoll irrapportat (ara sezzjoni 4. 8).
At 2 years, the rate of non-melanoma skin malignancies was significantly lower in the Rapamune conversion group as compared to the calcineurin inhibitors continuation group (1.8% and 6.9%).
Wara sentejn, ir- rata ta ’ malinjitajiet tal- ġilda li mhumiex melanoma, kienet sinifikament aktar baxxa fil- grupp ta ’ konverżjoni ta ’ Rapamune meta mqabbla mal- grupp li kompla fuq inibituri ta ’ calcineurin (1. 8% u 6. 9%).
In a subset of the study patients with a baseline GFR > 40 mL/ min and normal urinary protein excretion, calculated GFR was higher at 1 and 2 years in patients converted to Rapamune than for the corresponding subset of calcineurin inhibitor continuation patients.
F’ sottosett tal- pazjenti studjati b’ linja bażi ta ’ GFR > 40 ml/ min u eliminazzjoni normali ta ’ proteina awrinarja, il- GFR ikkalkulat kien ogħla fl- ewwel sena u sentejn f’ pazjenti kkonvertiti għal Rapamune milli għas- sottoset korrispondenti ta ’ pazjenti li tkomplew fuq inibitur ta ’ calcineurin.
The rates of acute rejection, graft loss, and death were similar, but urinary protein excretion was increased in the Rapamune treatment arm of this subset.
Ir- rati ta ’ riġettazzjoni akuta, telf tal- graft, u mewt kienu simili, imma l- eliminazzjoni ta ’ proteina awrinarja kienet mgħollija fid- driegħ tat- trattament ta ’ Rapamune ta ’ dan is- sottosett.
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 ’ riġettazzjoni 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).
Renal function was not better in the treatment arms with de novo Rapamune without a calcineurin inhibitor.
Il- funzjoni renali ma kinetx aħjar fid- driegħ b’ Rapamune de novo mingħajr inibitur ta ’ calcineurin.
An abbreviated dosing schedule of daclizumab was used in one of the studies.
Skeda ta ’ dożi abbrevjati għal daclizumab kienet użata fl- istudji.
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 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.
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 Rapamune group failed to demonstrate superiority to the control group in terms of the first occurrence of biopsy confirmed acute rejection, graft loss, or death.
Il- grupp li kien qed jieħu Rapamune naqas milli juri superjorità fuq il- grupp tal- kontroll fir- rigward tal- ewwel każijiet ta ’ rifjut akut ikkonfermat permezz ta ’ bijopsija, telf tal- graft jew mewt.
One death occurred in each group.
Mewt waħda seħħet f’ kull grupp.
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 urinarja (ara sezzjoni 4. 8).
An unacceptably high frequency of PTLD was seen in a paediatric clinical transplant study when full dose Rapamune was administered to children and adolescents in addition to full dose calcineurin inhibitors with basiliximab and corticosteroids (see section 4.8).
Kienet osservata frekwenza għolja mhix aċċettabbli ta ’ PTLD fi studju kliniku dwar it- trapjanti fuq it - tfal meta doża sħiħa ta ’ Rapamune ngħatat lil tfal u adolexxenti flimkien ma ’ doża sħiħa ta ’ impedituri ta ’ calcineurin flimkien ma ’ basiliximab u kortikosterojdi (ara sezzjoni 4. 8).
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.
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.
Upon repeated
Id- disponibilità sistematika ta ’ sirolimus f’ kumbinazzjoni ma ’ ciclosporin (Sandimune) mogħti fl- istess ħin hija ta ’ madwar 14%.
13 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 16h.
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 ijiem.
The blood to plasma ratio (B/ P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements.
Il- proporzjon fid- demm mal- plażma (B/ P) ta ’ 36 jindika li sirolimus huwa mqassam estensivament ġol- elementi formati tad- demm.
Pharmacokinetic parameters for sirolimus obtained from 19 renal transplant patients receiving microemulsion ciclosporin (4 hours prior to Rapamune) and corticosteroids, following daily doses of 2 mg Rapamune solution in a phase III clinical trial, were; Cmax, ss 12.2 6.2 ng/ ml, tmax, ss 3.01  2.40h, AUC, ss 158  70 ng h/ ml, CL/ F/ W 182 72 ml/ h/ kg (parameters calculated from LC-MS/ MS assay results).
Cmax, ss 12. 2±6. 2 ng/ ml, tmax, ss 3. 01± 2. 40h, AUCτ, ss 158±70 ng· h/ ml, CL/ F/ W 182±72 ml/ h/ kg (parametri kkalkulati minn reżultati ta ’ analiżi LC- MS/ MS).
There was no significant difference in any of these parameters over time up to 6 months after transplantation.
Ma kienx hemm differenza sinifikanti f’ dawn il- parametri fuq perjodu ta ’ żmien sa 6 xhur wara t- trapjant.
Mean sirolimus whole blood trough levels from the same phase III trial were 7.2 ng/ ml (4.0 to 11 ng/ ml, expressed as chromatographic assay values; n=226) for the 2 mg per day dose and 14 ng/ ml (8.0 to 22 ng/ ml, expressed as chromatographic assay values; n=219) for the 5 mg per day dose (see section 4.2).
Il- livell medjan ta ’ konċentrazzjoni ta ’ sirolimus fid- demm eżatt qabel ma tingħata d- doża li tmiss, meħuda minn l- istess studju ta ’ fażi III, kienu 7. 2 ng/ ml (4. 0 sa 11 ng/ ml, mfisser bħala valuri ta ’ assaġġ kromatografu; n=226) għad- doża ta ’ 2 mg kulljum u 17 ng/ ml (8. 0 sa
Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein.
Sirolimus huwa substrat kemm għal ċitokroma P450 IIIA4 (CYP3A4) kif ukoll għal P- glikoproteina.
Sirolimus is extensively metabolised by O-demethylation and/ or hydroxylation.
Sirolimus huwa metabolizzat estensivament b’ O- demethylation u/ jew hydroxylation.
Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood.
Seba ’ metaboliti ewlenin, li jinkludu hydroxyl, demethyl, u hydroxydemethyl, ġew identifikati fid- demm sħiħ.
Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity.
Sirolimus hu l- komponent prinċipali fid- demm sħiħ tal- bniedem u jikkontribwixxi għal aktar minn 90% tal- attività immunosoppressiva.
After a single dose of [14C] sirolimus in healthy volunteers, the majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine.
Wara doża waħda ta ’ [14C] sirolimus f’ voluntiera b’ saħħithom, il- parti l- kbira (91. 1%) ta ’ radjoattività nstabet fl- ippurgar, u ammont minuri biss (2. 2%) ġie eliminat fl- awrina.
Clinical studies of Rapamune did not include a sufficient number of patients > 65 years of age to determine whether they will respond differently than younger patients.
Studji kliniċi ta ’ Rapamune ma inkludewx numru suffiċjenti ta ’ pazjenti > 65 sena sabiex jiġi stabbilit jekk jirreaġixxux b’ mod differenti minn pazjenti ta ’ età iżgħar.
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.
In healthy volunteers, a high fat meal altered the bioavailability characteristics of oral liquid sirolimus.
F’ voluntiera b’ saħħithom, ikla li fiha livell għoli ta ’ xaħam bidlet il- karatteristiċi bijodisponibbli ta ’ soluzzjoni orali ta ’ sirolimus.
There was a 34% decrease in the peak blood sirolimus concentration (Cmax), a 3.5-fold increase in the time to peak concentration (tmax), and a 35% increase in total exposure (AUC).
Kien hemm tnaqqis ta ’ 34% fl- ogħla konċentrazzjoni ta ’ sirolimus tad- demm (Cmax), żjieda ta ’ 3. 5 darbiet f’ żmien biex tintlaħaq l- ogħla konċentrazzjoni (tmax), u żieda ta ’ 35% għall- kxif totali (AUC).
It is recommended that Rapamune be taken consistently either with or without food.
Huwa rakkomandat li Rapamune jittieħed b’ mod konsistenti jew mal - ikel jew fuq stonku vojt.
The use of orange juice and water to dilute Rapamune were equivalent with respect to Cmax, and AUC.
L- użu tal- meraq tal- larinġ u ilma biex idgħajjef Rapamune kien ekwivalenti rigward Cmax, u AUC.
In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/ F was larger for younger paediatric patients (580 ml/ h/ kg) than for older paediatric patients (450 ml/ h/ kg) as compared with adults (287 ml/ h/ kg).
F’ pazjenti pedjatriċi fuq dijalisi (tnaqqis ta ’ bejn 30% sa 50% fir- rata ta ’ filtrazzjoni glomerulari) f’ etajiet ta ’ bejn il- 5 u l- 11- il sena u t- 12 u t- 18- il sena, CL/ F medju normalizzat għal piż kien aktar f’ pazjenti pedjatriċi iżgħar (580 ml/ h/ kg) milli għal pazjenti pedjatriċi akbar (450 ml/ h/ kg) kif imqabbel ma ’ adulti (287 ml/ h/ kg).
There was a large variability for individuals within the age groups.
Kien hemm varjabilità għal individwi fil- gruppi tal- etajiet differenti.
Sirolimus concentrations were measured in concentration-controlled trials of paediatric renal-transplant patients who were also receiving ciclosporin and corticosteroids.
Il- konċentrazzjonijiet ta ’ sirolimus tkejlu fi provi kliniċi b’ konċentrazzjonijiet ikkontrollati fuq pazjenti pedjatriċi bi trapjant tal- kliewi li kienu qed jirċievu ciclosporin u kortikosterojdi wkoll.
The target for trough concentrations was 10-20 ng/ mL.
Il- mira għall- konċentrazzjonijiet l- aktar baxxi kienet ta ’ 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 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).
The younger children had a higher weight-normalized Cl/ F (214 mL/ h/ kg) compared with the adolescents (136 mL/ h/ kg).
It- tfal iżgħar kellhom CI/ F normalizzat ogħla meta mqabbel mal- piż (214 mL/ siegħa/ kg) meta mqabbel mal- adolexxenti (136mL/ siegħa/ kg).
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.
Madankollu, 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
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.
The longer half-lives observed in hepatically impaired patients delay reaching steady state.
Il- half- lives itwal osservati f’ pazjenti b’ indeboliment epatiku jdewmu milli jintlaħaq l- istat fiss.
The pharmacokinetics of sirolimus were similar in various populations with renal function ranging from normal to absent (dialysis patients).
Il- farmakokinetiċi ta ’ sirolimus kienu simili f’ popolazzjonijiet diversi b’ funzjoni renali li tvarja minn normali sa assenti (pazjenti tad- dijalisi).
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows: pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis.
Ma dehrux effetti mhux mixtieqa waqt studji kliniċi, iżda dehru f’ annimali li ġew esposti għal doża daqs dik klinika u jista ’ jkollhom rilevanza għall- użu kliniku, kif spjegat: vakwolazzjoni taċ- ċelluli tal- frixa, tħassir tat- tubi testikolari, ulċerazzjoni gastrointestinali, ksur tal- għadam u kallijiet, ematopojesi epatika, u fosfolipidosi pulmonarja.
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.
14 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.
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).
It is known that malignancies (lymphoma) secondary to the chronic use of immunosuppressive agents can occur and have been reported in patients in rare instances.
Huwa magħruf li malinjitajiet (limfoma) sekondarji għall- użu kroniku ta ’ mediċini immunosoppressivi jistgħu jseħħu u ġew irrapportati b’ mod rari f’ pazjenti.
In mouse, chronic ulcerative skin lesions were increased.
Fil- ġrieden, leżjonijiet ulċerattivi kroniċi fil- ġilda, żdiedu.
The changes may be related to chronic immunosuppression.
Il- bidliet jistgħu jkunu relatati ma ’ immunosoppressjoni kronika.
In rat, testicular interstitial cell adenomas were likely indicative of a species dependent response to lutenising hormone levels and are usually considered of limited clinical relevance.
Fil- firien, adenomi fiċ- ċelluli interstizzjali testikolari kienu probabilment indikattivi ta ’ reazzjoni dipendenti fuq l- ispeċi għal- livelli ta ’ ormon lewtenizzanti.
In reproduction toxicity studies decreased fertility in male rats was observed.
Fi studji ta ’ tossiċità riproduttiva ġie osservat tnaqqis fil- fertilità ta ’ firien irġiel.
Partly reversible reductions in sperm counts were reported in a 13-week rat study.
Tnaqqis parzjalment riversibbli fl- għadd tal- isperma kien irrapportat fi stħarriġ ta ’ 13- il ġimgħa fil- firien.
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 fil- firien u fi studju fuq ix- xadini.
(see section 4.6).
Fil- firien, sirolimus ikkawża tossiċità fl- embriju/ fetu li kienet tidher bħala mortalità u tnaqqis fil- piżijiet fetali (b’ dewmien assoċjati fl- ossifikazzjoni skeletrika) (ara sezzjoni 4. 6).
Polysorbate 80 Phosal 50 PG (phosphatidylcholine, propylene glycol, mono-, di-glycerides, ethanol (1.5% to 2.5%), soya fatty acids and ascorbyl palmitate).
Polysorbate 80, Phosal 50 PG (phosphatidyl choline, propylene glycol, mono - u di- glycerides, ethanol (1. 5% sa 2. 5%), soya fatty acids, u ascorbyl palmitate).
Rapamune must not be diluted in grapefruit juice or any other liquid other than water or orange juice (see section 6.6).
Rapamune m’ għandux jiġi mħallat fil- meraq tal- grejpfrut jew ma xi likwidu ieħor għajr l- ilma jew il- meraq tal- laring (ara sezzjoni 6. 6).
Rapamune oral solution contains polysorbate-80, which is known to increase the rate of di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC).
Rapamune soluzzjoni orali fih polysorbate- 80, li hu magħruf li jgħolli r- rata ta ’ estrazzjoni di - (2- ethylhexyl) phthalate (DEHP) minn polyvinyl chloride (PVC).
It is important to follow the instructions to administer Rapamune oral solution at once when a plastic container is used for the dilution and/ or administration (see section 6.6).
Huwa importanti li wieħed isegwi l- istruzzjonijiet sabiex tingħata s- soluzzjoni orali minnufih meta l- kontenitur tal- plastik jintuża għad- diluzzjoni u/ jew għoti (ara sezzjoni 6. 6).
30 days for opened bottle.
30 ġurnata għal flixkun miftuħ.
24 hours in the dosing syringe (at room temperature, but not to exceed 25 C).
24 siegħa fis- siringa ddożata (f’ temperatura tal- kamra, li ma teċċedix 25°C).
After dilution, (see section 6.6) the preparation should be used immediately.
Wara t- taħlita, (ara sezzjoni 6. 6) il- preparazzjoni għandha tiġi użata minnufih.
Store in a refrigerator at 2 C - 8  C.
Aħżen fi friġġ (2°C - 8°C).
Store in the original bottle in order to protect from light.
Aħżen fil- flixkun oriġinali sabiex tilqa ’ mid- dawl.
If necessary, the patient may store the bottles at room temperatures up to 25 C for a short period of time (24 hours).
Jekk ikun meħtieġ, il- pazjent jista ’ jżomm il- flixkien f’ temperatura ambjentali tal- kamra sa 25°C għal żmien qasir (24 siegħa).
6.5 Nature and contents of container
15 6. 5 In- natura tal- kontenitur u ta ’ dak li hemm ġo fih
60 ml type III amber glass bottles with syringe adapter and 30 amber, plastic dosing syringes.
60 ml flixken tal- ħġieġ ta ’ kulur ambra tat- tip III b’ adapter bis- siringa, u 30 siringa tad- doża, tal- plastik ta ’ kulur ambra.
Instructions for use and handling:
Istruzzjonijiet għall- użu u manipulazzjoni:
The dosing syringe should be used to withdraw the prescribed amount of Rapamune from the bottle.
Is- siringi tad- doża għandhom jiġu użati sabiex jiġbdu l- ammont preskritt ta ’ Rapamune mill- flixkun.
Empty the correct amount of Rapamune from the syringe into only a glass or plastic container with at least 60 ml of water or orange juice.
Battal l- ammont korrett ta ’ Rapamune mis- siringa f’ tazza jew kontenitur tal- plastik li mill- anqas għandu 60 ml ta ’ ilma jew meraq tal- larinġ.
No other liquids, including grapefruit juice, should be used for dilution.
L- ebda likwidu ieħor inkluż il- meraq tal- grejpfrut m’ għandu jiġi miżjud mat- taħlita.
Stir vigorously and drink at once.
Ħawwad tajjeb u ixrob mill- ewwel.
Refill the container with an additional volume (minimum of 120 ml) of water or orange juice, stir vigorously, and drink at once.
Erġa ’ imla l- kontenitur b’ volum addizzjonali (mill- anqas 120 ml) ta ’ ilma jew meraq tal- larinġ, ħawwad tajjeb u ixrob mill- ewwel.
14 March 2001 Date of latest renewal:
14 ta ’ Marzu 2001 Data tal- aħħar tiġdid:
15 March 2006
15 ta ’ Marzu 2006
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 tal- Aġenzija Ewropea dwar il- mediċini (EMEA) http: // www. emea. europa. eu.
Rapamune 1 mg coated tablets.
Rapamune 1 mg pilloli miksija.
Each tablet contains 1 mg sirolimus.
Kull pillola fiha 1 mg sirolimus.
Coated tablet.
Pillola miksija.
White coloured, triangular-shaped coated tablet marked “ RAPAMUNE 1 mg ” on one side.
Pillola bajda miksija, ta ’ għamla trijangulari u mmarkata “ RAPAMUNE 1 mg ” fuq naħa waħda.
It is recommended that Rapamune be used initially in combination with ciclosporin microemulsion and corticosteroids for 2 to 3 months.
Huwa rakkomandat li għall- ewwel Rapamune jingħata flimkien ma ’ mikroemulsjoni ta ’ ciclosporin u ta ’ kortikosterojdi għal bejn 2 u 3 xhur.
Bioavailability has not been determined for tablets after they have been crushed, chewed or split and therefore this cannot be recommended.
Il- bijodisponibilità ma ġietx stabbilita għal pilloli wara li dawn ġew imfarrka, imgħaddma jew maqsuma u għalhekk dawn ma jistgħux jiġu rakkomandati.
Suggested ciclosporin trough concentration ranges for the first 2-3 months after transplantation are 150 - 400 ng/ ml (monoclonal assay or equivalent technique).
Il- livelli suġġeriti tal- konċentrazzjoni l- aktar baxxa ta ’ ciclosporin għall- ewwel 2- 3 xhur wara t- trapjant, huma bejn 150- 400 ng/ ml (analiżi monoklonali jew xi tip ta ’ analiżi simili).
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:
17 Użu f’ pazjenti ta ’ razza sewda:
Use in children and adolescents ( 18 years):
Użu fi tfal u fl- addolexxenti (< 18- il sena):
The available data on safety and efficacy are not sufficient to recommend the use of Rapamune in children and adolescents less than 18 years of age (see sections 4.8 and 5.1).
Id- dejta disponibbli dwar is- sigurtà u l- effikaċja mhijiex biżżejjed biex ikun rakkomandat l- użu ta ’ Rapamune fit- tfal u fl- addolexxenti li għandhom inqas minn 18- il sena (ara sezzjonijiet 4. 8 u 5. 1)..
Clinical studies with Rapamune oral solution did not include a sufficient number of patients > 65 years of age to determine whether they will respond differently than younger patients.
Fl- istudji kliniċi bis- soluzzjoni orali ta ’ Rapamune, ma kienx hemm numru suffiċjenti ta ’ pazjenti anzjani > 65 sena, biex tkun tista ’ tgħid jekk jirrispondux differenti minn pazjenti ta ’ età iżgħar.
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.
F’ 35 każ ta ’ trapjant renali f’ pazjenti ta ’ > 65 sena, l- informazzjoni dwar il- konċentrazzjoni l- aktar baxxa ta ’ sirolimus, kienet simili għal dawk f’ popolazzjoni adulta (n=822) fl- età ta ’ bejn 18 u 65 sena.
Rapamune tablets administered to 12 renal transplant patients > 65 years of age also gave similar results to adult patients (n = 167) 18 to 65 years of age.
Ingħata riżultat simili bħal f’ pazjenti adulti (n=167) ta ’ bejn 18 u 65 sena meta pilloli Rapamune ngħataw lil 12- il pazjent b’ età ta ’ > 65 li kellhom trapjant renali.
To minimize variability, Rapamune should be taken at the same time in relation to ciclosporin, 4 hours after the ciclosporin dose, and consistently either with or without food (see section 5.2).
Sabiex titnaqqas l- inkonsistenza, Rapamune għandu jittieħed fl- istess ħin f’ relazzjoni ma ’ ciclosporin, 4 sigħat wara d- doża ta ’ ciclosporin, u b’ mod konsistenti jew mal- ikel jew fuq stonku vojt (ara sezzjoni 5. 2).
Patients can be switched from the solution to the tablet formulation on a mg per mg basis.
Pazjenti jistgħu jinqalbu minn fuq is- soluzzjoni għal fuq il- formulazzjoni tal- pilloli fuq bażi ta ’ mg għal mg.
It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or tablet strength to confirm that the trough concentration is within the recommended target range.
Hu rakkomandat li l- aktar konċentrazzjoni baxxa ttieħed 1 jew 2 ġimgħat wara li jinqalbu l- formulazzjonijiet jew il- qawwa tal- pilloli biex jikkonfermaw li l- aktar konċentrazzjoni baxxa tkun fil- firxa bersalljata rakkomandata.
Ciclosporin inhibits the metabolism of sirolimus, and
Ciclosporin jimpedixxi l- metaboliżmu ta ’ sirolimus, u b’ konsegwenza, il- livelli ta ’ sirolimus jonqsu meta ciclosporin jitwaqqaf, sakemm ma tiżdiedx id- doża ta ’ sirolimus.
19 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).
18 biex tpatti kemm għan- nuqqas tal- interazzjoni farmakokinetika (żieda doppja) kif ukoll l- ħtieġa immunosoppressiva awmentata fin- nuqqas ta ’ ciclosporin (żieda doppja).
Rapamune loading dose = 3 x (new maintenance dose – current maintenance dose).
Għandha tiġi kkunsidrata doża inizjali qawwija flimkien ma ’ doża ġdida ta ’ manteniment meta jkun meħtieġ li jiżdiedu kunsiderevolment l- konċentrazzjonijiet l- aktar baxxi ta ’ sirolimus: doża inizjali qawwija ta ’ Rapamune = 3 x (doża ġdida ta ’ manteniment – doża attwali ta ’ manteniment).
The maximum Rapamune dose administered on any day should not exceed 40 mg.
Id- doża massima ta ’ Rapamune mogħtija fi kwalunkwe ġurnata m’ għandiex taqbeż l- 40 mg.
If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days.
Jekk id- doża ta ’ stima ta ’ kuljum taqbeż l- 40 mg minħabba ż- żieda ta ’ doża inizjali qawwija, id- doża inizjali qawwija għandha tiġi mogħtija fuq jumejn.
Adjustments to the targeted range should be made according to the assay being utilized to determine the sirolimus trough concentrations.
Aġġustamenti fil- valuri tal- medda mixtieqa għandhom isiru skont l- assaġġ li jkun qed jintuża sabiex jistabilixxi l- aktar konċentrazzjonijiet baxxi ta ’ sirolimus.
20 In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely monitored.
19 F’ pazjenti b’ indeboliment epatiku, hu rakkomandat li l- livelli ta ’ konċentrazzjoni l- aktar baxxi ta ’ sirolimus fid- demm sħiħ ikunu mmonitorjati mill- qrib.
Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression (see section 4.8).
L- immunosoppressjoni tista ’ tirriżulta f’ aktar suxxetibilità għall- infezzjonijiet u l- possibilità ta ’ żvilupp ta ’ limfoma u malinjitajiet oħra, partikularment tal- ġilda (ara sezzjoni 4. 8).
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 BK u lewkoċefalopatija multifokali progressiva (PML) li hi assoċjata 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 jikkonsidraw fid- dijanjosi diverenzjali ta ’ pazjenti immunosoppressi b’ funzjoni renali li tkun sejra għall- agħar jew b’ sintomi newroloġiċi
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults), in patients receiving Rapamune.
Kien hemm rapporti ta ’ akkumulazzjoni ta ’ fluwidu, li jinkludu edema periferali, limfoedema, effużjoni plewrali u effużjonijiet perikardjali (li jinkludu effużjonijiet emodinamikament sinifikanti fi tfal u adulti), f’ pazjenti li jirċievu Rapamune.
21 Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.
20 Profilassi għal ċitomegalovirus (CMV) hu rakkomandat li jintuża għal 3 xhur wara t- trapjant, speċjalment minn pazjenti li għandhom riskju għoli għall- mard CMV.
The risk/ benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune.
Ir- riskju/ benefiċċju għandu jkun ikkonsidrat f’ pazjenti li jbatu regolarment minn iperlipidimja, qabel jinbeda t- trattament b’ reġimen immunosoppressiv li jinkludi Rapamune.
Similarly the risk/ benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidemia.
Hekk ukoll ir- riskju/ benefiċċju ta ’ terapija ta ’ Rapamune għandu jkun evalwat mill- ġdid f’ pazjenti li jbatu minn iperlipidimja refrattorja severa.
In clinical trials, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/ or fibrates was well tolerated.
Fi studji kliniċi, l- amministrazzjoni ta ’ Rapamune ma ’ prodotti li jinibixxu HMG- CoA reductase u/ jew fibrati kien ittolerat tajjeb.
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.
Is - sigurtà u l- effikaċja tal- konverżjoni minn inibituri ta ’ calcineurin għal Rapamune f’ pazjenti bi trapjant renali mantenut għadhom ma ġewx stabbiliti.
The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced haemolytic uraemic syndrome/ thrombotic thrombocytopenic purpura/ thrombotic microangiopathy (HUS/ TTP/ TMA).
L- użu konkomitanti ta ’ Rapamune ma ’ impeditur ta ’ calcineurin jista ’ jżid ir- riskju ta ’ sindrome uremiku emolitiku mqanqal minn inibitur ta ’ calcineurin/ purpura tromboċitopenika trombotika/ mikroanġjopatija trombotika (HUS/ TTP/ TMA).
Sirolimus tablets contain sucrose and lactose.
Pilloli ta ’ sirolimus fihom sukrosju u lattosju.
In those patients with a history of sucrase insufficiency, isomaltase insufficiency, fructose intolerance, glucose malabsorption, galactose malabsorption, galactose intolerance (e. g., galactosemia), or Lapp lactase deficiency, a careful risk/ benefit assessment should be performed prior to prescribing sirolimus tablets.
F’ dawk il- pazjenti bi storja ta ’ insuffiċjenza ta ’ sucrase, insuffiċjenza ta ’ isomaltase, intolleranza ta ’ fruktosju, malassorbiment ta ’ glukosju, malassorbiment ta ’ galaktosju, intoleranza galaktosja (eż. galaktosemija), jew Lapp lactase deficiency, stima bir- reqqa ta ’ riskju/ siwi għandha tiġi magħmula qabel ma ’ pilloli ta ’ sirolimus jinkitbu b’ riċetta ta ’ tabib.
Sirolimus is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver.
Sirolimus jiġi metaboliżżat b’ mod estensiv mill- isoenzimi CYP3A4 fil- ħajt tal- musrana u fil- fwied.
Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole,
Inibituri ta ’ CYP3A4 (bħal
22 telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels.
21 ketoconazole, voriconazole, itraconazole, telithromycin jew clarithromycin) inaqqsu l- metaboliżmu ta ’ sirolimus u jżidu l- livelli ta ’ sirolimus.
Sirolimus administered concomitantly (5 mg), and at 2h (5 mg) and 4h (10 mg) after CsA (300 mg) resulted in increased sirolimus AUC by approximately 183%, 141% and 80% respectively.
Sirolimus (5 mg) mogħti fl- istess ħin, u sagħtejn (5 mg) u erba’ sigħat wara (10 mg) CsA (300 mg) rriżulta f’ żieda fl- AUC ta; sirolimus ta ’ bejn wieħed u ieħor 183%, 141% u 80% rispettivament.
Rifampicin (CYP3A4 inducer):
Rifampicin (stimulatur ta ’ CYP3A4):
Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from Rapamune oral solution as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively.
Meta doża multipla ta ’ ketoconazole ttieħdet, din affettwat b’ mod sinifikattiv ir- rata u l- estenzjoni tal- assorbiment u tal- espożizzjoni ta ’ sirolimus mis- soluzzjoni orali ta ’ Rapamune kif ġie rifless biż- żieda f’ sirolimus Cmax, tmax, u AUC ta ’ 4. 4 darbiet, 1. 4 darbiet, u 10. 9 darbiet, rispettivament.
No clinically significant pharmacokinetic interaction was observed between Rapamune oral solution and 0.3 mg norgestrel/ 0.03 mg ethinyl estradiol.
L- ebda interazzjoni farmakokinetika klinikament sinifikanti ma ġiet osservata bejn soluzzjoni orali ta ’ Rapamune u 0. 3 mg norgestrel/ 0. 03 mg ethinyl estradiol.
Although the results of a single dose drug interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction,
Għalkemm ir- riżultati ta ’ studju ta ’ interazzjoni reċiproka b’ doża waħda ma ’ kontraċettiv orali ssuġġerew in- nuqqas ta ’
23 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.
22 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.
John's wort, (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin).
John’ s Wort (Hypericum perforatum), antikonvulsivi: caramazepine, phenobarbital, phenytoin).
Although sirolimus inhibits human liver microsomal cytochrome P450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/ 5 in vitro, the active substance is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune.
Għalkemm sirolimus in vitro jinibixxi ċitokroma mikrosomali tal- fwied uman P450 CYP2C9, CYP2C19, CYP2D6, u CYP3A4/ 5, madankollu s- sustanza attiva mhix mistennija li tfixkel l- attività ta ’ dawn l- isoenzimi in vivo, ġaladarba l- konċentrazzjonijiet ta ’ sirolimus neċessarji biex jikkawżaw inibizzjoni huma aktar għoljin f’ pazjenti li jirċievu dożi terapewtiċi ta ’ Rapamune.
The most commonly reported adverse drug reactions (occuring 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).
Żieda ta ’ kreatinina fid- demm u żieda fil- lactate dehydrogenase (LDH) fid- demm.