qanastek/EMEA-V3 huggingface dataset:
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).
Bħala medja, id- doża ta ’ sirolimus għandha tkun 4 darbiet aktar ogħla biex tpatti kemm għan- nuqqas tal- interazzjoni farmakokinetika (żieda doppja) kif ukoll l- ħtieġa immunosoppressiva awmentata fin- nuqqas ta ’ ciclosporin (żieda doppja).
The rate at which the dose of sirolimus is increased should correspond to the rate of ciclosporin elimination.
Ir- rata taż- żieda tad- doża ta ’ sirolimus għandha tikkorispondi mar- rata tal- eliminazzjoni ta ’ ciclosporin.
If further dose adjustment(s) are required during maintenance therapy (after discontinuation of ciclosporin), in most patients these adjustments can be based on simple proportion: new Rapamune dose = current dose x (target concentration/ current concentration).
Jekk ikunu meħtieġa aktar aġġustament( i) fid- doża waqt terapija ta ’ manteniment (wara twaqqif ta ’ ciclosporin), fil- parti l- kbira tal- pazjenti dawn l- aġġustamenti jistgħu jiġu bbażżati fuq proporzjon sempliċi: doża ġdida Rapamune = doża attwali x (konċentrazzjoni bersalljata/ konċentrazzjoni attwali).
The
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).
3 maximum Rapamune dose administered on any day should not exceed 40 mg.
Jekk id- doża ta ’
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.
3 stima ta ’ kuljum taqbeż l- 40 mg minħabba ż- żieda ta ’ doża inizjali qawwija, id- doża inizjali qawwija għandha tiġi mogħtija fuq jumejn.
Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).
Il- konċentrazzjonijiet l- aktar baxxi ta ’ sirolimus għandhom jiġu mmonitorjati għal tal- anqas 3 sa 4 ijiem wara d- doża( i) inizjali.
In patients with severe hepatic impairment, monitoring should be performed every 5 to 7 days until 3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment or after loading dose due to the delay in reaching steady state because of the prolonged half-life.
F’ pazjenti b’ indeboliment epatiku sever, il- monitoraġġ għandu jsir bejn kull 5 sa 7 ijiem sakemm jidhru 3 livelli baxxi konsekuttivi ta ’ konċentrazzjonijiet stabbli ta ’ sirolimus wara tibdil fid- doża jew wara doża inizjali qawwija li tingħata minħabba dewmien fl- ilħuq ta ’ stat fiss minħabba l- half- life mtawla.
The recommended 24-hour trough concentration ranges 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.
Several assay methodologies have been used to measure the whole blood concentrations of sirolimus.
Diversi metodoloġiji ta ’ assaġġ ġew użati biex jitkejlu l- konċentrazzjonijiet fid- demm sħiħ ta ’ sirolimus.
Currently in clinical practice, sirolimus whole blood concentration are being measured by both chromatographic and immunoassay methodologies.
Attwalment, fil- prattika klinika, konċentrazzjonijiet fid- demm sħiħ ta ’ sirolimus qed jiġu mkejlin kemm b’ metodoloġiji kromatografiċi u ta ’ immunoassaġġ.
The concentration values obtained by these different methodologies are not interchangeable.
Il- valuri ta ’ konċentrazzjoni miksubin b’ dawn il- metodoloġiji differenti ma jinbidlux waħda mal- oħra.
When using a proprietary immunoassay system, always refer to the manufacturer’ s information to correlate values to a reference chromatographic assay.
Meta tintuża sistema ta ’ immunoassaġġ proprjetarja, dejjem ikkonsulta l- informazzjoni tal- manifattur biex tikkorrelata valuri ma ’ assaġġ kromatografiku ta ’ riferiment.
All sirolimus concentrations reported in this Summary of Product Characteristics were either measured using chromatographic methods or have been converted to chromatographic method equivalents.
Il- konċentrazzjonijiet kollha ta ’ sirolimus irrapportati f’ dan is- Sommarju ta ’ Karatteristiċi tal- Prodott kienu mkejlin jew bl- użu ta ’ metodi kromatografiċi jew ġew mibdula għal metodi kromatografiċi ekwivalenti.
Adjustments to the targeted range should be made according to the assay being utilised 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.
Other considerations for use:
Konsiderazzjonijiet oħra għall- użu:
Ciclosporin (microemulsion) and other medicinal or non-medicinal products may interact with sirolimus (see section 4.5).
Ciclosporin (mikroemulsjoni) u prodotti oħra medicinali jew mhumiex jistgħu jaffettwaw lil sirolimus (ara sezzjoni 4. 5).
Rapamune has not been adequately studied in patients at high immunological risk (see section 5.1).
Rapamune ma ġiex studjat adegwatament f’ pazjenti li kienu f’ riskju immunoloġiku għoli (ara sezzjoni 5. 1).
Concomitant use with other immunosuppressive agents Sirolimus has been administered concurrently with the following agents in clinical studies: ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies.
Użu konkomitanti b’ mediċini immunosoppressivi oħra Fi studji kliniċi sirolimus ġie mogħti fl- istess waqt ma ’ dawn il- mediċini li ġejjin: ciclosporin, azathioprine, mycophenolate mofetil, kortikosterojdi u antikorpi ċitotossiċi.
Sirolimus in combination with other immunosuppressive agents has not been extensively investigated.
Sirolimus flimkien ma ’ mediċini immunosoppressivi oħra ma ġiex investigat estensivament.
Based on information from subsequent clinical trials, the use of Rapamune, mycophenolate mofetil, and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not recommended in the de novo renal transplant setting (see section 5.1).
Minn informazzjoni miġbura minn provi kliniċi sussegwenti, l- użu ta ’ Rapamune, mycophenolate mofetil u kortikosterojdi, flimkien mal- induzzjoni minn antikorpi ta ’ riċetturi IL- 2 (IL2R Ab), mhix rakkomandata fl- ambjent ta ’ trapjanti renali de novo (ara sezzjoni 5. 1).
Immunosuppressants may affect response to vaccination.
L- immunosoppressuri jistgħu jeffetwaw ir- rispons għat- tilqim.
During treatment with immunosuppressants, including Rapamune, vaccination may be less effective.
It- tilqim jista ’ jkun anqas effettiv matul trattament b’ mediċini li jnaqqsu l- immunità, inkluż Rapamune.
The use of live vaccines should be avoided during treatment with Rapamune.
L- użu ta ’ vaċċini (ħajjin) għandu jiġi evitat waqt it- trattament b’ Rapamune.
In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely monitored.
F’ pazjenti b’ indeboliment epatiku, hu rakkomandat li l- livelli ta ’ konċentrazzjoni l- aktar baxxi ta ’ sirolimus fid- demm sħiħ ikunu mmonitorjati mill- qrib.
In patients with severe hepatic impairment, reduction in maintenance dose by one half is recommended based on decreased clearance (see sections 4.2 and 5.2).
F’ pazjenti li għandhom indeboliment epatiku sever, it- tnaqqis bin- nofs fid- doża ta ’ manteniment hu rakkomandat skont it- tnaqqis fit- tneħħija (ara sezzjonijiet 4. 2 u 5. 2).
Since half-life is prolonged in these patients, therapeutic drug monitoring after a loading dose or a change of dose should be performed for a prolonged period of time until stable concentrations are reached (see sections 4.2 and 5.2).
Peress li l- half- life hi mtawla f’ dawn il- pazjenti monitoraġġ tal- mediċina terapewtika wara doża inizjali qawwija jew bidla fid- doża għandha tiġi mwettqa għal perjodu mtawwal ta ’ żmien sakemm jintlaħqu konċentrazzjonijiet stabbli (ara sezzjonijiet 4. 2 u 5. 2).
Co-administration of sirolimus with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) is not recommended (see section 4.5).
L- għoti ta ’ sirolimus flimkien ma’ mediċini li jinibixxu b’ mod qawwi CYP3A4 (eż. ketoconazole, voriconazole, itraconazole, telithromycin jew clarithromycin) jew stimulanti ta ’ CYP3A4 (eż. rifampin, rifabutin) mhix rakkomandata (ara sezzjoni 4. 5).
4 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).
4 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).
Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections, fatal infections, and sepsis.
Tnaqqis żejjed tas- sistema tal- immunità tista ’ ukoll iżżid is- suxxetibilità għall- infezzjonijiet, inklużi infezzjonijiet opportunistiċi, infezzjonijiet fatali, u sepsis.
Patients treated with immunosuppressants, including Rapamune, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal).
Pazjenti trattati b’ immunosoppressanti, li jinkludu Rapamune, jinsabu f’ riskju ogħla ta ’ infezzjonijiet opportunistiċi (batteriċi, fungali, virali u protożoali).
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 lewkoenċefalopatija 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 jikkunsidraw fid- dijanjosi diverenzjali ta ’ pazjenti immunosoppressi b’ funzjoni renali li tkun sejra għall- agħar jew b’ sintomi newroloġiċi.
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended.
Is- sigurtà u l- effikaċja ta ’ Rapamune bħala terapija immunosoppressiva ma ġietx stabbilità f’ pazjenti li kellhom trapjant tal- fwied jew tal- pulmun, u għalhekk, l- użu tiegħu mhux rakkomandat.
In two clinical studies in de novo liver transplant patients the use of sirolimus plus ciclosporin or tacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss or death.
F’ żewġ studji kliniċi f” pazjenti li kellhom trapjant tal- fwied de novo, l- użu ta ’ sirolimus flimkien ma ’ ciclosporin jew ma ’ tacrolimus kien assoċjat maż- żieda ta ’ trombożi fl- arterja epatika, li kkaġuna t- telf tat- tessut tat- trapjant jew mewt.
There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence.
Kien hemm rapporti ta ’ fejqan indebolit jew imdewwem ta ’ feriti f’ pazjenti li qed jirċievu Rapamune li jinkludi limfosel jew ftuħ tal- ferita.
Patients with a BMI greater than 30 kg/ m2 may be at increased risk of abnormal wound healing based on data from the medical literature.
Pazjenti li għandhom BMI ogħla minn 30 kg/ m2 għandhom mnejn ikunu f’ riskju akbar ta ’ fejqan anormali tal- feriti minn tagħrif fil- letteratura medika.
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.
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 rapportati 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.
Hypersensitivity reactions, including anaphylactic/ anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus (see section 4.8).
Sensittività eċċessiva, inklużi reazzjonijiet anafilattiċi/ anafilattojdi, anġjoedima, dermatite eksfoljattiva, u vaskulite ipersensittiva kienu assoċjati mat- teħid ta ’ sirolimus (ara sezzjoni 4. 8).
In rare cases, the concomitant administration of sirolimus and ACE inhibitors has resulted in angioneurotic oedema-type reactions.
F’ każijiet rari, l- għoti ta ’ sirolimus flimkien ma ’ inibituri tal- ACE irriżultaw f’ reazzjonijiet tat- tip edima anġjonewrotika.
As usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Bħas- soltu għal pazjenti li jinsabu f’ riskju akbar tal- kanċer tal- ġilda, li huma esposti għad- dawl tax- xemx u dawl UV għandhom jilbsu ilbies prottettiv u jużaw krema kontra r- raġġi tax- xemx li għandha fattur għoli ta ’ protezzjoni.
Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis.
Każijiet ta ’ pulmonite kkawżati minn Pneumocystis carinii kienu rapportati f’ pazjenti li ma ngħatawx profilassi antimikrobjali.
Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation.
Għalhekk profilassi antimikrobjali kontra l- pulmonite kkawżata minn Pneumocystis carinii għandha tingħata għall- ewwel 12- il xahar ta ’ wara t- trapjant.
Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.
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 use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.
L- użu ta ’ Rapamune minn pazjenti li għamlu trapjant tal- kliewi kien assoċjat ma żieda ta ’ kolesterol u triġliċerdi fis- serum li seta ’ kien jeħtieġ kura.
Patients administered Rapamune should be monitored for hyperlipidemia using laboratory tests and if hyperlipidemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated.
Pazjenti li jingħataw Rapamune għandhom jiġu mmonitorjati għal iperlipidimja permezz ta ’ testijiet tal- laboratorju u jekk tinstab l- iperlipidimja, interventi sussegwenti bħal ma ’ huma d- dieta, l- eżerċizzju, u mediċini li jbaxxu l- lipidi (xaħmijiet) għandhom jinbdew.
The risk/ benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including
Hekk ukoll ir- riskju/ benefiċċju ta ’ terapija ta ’ Rapamune għandu jkun evalwat mill- ġdid f’ pazjenti li jbatu minn iperlipidimja refrattorja severa.
Similarly the risk/ benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidemia.
5 Fi studji kliniċi, l- amministrazzjoni ta ’ Rapamune ma ’ prodotti li jinibixxu HMG- CoA reductase u/ jew fibrati kien ittolerat tajjeb.
During Rapamune therapy, patients administered an HMG-CoA reductase inhibitor and/ or fibrate, should be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the respective Summary of Product Characteristics of these agents.
Matul it- terapija ta ’ Rapamune, il- pazjenti li jieħdu prodotti li jinibixxu HMG- CoA reductase u/ jew fibrati, għandhom jiġu monitorati għall- possibilità ta ’ żvilupp ta ’ rabdomajoliżi u effetti avversi kif deskritti fis- Sommarju tal- Karatteristiċi tal- Prodott ta ’ dawn is - sustanzi.
Renal function should be monitored during concomitant administration of Rapamune and ciclosporin.
Il- funzjoni renali għandha tiġi mmonitorjata meta Rapamune jingħata flimkien ma ’ ciclosporin.
Appropriate adjustment of the immunosuppression regimen should be considered in patients with elevated serum creatinine levels.
Aġġustament adattat tar- reġimen tal- immunosoppressjoni għandu jiġi konsidrat f’ pazjenti b’ livelli għoljin ta ’ kreatinina fis- serum.
Caution should be exercised when co-administering other agents that are known to have a deleterious effect on renal function.
Għandha tiġi eżerċitata l- kawtela meta fl- istess ħin jiġu amministrati mediċini oħra magħrufa li huma ta ’ ħsara għall- funzjoni tal- kliewi.
Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and placebo or azathioprine controls.
Pazjenti li ħadu ciclosporin u Rapamune għal aktar minn 3 xhur, kellhom livelli aktar ogħla ta ’ kreatinina fis- serum u livelli aktar baxxi fir- rati kkalkulati ta ’ filtrazzjoni glomerulari meta mqabbla ma ’ pazjenti li ħadu ciclosporin u plaċebo, jew b’ kontrolli ta ’ azathioprine.
Patients who were successfully withdrawn from ciclosporin had lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower incidence of malignancy, compared to patients remaining on ciclosporin.
Pazjenti li twaqqfu b’ suċċess milli jieħdu ciclosporin kellhom livelli aktar baxxi ta ’ kreatinina fis- serum u rati aktar ogħla ta ’ filtrazzjoni glomerulari kkalukati, kif ukoll inċidenza aktar baxxa ta ’ malinjità meta mqabbla ma ’ pazjenti li baqgħu fuq ciclosporin.
The continued co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended.
It- tkomplija ta ’ għoti flimkien ta ’ ciclosporin u Rapamune bħala terapija ta ’ manteniment ma jistgħux ikunu rrakkomandati.
In patients with delayed graft function, sirolimus may delay recovery of renal function.
F’ pazjenti b’ funzjoni mdawwem tal- graft, sirolimus jista ’ jdewwem l- irkupru tal- funzjonament renali.
Periodic quantitative monitoring of urinary protein excretion is recommended.
Huwa rakkomandat li jkun hemm monitoraġġ kwantitattiv perjodiku tal- eliminazzjoni tal- proteini fl - awrina.
In a study evaluating conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to Rapamune (see section 5.1).
Fi studju li evalwa l- konverżjoni minn impedituri ta ’ calcineurin għal Rapamune f’ pazjenti bi trapjant renali mantenut, iż- żieda fl- eliminazzjoni ta ’ proteini fl- awrina kienet osservata b’ mod komuni ħafna għal bejn 6 xhur sa 24 xahar wara konverżjoni għal Rapamune (ara sezzjoni 5. 1).
New onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study (see section 4.8).
Ġie rapportat ukoll li ħarġet nefrożi (sindromu nefrotiku) fi 2% tal- pazjenti fl- istudju (ara sezzjoni 4. 8).
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 ’ sindromu uremiku emolitiku mqanqal minn inibitur ta ’ calcineurin/ purpura tromboċitopenika trombotika/ mikroanġjopatija trombotika (HUS/ TTP/ TMA).
Sirolimus is extensively metabolised 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.
Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine.
Sirolimus huwa wkoll substrat għall- pompa li tarmi ’ l barra mediċini differenti, P- glikoproteina (P- gp) li tinsab fil- musrana ż- żgħira.
Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins.
Għalhekk, l- assorbiment u l- eliminazzjoni sussegwenti ta ’ sirolimus jistgħu jkunu influwenzati minn sustanzi li jaffettwaw dawn il- proteini.
Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels.
Inibituri ta ’ CYP3A4 (bħal ketoconazole, voriconazole, itraconazole, telithromycin jew clarithromycin) inaqqsu l- metaboliżmu ta ’ sirolimus u jżidu l- livelli ta ’ sirolimus.
Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels.
Induċituri ta ’ CYP3A4 (bħal rifampin jew rifabutin) iżidu l- metaboliżmu ta ’ sirolimus u jnaqqsu l- livelli ta ’ sirolimus.
Co-administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended (see section 4.4).
L- għoti ta ’ sirolimus flimkien ma ’ inibituri qawwija li jmorru kontra t- tkattir ta ’ CYP3A4 jew mediċini li jistimulaw CYP3A4 mhumiex rakkomandati (ara sezzjoni 4. 4).
Ciclosporin (CYP3A4 substrate):
Ciclosporin (substrat ta ’ CYP3A4):
The rate and extent of sirolimus absorption was significantly increased by ciclosporin A (CsA).
Ir- rata u l- firxa tal- assorbiment ta ’ sirolimus kienu sinifikattivament miżjuda b’ ciclosporin A (CsA).
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.
The effect of CsA was also reflected by increases in sirolimus Cmax and tmax.
L- effett ta ’ CsA kien rifless b’ żieda f’ Cmax, u fit- tmax ta ’ sirolimus.
When given 2 hours before CsA administration, sirolimus Cmax and AUC were not affected.
Meta ġie mogħti sagħtejn qabel l- għotja ta ’ CsA, sirolimus Cmax u AUC ma kinux affettwati.
Single-dose sirolimus did not affect the pharmacokinetics of ciclosporin (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart.
Doża waħdanija ta ’ sirolimus meta meħuda ma ’ cyclosprin, flimkien jew b’ 4 sigħat differenza bejniethom, ma effetwatx il- farmakokinetika ta ’ ciclosporin (mikroemulsjoni) f’ voluntiera b’ saħħithom.
It is recommended that Rapamune be administered 4 hours after ciclosporin (microemulsion).
Huwa rakkomandat li Rapamune jittieħed 4 sigħat wara ciclosporin (mikroemulsjoni).
6 Rifampicin (CYP3A4 inducer):
6 Rifampicin (stimulatur ta ’ CYP3A4):
Administration of multiple doses of rifampicin decreased sirolimus whole blood concentrations following a single 10 mg dose of Rapamune oral solution.
L- għoti ta ’ dożi multipla ta ’ rifampicin naqqas il- konċentrazzjoni ta ’ sirolimus fid- demm wara li ttieħdet doża waħda ta ’ 10 mg ta ’ Rapamune soluzzjoni orali.
Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased AUC and Cmax by approximately 82% and 71%, respectively.
Rifampicin żied it- tneħħija ta ’ sirolimus b’ madwar 5. 5 darbiet u naqqas AUC u Cmax b’ madwar 82% u 71%, rispettivament.
Co-administration of sirolimus and rifampicin is not recommended (see section 4.4).
Mhux rakkomandat li sirolimus u rifampicin jittieħdu flimkien (ara sezzjoni 4. 4)
Ketoconazole (CYP3A4 inhibitor):
Ketoconazole (inibitur ta ’ CYP3A4):
Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure 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 kif ġie rifless biż- żieda f’ sirolimus Cmax, tmax, u AUC ta ’ 4. 4 darbiet, 1. 4 darbiet, u 10. 9 darbiet, rispettivament.
Co-administration of sirolimus and ketoconazole is not recommended (see section 4.4).
Mhux rakkomandat li sirolimus u ketoconazole jingħataw flimkien (ara sezzjoni 4. 4).
Voriconazole (CYP3A4 inhibitor):
Voriconazole (inibitur ta ’ CYP3A4):
Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7-fold and 11-fold respectively.
Sirolimus (2 mg f’ doża waħdanija) meħud ma ’ doża multipla ta ’ voriconazole orali (400 mg kull 12- il siegħa għal jum wieħed biss, u 100 mg kull 12- il siegħa għal 8 ijiem), minn voluntiera b’ saħħithom wera żieda ta ’ Cmax u AUC, b’ rata medja ta ’ 7 darbiet u 11- il darba, rispettivament.
Co-administration of sirolimus and voriconazole is not recommended (see section 4.4).
Mhux rakkomandat li sirolimus u voriconazole jingħataw flimkien (ara sezzjoni 4. 4).
Diltiazem (CYP3A4 inhibitor):
Diltiazem (inibitur ta ’ CYP3A4):
The simultaneous oral administration of 10 mg of Rapamune oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus.
L- għoti mill- ħalq ta ’ 10 mg ta ’ soluzzjoni orali ta ’ Rapamune flimkien ma ’ 120 mg ta ’ diltiazem affettwaw b’ mod sinifikanti l- bijodisponibilità ta ’ sirolimus.
Sirolimus Cmax, tmax, and AUC were increased 1.4-fold, 1.3-fold, and 1.6-fold, respectively.
Sirolimus Cmax, tmax, u AUC żdiedu b’ 1. 4 darbiet, 1. 3 darbiet, u 1. 6 darbiet, rispettivament.
Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem.
Sirolimus ma affettwax il- farmakokinetiċi ta ’ diltiazem jew il- metaboliti tiegħu ta ’ desacetyldiltiazem u desmethyldiltiazem.
If diltiazem is administered, sirolimus blood levels should be monitored and a dose adjustment may be necessary.
Jekk diltiazem jiġi mogħti, il- livelli ta ’ sirolimus fid- demm għandhom jiġu mmonitorjati, u aġġustament fid- doża jista ’ jkun neċessarju.
Verapamil (CYP3A4 inhibitor):
Verapamil (inibitur ta ’ CYP3A4):
Multiple-dose administration of verapamil and sirolimus oral solution significantly affected the rate and extent of absorption of both drugs.
Ir- rata u l- firxa ta ’ assorbiment ta ’ verapamil u soluzzjoni orali ta ’ sirolimus kienu effetwati sinifikattivament meta dawn ittieħdu bħala doża multipla flimkien.
Whole blood sirolimus Cmax, tmax, and AUC were increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively.
Cmax, tmax, u AUC ta ’ sirolimus fid- demm sħiħ żdiedu b’ 2. 3 darbiet, b’ 1. 1 darbiet, u 2. 2 darbiet rispettivament.
Plasma S-(-) verapamil Cmax and AUC were both increased 1.5-fold, and tmax was decreased 24%.
Cmax u AUC ta ’ S - (-) verapamil fil- plażma żdiedu b’ 1. 5 darbiet, u tmax naqset b’ 24%.
Sirolimus levels should be monitored and appropriate dose reductions of both medications should be considered.
Il- livell ta ’ sirolimus għandu jiġi monitorjat u tnaqqis ta ’ doża propizja taż- żewġ mediċini għandha tkun ikkonsidrata.
Erythromycin (CYP3A4 inhibitor):
Erythromycin (inibitur ta ’ CYP3A4):
Multiple-dose administration of erythromycin and sirolimus oral solution significantly increased the rate and extent of absorption of both drugs.
L- għoti flimkien ta ’ dożi multipla ta ’ erythromycin u ta ’ soluzzjoni orali ta ’ sirolimus, żied b’ mod sinifikanti r- rata u l- ammont ta ’ assorbiment taż- żewġ mediċini.
Whole blood sirolimus Cmax, tmax, and AUC were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively.
Cmax, tmax, u AUC ta ’ sirolimus fid- demm sħiħ żdiedu b’ 4. 4 darbiet, b’ 1. 4 darbiet, u 4. 2 darbiet rispettivament.
The Cmax, tmax, and AUC of plasma erythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively.
Cmax, tmax u AUC ta ’ erythromycin fil- plażma żdiedu b’ 1. 6 darbiet, b’ 1. 3 darbiet, u b’ 1. 7 darbiet rispettivament.
Sirolimus levels should be monitored and appropriate dose reductions of both medications should be considered.
Il- livell ta ’ sirolimus għandu jiġi mmonitorjat, u tnaqqis ta ’ doża propizja taż- żewġ mediċini għandha tkun ikkonsidrata.
No clinically significant pharmacokinetic interaction was observed between sirolimus and 0.3 mg norgestrel/ 0.03 mg ethinyl estradiol.
L- ebda interazzjoni farmakokinetika klinikament sinifikanti ma ġiet osservata bejn sirolimus 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, 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.
Għalkemm ir- riżultati ta ’ studju ta ’ interazzjoni reċiproka b’ doża waħda ma ’ kontraċettiv orali ssuġġerew in- nuqqas ta ’ 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 inhibitors of 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).
Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e. g.
Mediċini li jistimulaw CYP3A4 jistgħu jżidu l- metaboliżmu ta ’ sirolimus u jnaqqsu l- livelli ta ’ sirolimus fid- demm (eż.
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
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
7 patients receiving therapeutic doses of Rapamune.
7 inibizzjoni huma aktar għoljin f’ pazjenti li jirċievu dożi terapewtiċi ta ’ Rapamune.
Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels.
Inibituri tal- P- gp jistgħu jnaqqsu l- efflus ta ’ sirolimus miċ- ċelluli intestinali u jżidu l- livelli ta ’ sirolimus.
Grapefruit juice affects CYP3A4 mediated metabolism and should therefore be avoided.
Il- meraq tal- grejpfrut jaffettwa l- metaboliżmu permezz ta ’ CYP3A4 u għalhekk m’ għandux jittieħed.
Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents such as cisapride and metoclopramide.
Interazzjonijiet farmakokinetiċi jistgħu jiġu osservati b’ sustanzi prokinetiċi gastrointestinali bħal cisapride u metoclopramide.
No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/ sulphamethoxazole.
Ma ġiet osservata l- ebda interazzjoni farmakokinetika klinikament sinifikanti bejn sirolimus u xi waħda minn dawn is- sustanzi: acyclovir, atorvastatin, digoxin, glibenclamide, methlprednisolone, nifedipine, prednisolone, u trimethoprim/ sulphametooxazole.
There are no adequate data from the use of sirolimus in pregnant women.
M’ hemmx tagħrif biżżejjed dwar l- użu ta ’ sirolimus waqt it- tqala.
Rapamune should not be used during pregnancy unless clearly necessary.
Rapamune m’ għandux jintuża waqt it- tqala jekk m’ hemmx bżonn ċar.
Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped.
Kontraċettivi effettivi għandhom jintużaw matul it- terapija ta ’ Rapamune u għal 12- il ġimgħa wara li titwaqqaf il- mediċina.
Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats.
Wara l- għoti ta ’ sirolimus radjutikkettat, ir- radjuattività tiġi eliminata fil- ħalib tal- firien li jreddgħu.
It is not known whether sirolimus is excreted in human milk.
Mhux magħruf jekk sirolimus jinstabx fil- ħalib tal- bnedmin.
Because of the potential for adverse reactions in nursing infants from sirolimus, nursing should be discontinued during therapy.
Minħabba l- effetti negattivi li sirolimus jista ’ jkollu fuq it- trabi li qed jerdgħu, it- treddigħ għandu jitwaqqaf matul it- terapija.
Impairments of sperm parameters have been observed among some patients treated with Rapamune.
Fost xi pazjenti trattati b’ Rapamune kienu osservati indebolimenti fil- parametri ta ’ sperma.
These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).
F’ ħafna każijiet dawn l- effetti kienu riversibbli malli twaqqaf Rapamune (ara sezzjoni 5. 3).
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, u żieda fil- lactate dehydrogenase (LDH) fid- demm.
The incidence of any adverse event(s) may increase as the trough sirolimus level increases.
L- inċidenza ta ’ kull reazzjoni( jiet) avversa( i) tista ’ tiżdied kif jiżdied l- aktar livell baxx ta ’ sirolimus.
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.
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.
Only events for which there is at least reasonable suspicion of a causal relationship to Rapamune treatment are listed.
F’ din il- lista hawn imniżżla biss dawk il- każijiet li għall- inqas hemm suspett raġonevoli ta ’ relazzjoni tagħhom mat- trattament b’ Rapamune.
Most patients were on immunosuppressive regimens which included Rapamune in combination with other immunosuppressive agents.
Il- maġġoranza tal- pazjenti kienu fuq reġimens immunosoppressivi li inkludew Rapamune flimkien ma ’ mediċini immunosoppressivi oħra.
8 System Organ Class
8 Sistema tal- Klassifika tal- Organi Infezzjonijiet u
Very common ( 1/ 10)
Komuni ħafna (≥1/ 10) Infezzjoni tal- apparat
Common ( 1/ 100 to < 1/ 10)
Komuni (≥1/ 100 sa < 1/ 10) Sepsis
Uncommon ( 1/ 1000 to < 1/ 100)
Mhux komuni (≥1/ 1, 000 sa < 1/ 100)
Rare ( 1/ 10000 to < 1/ 1000)
Rari (≥1/ 10, 000 sa < 1/ 1, 000)
Urinary tract infection
awrinarju
Sepsis Pneumonia Pyelonephritis Herpes simplex Fungal, viral, and bacterial infections (such as mycobacterial infections, including tuberculosis, Epstein-Barr virus, CMV, and Herpes zoster)
Pulmonite Pijelonefrite Herpes simplex Infezzjonijiet fungali, virali, u batteriċi (bħal infezzjonijiet majkobatteriċi, li jinkludu tuberkolosi, il- virus ta ’ Epstein- Barr, CMV, u Herpes zoster)
Skin Cancer
Kanċer tal- ġilda
Lymphoma / post transplant lymphoproliferative disorder
Limfoma / disturb limfoproliferattiv ta ’ wara t- trapjant
Blood and lymphatic system disorders
Disturbi tad- demm
Thrombocytopenia Anaemia
Tromboċitopenja
Thrombotic thrombocytopenic purpura/ haemolytic uraemic syndrome Leukopenia Neutropenia
Purpura
Immune system disorders
tromboċitopenika trombotika / sindromu uremiku emolitiku Lewkopenja Newtropenja
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)
Metabolism and Hypokalaemia nutrition disorders
Disturbi fil- qalb
Hypophosphataemia Hypercholesterolaemia Hyperglycaemia Hypertriglyceridaemia
Effużjoni perikardjali (li tinkludi efużjonijiet emodinamikament sinifikanti fi tfal u adulti)
9 System Organ Class Nervous system disorders
9 Sistema tal- Klassifika tal- Organi Disturbi
Very common ( 1/ 10) Headache
Komuni ħafna (≥1/ 10)
Common ( 1/ 100 to < 1/ 10)
Komuni (≥1/ 100 sa < 1/ 10) Pnewmonite
Uncommon ( 1/ 1000 to < 1/ 100)
Mhux komuni (≥1/ 1, 000 sa < 1/ 100) Emorraġija
Rare ( 1/ 10000 to < 1/ 1000)
Rari (≥1/ 10, 000 sa < 1/ 1, 000) Proteinosi
Cardiac disorders
respiratorji, toraċiċi u medjastinali
Tachycardia
Effużjoni plewrali Epistassi
Pericardial effusion (including haemodynamically significant effusions in children and adults)
pulmonari
Lymphocele Hypertension
alveolari
Deep vein thrombosis Pneumonitis Pleural effusion Epistaxis
Disturbi gastrointestinali Disturbi fil- fwied u fil- marrara
Pulmonary embolism Pulmonary haemorrhage
Uġigħ addominali, Dijarea Stitikezza Tqalligħ
Lymphoedema Alveolar proteinosis
Stomatite Testijiet tal- funzjoni tal- fwied b’ riżultat abnormali
Gastrointestinal disorders
Pankreatite
Abdominal pain Diarrhoea Constipation Nausea
Disturbi fil- ġilda u fit- tessuti ta ’ taħt il- ġilda
Stomatitis
Akne
Pancreatitis
Raxx
Hepatobiliary disorders
Disturbi muskolu - skeletrali u tal- connective tissue
Liver function tests abnormal
Artralġja
Skin and subcutaneous tissue disorders
Osteonekrosi
Acne
Disturbi fil- kliewi u fis- sistema urinarja
Rash
Proteinurja
Musculoskeletal and connective tissue disorders
Sindromu nefrotiku (ara sezzjoni 4. 4)
Arthralgia
Disturbi ġenerali u
Osteonecrosis
Edema periferali
Renal and urinary disorders
Fejqan imdgħajjef
Proteinuria
kundizzjonijiet ta ’ mnejn jingħata
Nephrotic syndrome (see section 4.4)
Deni Uġigħ
General disorders and administration site conditions
Edema
Oedema peripheral Pyrexia Pain
Investigazzjonijiet
Impaired healing Oedema
Lactate dehydrogenase
Investigations
Aspartate
Blood lactate dehydrogenase increased Blood creatinine increased
fid- demm mgħollija Żieda fil- kreatinina fid- demm
Aspartate aminotransferase increased Alanine aminotransferase increased
aminotransferase mgħollija Alanine aminotransferase mgħollija
Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin (see section 4.4).
L- immunosoppressjoni żżid is- suxxetibilità għall- iżvilupp ta ’ limfoma u malinjitajiet oħra, partikolarment tal- ġilda (ara sezzjoni 4. 4.).
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 irrapportati f’ pazjenti trattati b’ immunosoppressanti, li jinkludu Rapamune.
10 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.
There have been rare reports of fatal hepatic necrosis with elevated trough sirolimus levels.
Rapporti rari ta ’ nekrożi epatika fatali ġew irrapportati ma’ żidiet fil- livelli l- aktar baxxi ta ’ sirolimus.
Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliterans organising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including Rapamune.
Każijiet ta ’ mard interstizzjali tal- pulmun (li jinkludu pulmonite u infrekwentement bronchitis obliterans organizing pneumonia (BOOP) u fibrożi pulmunarja), x’ uħud minnhom fatali, bl- ebda etjoloġija infettiva identifikata, seħħew f’ pazjenti li qegħdin jingħataw reġimens immunosoppressivi li jinkludu Rapamune.
In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune.
F’ xi każijiet il- mard interstizzjali tal- pulmun irriżolva billi twaqqfet jew tnaqqset id- doża ta ’ Rapamune.
The risk may be increased as the trough sirolimus level increases.
Ir- riskju jista ’ jiżdied jekk il- livelli l- aktar baxxi ta ’ sirolimus jogħlew.
Impaired healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia, and anastomotic disruption (e. g. wound, vascular, airway, ureteral, biliary).
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).
In patients with delayed graft function, sirolimus may delay recovery of renal function.
F’ pazjenti b’ funzjoni dewwiema tal- graft, sirolimus jista ’ jdewwem l- irkupru tal- funzjoni renali.
The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/ TTP/ TMA.
10 L- użu ta ’ sirolimus flimkien ma ’ impeditur ta ’ calcineurin jista ’ jżid ir- riskju ta ’ HUS/ TTP/ TMA imqanqlin minn impeditur ta ’ calcineurin.
Focal segmental glomerulosclerosis has been reported.
Glomerulosklerosi segmentali fokali ġiet irrappurtata.
In an ongoing study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (target levels of 12 - 20 ng/ mL) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 mL/ min (see section 5.1).
Fi studju għaddej li jevalwa s- sigurtà u l- effikaċja ta ’ bidla minn inibituri ta ’ calcineurin għal sirolimus (livelli mmirati ta ’ 12 – 20 ng/ ml) f’ pazjenti bi trapjant renali mantenut, ir- rekrutaġġ kien imwaqqaf fis- sottogrupp ta ’ pazjenti (n=90) b’ rata ta ’ filtrazzjoni glomerulari fil- linja bażi ta ’ anqas minn 40 ml/ min (ara sezzjoni 5. 1).
There was a higher rate of serious adverse events including pneumonia, acute rejection, graft loss and death in this sirolimus treatment arm (n=60, median time post-transplant 36 months).
Kien hemm rata ogħla ta ’ reazzjonijiet avversi serji, li jinkludu pulmonite, riġettazzjoni akuta, telf tal- graft u mewt f’ din id- driegħ ta ’ trattament b’ sirolimus (n=60, żmien medjan wara t- trapjant, 36 xahar).
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).
Popolazzjoni pedjatrika 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 akut 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 mhumiex 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).
Among 89 patients known to be EBV seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD.
Fost 89 pazjent magħrufa 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 ta ’ < 18- il sena.