qanastek/EMEA-V3 huggingface dataset:
Co-administration of multiple twice-daily doses of 1000 mg metformin with 50 mg sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
L- amministrazzjoni flimkien ta ’ dożi multipli darbtejn kuljum ta ’ 1000 mg ta ’ metformin ma ’ 50 mg ta ’ sitagliptin ma biddilx b’ mod sinifikanti l- effett farmakokinetiku ta ’ sitagliptin f’ pazjenti b’ dijabete tat- tip 2.
A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin.
Sar studju biex iqis l- effett ta ’ cyclosporine, inibitur qawwi ta ’ p- glycoprotein, fuq l - effett farmakokinetiku ta ’ sitagliptin.
Coadministration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively.
L- amministrazzjoni flimkien ta ’ doża waħda orali ta ’ 100 mg ta ’ sitagliptin u doża waħda orali ta ’ 600 mg ta ’ cyclosporine kattar il - AUC u Cmax ta ’ sitagliptin bejn wieħed u ieħor b’ 29% u 68%, rispettivament.
These changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful.
Dawn il- bidliet fl- effetti farmakokinetiċi ta ’ cyclosporine ma tqisux li għandhom relevanza klinika.
The renal clearance of sitagliptin was not meaningfully altered.
Il- clearance renali ta ’ sitagliptin ma tbiddlitx b’ mod sinifikanti.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Għalhekk, ma kienx mistenni li jkun hemm interazzjonijiet sinifikanti ma ’ inibituri oħra ta ’ p- glycoprotein.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8.
Studji in vitro indikaw li l- enżima prinċipali responsabbli għall- metaboliżmu limitat ta ’ sitagliptin hija CYP3A4, b’ kontribuzzjoni minn CYP2C8.
In patients with normal renal function, metabolism, including via CYP3A4, plays only a small role in the clearance of sitagliptin.
F’ pazjenti b’ funzjoni renali normali, il- metaboliżmu, inkluż permezz ta ’ CYP3A4, għandu biss sehem żgħir fit- tneħħija ta ’ sitagliptin.
Metabolism may play a more significant role in the elimination of sitagliptin in the setting of severe renal insufficiency or ESRD.
Il- metaboliżmu jista ’ jkollu sehem iktar sinifikanti fl- eliminazzjoni ta ’ sitagliptin fil- każ ta ’ insuffiċjenza renali qawwija jew ESRD.
For this reason, it is possible that potent CYP3A4 inhibitors (i. e. ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in patients with severe renal insufficiency or ESRD.
Għal din ir- raġuni, jista ’ jkun li inibituri CYP3A4 qawwija (i. e. ketoconazole, itraconazole, ritonavir, clarithromycin) jistgħu ibiddlu l- karatteristiċi farmakokinetiċi ta ’ sitagliptin f’ pazjenti b’ insuffiċjenza renali qawwija jew ESRD.
The effects of potent CYP3A4 inhibitors in the setting of renal insufficiency has not been assessed in a clinical study.
L- effetti ta ’ inibituri CYP3A4 qawwija fil- każ ta ’ insuffiċjenza renali ma tqisitx fi studju kliniku.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and OAT3.
Studji ta ’ transport in vitro wrew li sitagliptin huwa sustrat għal p- glycoprotein u OAT3.
OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid, although the risk of clinically meaningful interactions is considered to be low.
Sitagliptin li t- trasport tiegħu kien medjat permezz ta ’ OAT3 kien inibit in vitro b’ probenecid, għalkemm ir- riskju ta ’ interazzjonijiet klinikament relevanti huwa meqjus li hu baxx.
Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Ma ġietx evalwata in vivo l - amministrazjoni fl- istess ħin ta ’ inibituri OAT3.
Effects of sitagliptin on other medicinal products In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes.
Effetti ta ’ sitagliptin fuq prodotti mediċinali oħra Tagħrif in vitro jagħti x’ jifhem li sitagliptin la jinibixxi u l- anqas jinduċi l- isoenżimi CYP450.
In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).
Fi studji kliniċi, sitagliptin ma biddilx b’ mod sinifikanti l- effetti farmakokinetiċi ta ’ metformin, glyburide, simvastatin, rosiglitazone, warfarin, jew kontraċettivi orali, u dan ipprovda evidenza in vivo ghal tendenza baxxa ta’ ta ’ interazzjonijiet ma ’ sustrati ta ’ CYP3A4, CYP2C8, CYP2C9, jew trasportatur organiku katjoniku (OCT).
Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of p- glycoprotein in vivo.
Sitagliptin ftit kellu effett fuq il- konċentrazzjonijiet ta ’ digoxin fil- plażma, ujista ’ jkun inibitur ħafif ta ’ p- glycoprotein in vivo.
Sitagliptin had a small effect on plasma digoxin concentrations.
Sitagliptin kellu effett żgħir fuq konċentrazzjonijiet ta ’ digoxin fil- plażma.
Following administration of 0.25 mg digoxin concomitantly with 100 mg of Januvia daily for 10 days, the plasma AUC of digoxin was increased on average by 11%, and the plasma Cmax on average by 18%.
Wara li 0. 25 mg ta ’ digoxin ingħata flimkien ma ’ 100 mg ta ’ Januvia MSD kuljum għal 10 ijiem, il- plażma AUC ta ’ digoxin kiber b’ medja ta ’ 11%, u l- plażma Cmax b’ medja ta ’ 18%.
However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
Mhux rakkomandat li tinbidel id - doża ta ’ digoxin Madankollu, pazjenti li għandhom riskju ta ’ tossiċità b’ digoxin għandhom jitħallew taħt sorveljanza għal dan meta sitagliptin u digoxin jingħataw flimkien.
Pregnancy There are no adequate data from the use of Januvia in pregnant women.
Tqala Mhemmx biżżejjed informazzjoni dwar l- użu ta ’ Januvia minn nisa tqal.
Studies in animals have shown reproductive toxicity at high doses (see section 5.3).
Studji fuq l- annimali urew tossiċità riproduttiva f’ dozi gholjin (ara sezzjoni 5. 3).
The potential risk for humans is unknown.
Il- potenzjal ta ’ riskju fil- bnedmin mhux magħruf.
Due to lack of human data, Januvia should not be used during pregnancy.
Minħabba n- nuqqas ta ’ informazzjoni dwar l- użu fil- bnedem, Januvia m’ għandux jintuża waqt it- tqala.
Lactation It is unknown whether sitagliptin is excreted in human breast milk.
Treddigħ Mhux nagħruf jekk sitagliptin jitneħħiex mal- ħalib tas- sider uman.
Animal studies have shown excretion of sitagliptin in breast milk.
Studji fl- annimaliurew li sitagliptin jitneħħa mal- ħalib tas- sider.
Januvia should not be used during breast-feeding.
Januvia m’ għandux jintuża waqt treddigh ta ’ trabi.
4 4.7 Effects on ability to drive and use machines
4 4. 7 Effetti fuq il- ħila biex issuq u tħaddem magni
However, when driving or operating machines, it should be taken into account that dizziness and somnolence have been reported.
Madankollu, meta ssuq jew tħaddem magni, jrid jigi ikkunsidrat li sturdament u ngħas gew irrappurtati.
In 9 large clinical trials of up to 2 years in duration, over 2700 patients have received treatment with Januvia 100 mg per day alone or in combination with metformin, a sulphonylurea (with or without metformin) or a PPARγ agent.
F’ 9 provi kliniċi kbar li damu sa sentejn, iktar minn 2700 pazjent irċieva trattament b’ 100 mg kuljum ta ’ Januvia waħedha jew flimkien ma ’ metformin, sulphonylurea (b’ metformin jew mingħajru) jew aġent PPARγ.
In these trials, the rate of discontinuation due to adverse experiences considered drug-related was 0.8% with 100 mg per day and 1.5% with other treatments.
F’ dawn il- provi, ir- rata ta ’ dawk li waqfu jieħdu l- mediċina minħabba esperjenzi avversi kunsidrati marbuta mal- mediċina kienet 0. 8% b’ 100 mg kuljum u 1. 5% ma ’ trattamenti oħra.
No adverse reactions considered as drug-related were reported in patients treated with sitagliptin occurring in excess (> 0.2% and difference > 1 patient) of that in patients treated with control.
Il- pazjenti li ħadu sitagliptin ma kellhomx iktar reazzjonijiet avversi kunsidrati marbuta mal- mediċina (> 0. 2% u differenza ta ’ > 1 pazjent) meta mqabbla ma ’ pazjenti li ħadu kura ta ’ kontroll.
Adverse reactions considered as drug-related reported in patients treated with sitagliptin occurring in excess (> 0.2% and difference > 1 patient) of that in patients treated with placebo are listed below (Table 1) by system organ class and frequency.
Reazzjonijiet avversi meqjusin bħala relatati mal- mediċina rrapportati f’ pazjenti ttrattati b’ sitagliptin li seħħew b’ mod aktar frekwenti (> 0. 2% u differenza > 1 pazjent) f’ pazjenti ttrattati bi plaċebo huma elenkati hawn taħt (Tabella 1) skond is- sistema tal- klassifika ta ’ l- organi u l- frekwenza.
Frequencies are defined as: very common (≥ 1/ 10); common (≥ 1/ 100, < 1/ 10); uncommon (≥ 1/ 1000, < 1/ 100); rare (≥ 1/ 10000, < 1/ 1000); and very rare (< 1/ 10000).
Il- frekwenzi huma definiti kif ġej: komuni ħafna (≥ 1/ 10); komuni (≥ 1/ 100, < 1/ 10); mhux komuni (≥ 1/ 1000, < 1/ 100); rari (≥ 1/ 10000, < 1/ 1000); u rari ħafna (< 1/ 10000).
Frequency of adverse reaction by treatment regimen
Il- frekwenza tar- reazzjonijiet avversi identifikati minn studji kliniċi kkontrollati minn plaċebo
Sitagliptin with Sitagliptin with Sitagliptin with 1 2
Frekwenza tar- reazzjoni avversa skond ir- reġimen tat- trattament
Sitagliptin with
Sitagliptin
Metformin
Sitagliptin
a Sulfonylurea
b’ Metformin1
Metformin and a a PPARγ Agent Sulfonylurea3 (pioglitazone)4
b’ Metformin u Sulfonylurea3
Metabolism and nutrition disorders
b’ Aġent PPARγ (pioglitazone) 4
hypoglycaemia*
Disturbi fil - metaboliżmu u n - nutrizzjoni
Very common
ipogliċemija *
Nervous system disorders somnolence
Komuni ħafna
Gastrointestinal disorders
Disturbi fis - sistema nervuża ngħas Mhux komuni
diarrhea nausea flatulence constipation upper abdominal pain
Disturbi gastrointestinali dijarrea dardir gass stitikezza uġigħ fil- parti ta ’ fuq ta ’ l- addome
General disorders peripheral oedema
Disturbi ġenerali
Investigations blood glucose decreased *
Investigazzjonijie t livell imnaqqas ta ’ Mhux komuni glucose fid- demm
In clinical trials of Januvia as monotherapy and sitagliptin as part of combination therapy with metformin or pioglitazone, rates of hypoglycaemia reported with sitagliptin were similar to rates in patients taking placebo.
5 * Fi provi kliniċi ta ’ Januvia bħala monoterapija u sitagliptin bħala parti minn terapija ta ’ kombinazzjoni b’ metformin jew pioglitazone, rati ta ’ ipogliċemija rrapportati bi sitagliptin kienu simili għal rati f’ pazjenti li jieħdu plaċebo.
5 1 In this placebo-controlled 24-week study of sitagliptin 100 mg once daily in combination with metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/ metformin compared to treatment with placebo/ metformin was 9.3% and 10.1%, respectively.
1 F’ dan l- istudju ta ’ 24 ġimgħa kkontrollat bi plaċebo ta ’ Sitagliptin 100 mg darba kuljum flimkien ma ’ metformin, l- inċidenza ta ’ reazzjonijiet avversi kkunsidrati marbuta mal- mediċina f’ pazjenti ttrattati bi sitagliptin/ metformin meta mqabbla ma ’ trattament bi plaċebo/ metformin kienet ta ’ 9. 3% u 10. 1%, rispettivament.
In an additional 1-year study of sitagliptin 100 mg once daily in combination with metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/ metformin compared to sulphonylurea/ metformin was 14.5% and 30.3%, respectively.
Fi studju addizzjonali ta ’ sena fejn sitagliptin 100 mg darba kuljum ttieħdet flimkien ma ’ metformin, l- inċidenza ta ’ reazzjonijiet avversi kkunsidrati marbuta mal- mediċina f’ pazjenti li ħadu sitagliptin/ metformin meta mqabbla ma ’ sulphonylurea/ metformin kienet ta ’ 14. 5% u 30. 3%, rispettivament.
2 In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/ glimepiride compared to treatment with placebo/ glimepiride was 11.3% and 6.6%, respectively.
Fi studji miġbura flimkien li damu sa sena u li qabblu sitagliptin/ metformin ma ’ aġenti ta ’ sulphonylurea/ metformin, ir- reazzjonijiet avversi kunsidrati marbuta mal- mediċina li dehru aktar (> 0. 2% u differenza ta ’ > 1 pazjent)) f’ pazjenti li ħadu sitagliptin 100 mg minn f’ pazjenti li ħadu aġent ta ’ sulphonylurea, huma kif ġejjin: anoressija (Disturbi fil- metaboliżmu u n- nutrizzjoni; frekwenza mhux komuni) u tnaqqis fil- piż (Investigazzjonijiet; frekwenza mhux komuni) 2 F’ dan l- istudju ta ’ 24 ġimgħa ta ’ 100 mg ta ’ sitagliptin darba kuljum flimkien ma ’ glimepiride, l - inċidenza ta ’ reazzjonijiet mhux mixtieqa li setgħu jitqiesu li kienu marbuta mal- mediċina f’ pazjenti kkurati bi sitagliptin/ glimepiride meta mqabbla ma ’ kura bi plaċebo/ glimepiride kienet ta ’ 11. 3% u 6. 6% rispettivament.
3 In this 24-week study of sitagliptin 100 mg once daily in combination with glimepiride and metformin, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin in combination with glimepiride/ metformin compared to treatment with placebo in combination with glimepiride/ metformin was 18.1% and 7.1%, respectively.
3 F’ dan l- istudju ta ’ 24 ġimgħa ta ’ 100 mg ta ’ sitagliptin darba kuljum flimkien ma ’ glimepiride u metformin, l- inċidenza ta ’ reazzjonijiet mhux mixtieqa li setgħu jitqiesu li kienu marbuta mal - mediċina f’ pazjenti kkurati bi sitagliptin flimkien ma ’ glimepiride/ metformin meta mqabbla ma ’ kura bi plaċebo flimkien ma ’ glimepiride/ metformin kienet ta ’ 18. 1% u 7. 1% rispettivament.
4 In this 24-week study of the combination of sitagliptin 100 mg once daily and pioglitazone, the incidence of adverse reactions considered as drug-related in patients treated with sitagliptin/ pioglitazone compared to patients treated with placebo/ pioglitazone was 9.1% and 9.0%, respectively.
4 F’ dan l- istudju ta ’ 24 ġimgħa tal- kombinazzjoni ta ’ sitagliptin 100 mg darba kuljum u pioglitazone l- inċidenza ta ’ reazzjonijiet negattivi minħabba l- mediċina f’ pazjenti li ħadu sitagliptin/ pioglitazone meta mqabbla ma ’ pazjenti li ħadu plaċebo/ pioglitazone kienet ta ’ 9. 1% u 9. 0%, rispettivament.
In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily alone compared to placebo, adverse reactions considered as drug-related reported in patients treated with sitagliptin in excess (> 0.2% and difference > 1 patient) of that in patients receiving placebo are headache, hypoglycaemia, constipation, and dizziness.
Barra minn hekk, fi studji li damu sa 24 ġimgħa b’ terapija waħda ta ’ sitagliptin 100 mg darba kuljum waħedha mqabbla ma ’ plaċebo, reazzjonijiet avversi kunsidrati marbuta mal- mediċina li dehru aktar (> 0. 2% u differenza ta ’ > 1 pazjent) f’ pazjenti li hadu Januvia minn f’ pazjenti li ħadu plaċebo, huma uġigħ ta ’ ras, ipogliċemija, stitikezza, u sturdament
In addition to the drug-related adverse experiences described above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5% and more commonly in patients treated with Januvia included upper respiratory tract infection and nasopharyngitis.
Ma ’ dawn l- esperjenzi avversi kunsidrati marbuta mal- mediċina deskritti hawn fuq esperjenzi avversi rrapportati bla referenza għar- relazzjoni kawża- effet mal- kura u li ġraw mill- inqas f' 5% u b’ mod iktar komuni f’ pazjenti fuq Januvia, kienu jinkludu, infezzjoni fil- parti ta ’ fuq tal- passaġġ respiratorju u nażofarinġite.
Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with Januvia (not reaching the 5% level, but occurring with an incidence of > 0.5% higher with Januvia than that in the control group) included osteoarthritis and pain in extremity.
Esperjenzi ohra avversi rraportati bla referenza għar- relazzjoni kawża- effett mal- kura, li seħħew b’ mod iktar frekwenti f’ pazjenti kkurati b’ Januvia (dawn ma laħqux il- livell ta ’ 5%, imma seħħew b’ inċidenza ta ’ > 0. 5% ogħla b ’ Januvia milli fil- grupp ta ’ kontroll), kienu jinkludu ostjoartrite u uġigħ fl- estremitajiet.
In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice daily (sitagliptin/ metformin 50 mg/ 500 mg or 50 mg/ 1000 mg), the overall incidence of adverse reactions considered as drug-related in patients treated with the combination of sitagliptin and metformin compared to patients treated with placebo was 14.0% and 9.7%, respectively.
Fi studju ta ’ 24 ġimgħa ta ’ terapija ta ’ kombinazzjoni inizjali bi sitagliptin u metformin mogħtija darbtejn kuljum (sitagliptin/ metformin 50 mg/ 500 mg jew 50 mg/ 1000 mg), l- inċidenza totali ta ’ reazzjonijiet avversi meqjusin relatati mal- mediċina f’ pazjenti ttratti b’ kombinazzjoni ta ’ sitagliptin u metformin meta mqabbla ma ’ pazjenti ttrattati bi plaċebo kienet ta ’ 14. 0% u 9. 7%, rispettivament.
The overall incidence of adverse reactions considered as drug-related in patients treated with the combination of sitagliptin and metformin was comparable to metformin alone (14.0% each) and greater than sitagliptin alone (6.7%), with the differences relative to sitagliptin alone primarily due to gastrointestinal adverse reactions.
L - inċidenza totali ta ’ reazzjonijiet avversi meqjusin relatati mal- mediċina f’ pazjenti ttratti b’ kombinazzjoni ta ’ sitagliptin u metformin kienet komparabbli ma ’ dik ta ’ metformin waħdu (14. 0% kull wieħed) u ikbar milli sitagliptin waħdu (6. 7%), bid- differenzi fir- rigward ta ’ sitagliptin waħdu, primarjament dovuti għal reazzjonijiet avversi gastrointestinali.
Across clinical studies, a small increase in white blood cell count (approximately 200 cells/ microl difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/ microl) was observed due to an increase in neutrophils.
6 F’ numru ta ’ studji kliniċi, kienet osservata żieda żgħira fil- għadd taċ- ċelloli bojod (bejn wieħed u ieħor differenza ta ’ 200 ċellula/ microl f’ WBC meta mqabbel mal- plaċebo: linja medja bażika WBC bejn wieħed u ieħor ta ’ 6600 ċellula/ microl) minħabba żieda fin- newtrofili.
This observation was seen in most but not all studies.
Din l- osservazjoni ma saritx fl- istudji kollha imma f’ ħafna minnhom.
This change in laboratory parameters is not considered to be clinically relevant.
Din il- bidla fil- parametri tal- laboratorju ma titqiesx klinikament relevanti.
6 No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with Januvia treatment.
F’ kura b ’ Januvia ma ġewx osservati bidliet b’ relevalnza klinika fis- sinjali vitali jew fl- ECG (inkluż l - intervall QTc).
Post-marketing Experience:
Esperjenza ta ’ Wara t- Tqegħid fis- Suq:
During post-marketing experience the following additional side effects have been reported (frequency not known): hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions including Stevens-Johnson syndrome (see section 4.4).
Waqt l- esperjenza ta ’ wara t- tqegħid fis- suq ġew irrappurtati effetti sekondarji oħra (il- frekwenza mhix magħrufa): reazzjonijiet ipersensittivi inkluż anafilassi, anġjoedema, raxx, urtikarja u kundizzjonijiet ta ’ ġilda li titqaxxar inkluż is- sindromu ta ’ Stevens- Johnson (ara s- sezzjoni 4. 4).
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were generally well tolerated.
Waqt provi kliniċi kkontrollati f’ persuni f’ saħħithom, dożi waħdanin ta ’ sitagliptin sa 800 mg ġeneralment kienu ttollerati sew.
Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin.
Iż- żidiet minimi fi QTc, li ma tqisux klinikament relevanti, kienu osservati fi studju wieħed b’ doża ta ’ sitagliptin ta ’ 800 mg.
There is no experience with doses above 800 mg in humans.
M’ hemmx esperjenza b’ dożi ikbar minn 800 mg fil- bniedem..
In the event of an overdose, it is reasonable to employ the usual supportive measures, e. g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Fil- każ ta ’ doża eċċessiva, ikun raġonevoli li jintużaw il- miżuri ta ’ appoġġ tas- soltu, ngħidu aħna jitneħħa materjal mhux assorbit mill- apparat gastro- intestinali, isir monitoraġġ kliniku (inkluż elettrokardjogramma), u tinbeda terapija ta ’ appoġg jekk hemm bżonn.
Sitagliptin is modestly dialyzable.
Sitagliptin huwa kemmxejn dijaliżabbli.
In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session.
Fi studji kliniċi, bejn wieħed u ieħor 13. 5% tad- doża tneħħiet wara sessjoni ta ’ emodijalisi ta ’ bejn 3 u 4 sigħat.
Prolonged hemodialysis may be considered if clinically appropriate.
Tista ’ titqies l- emodijalisi fit- tul jekk hi klinikament f’ waqtha.
It is not known if sitagliptin is dialyzable by peritoneal dialysis.
Mhux magħruf jekk sitagliptin hux dijaliżabbli permezz ta ’ dijalisi peritonali.
DPP-4 Inhibitor, ATC code:
Kategorija farmakoterapewtika: inibitur DPP- 4, Kodiċi ATC:
Januvia is a member of a class of oral anti-hyperglycaemic agents called dipeptidyl peptidase 4 (DPP-4) inhibitors.
Januvia hija membru ta ’ klassi ta ’ aġenti anti- ipergliċemiċi orali li jissejħu inibituri dipeptidyl peptidase 4 (DPP- 4).
The improvement in glycaemic control observed with this agent may be mediated by enhancing the levels of active incretin hormones.
It- titjib osservat fil- kontroll gliċemiku b’ dan l- aġent jista ’ jiġi medjat billi jitkattru l- livelli ta ’ l- ormoni attivi ta ’ incretin.
Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal.
L- ormoni incretin, inkluż il- peptide- 1 (GLP- 1) li qisu glucagon, u l- polypeptide insulinotropika li tiddependi mill- glucose (GIP), jintreħħew mill- intestini matul il- ġurnata, u l- livelli jogħlew wara ikla.
The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis.
L- incretini huma parti mis- sistema endogena li hija nvoluta fir- regolazzjoni fiżjoloġika ta ’ l- omeostażi tal- glucose.
When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP.
Meta l- konċentrazzjonijiet ta ’ glucose fid- demm ikunu normali jew elevati, GLP- 1 and GIP ikattru s- sinteżi ta ’ l- insulina u jerħuha miċ - ċelluli beta tal- pankreas permezz ta ’ mogħdijiet ta ’ senjalazzjoni bejn iċ- ċelluli li jinvolvu AMP ċiklika.
Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release.
F’ annimali bid- dijabete ta ’ tip 2 il- kura b ’ GLP- 1 jew b’ inibituri DPP- 4 uriet titjib fil - - livell ta ’ rispons taċ- ċelluli beta għall- glucose, u stimulat kemm tintreħa u l- bijosintesi ta ’ l- insulina.
With higher insulin levels, tissue glucose uptake is enhanced.
F’ livelli ogħla ta ’ insulina, it- tessuti iktar jieħdu insulina.
In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells.
Ukoll, GLP- 1 inaqqas is- sekrezzjoni ta ’ glucagons miċ- ċelluli alfa tal- pankreas.
Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels.
Konċentrazzjonijiet inqas ta ’ glucagons, flimkien ma ’ livelli ogħla ta ’ insulina, iwasslu għal tnaqqis fil- produzzjoni ta ’ glucose mill- fwied, li jwassal għal tnaqqis fil- livell ta ’ glucose fid- demm.
The effects of GLP-1 and GIP are glucose-dependent such that when blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed.
L- effetti ta ’ GLP- 1 u GIP- 2 jiddependu mill- glucose b’ tali mod li meta l- konċentrazzjonijiet ta ’ glucose fid- demm huma baxxi, stimulazzjoni ta’ rilaxx ta ’ l- insulina u trażżin tas- sekrezzjoni tal- glucagon mil- GLP- 1, ma humiex osservati.
For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations.
Kemm għal GLP- 1 kif ukoll għal GIP, ir- rilaxx ta ’ l- insulin jiġi stimulat aktar hekk kif glucose jogħla iktar mill- konċentrazzjonijiet normali.
Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia.
Apparti dan, GLP- 1 ma jfixkilx ir- rispons normali tal- glucagon għall- ipogliċemija.
The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products.
L- attività ta ’ GLP - 1 u GIP hija limitata mill- enżima DPP- 4, li malajr tidroliżża l- ormoni incretin ġo prodotti inattivi.
Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP.
Sitagliptin tipprevjeni l- idroliżi ta ’ l- ormoni incretin mill- DPP- 4, u dan ghalkekk iwassal għal żieda fil- konċentrazzjonijiet ta ’ forom attivi ta ’ GLP- 1 u GIP fil- plażma.
By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose- dependent manner.
Billi tkattar il- livelli ta ’ incretin 7 attiv, sitgliptin twassal biex tintreħa iktar insulina u jonqsu l- livelli ta ’ glucagon b’ mod li hu marbut mal- glucose.
In patients with type 2 diabetes with hyperglycaemia, these changes in insulin and glucagon levels lead to lower hemoglobin A1c (HbA1c) and lower fasting and postprandial glucose concentrations.
F’ pazjenti b’ dijabete tat- tip 2 bl- ipergliċemija, dawn il- bidliet fil- livelli ta ’ l- insulina u glucagon inaqqsu l- emoglobina A1c (HbA1c) u jnaqqsu l- livelli ta ’ konċentrazzjonijiet ta ’ glucose meta sajjem u wara l- ikel.
Sitagliptin is a potent and
Il- mekkaniżmu ta ’ sitagliptin marbut ma ’ glucose huwa distint mill- mekkaniżmu ta ’ sulphonylureas, li jżidu s- sekrezzjoni ta ’ l- insulina anke meta l- livelli ta ’ glucose huma baxxi u jista ’ jwassal għal ipogliċemija f’ pazjenti ta ’ dijabete tat- tip 2 u f’ suġġetti normali.
7 highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.
Sitagliptin huwa inibitur qawwi u selettiv ħafna ta ’ l- enżima DPP- 4 u ma trażżanx l- enżimi DPP- 8 u DPP- 9 li huma relatati mill- qrib, f’ konċentrazzjonijiet terapewtiċi.
Overall, sitagliptin improved glycaemic control when given as monotherapy, when used in combination with metformin (initial or add-on therapy), in combination with a sulphonylurea (with or without metformin), and in combination with a thiazolidinedione, as measured by clinically relevant reductions in HbA1c from baseline at study endpoint (see Table 2).
B’ mod ġenerali, sitagliptin tejjeb il- kontroll glikajemiku meta mogħti bħala monoterapija, meta wżat f’ kombinazzjoni ma ’ metformin (terapija inizjali jew miżjuda), u f’ kombinazzjoni ma ’ sulphonylurea (bi jew mingħajr metformin), u f’ kombinazzjoni ma ’ thiazolidinedione, kif imkejla bi tnaqqis klinikament relevanti f’ HbA1c mil- linja bażi fi tmiem l- istudju (ara t- Tabella 2).
Two studies were conducted to evaluate the efficacy and safety of Januvia monotherapy.
Saru żewġ studji biex jevalwaw l- effikaċja u s- sigurtà ta ’ terapija b’ Januvia waħedha.
Treatment with sitagliptin at 100 mg once daily as monotherapy provided significant improvements in HbA1c, fasting plasma glucose (FPG), and 2-hour post-prandial glucose (2-hour PPG), compared to placebo in two studies, one of 18- and one of 24-weeks duration.
Il- kura b’ sitagliptin 100 mg darba kuljum bħala monoterapija wassal għal titjib sinifikanti fil- HbA1c (- 0. 60% u - 0. 79% ta ’ bidla meta mqabbel mal- plaċebo fl- istudji ta ’ 18 u 24 ġimgħa, rispettivament, bil- linja bażi HbA1c ta ’ bejn wieħed u ieħor 8% fiż- żewġ studji), fil- livell ta ’ glucose fil- plażma meta sajjem (FPG), u fil- livell ta ’ glucose sagħtjen wara l- ikel (PPG ta ’ sagħtejn), meta mqabbel mal- plaċebo f’ żewġ studji, wieħed ta ’ 18- il ġimgħa u l- ieħor ta ’ 24 ġimgħa.
Improvement of surrogate markers of beta cell function, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and measures of beta cell responsiveness from the frequently-sampled meal tolerance test were observed.
It- titjib f’ markaturi sostitutivi tal - funzjoni taċ- ċeluli beta, inkluż HOMA- β (Mudell Omeostatiku ta ’ Assessjar- β), il- proporzjon bejn proinsulina u insulina, u l- kejl tar- rispons taċ- ċelluli beta minn kampjuni meħuda frekwentament fit - test tat- tolleranza għall- ikel ġew osservati.
The observed incidence of hypoglycaemia in patients treated with Januvia was similar to placebo.
L- inċidenza li ġiet osservata ta ’ ipogliċemija f’ pazjenti li ġew ikkurati b’ Januvia kienet bħal tal- plaċebo.
Body weight did not increase from baseline with sitagliptin therapy in either study, compared to a small reduction in patients given placebo.
Il- piż tal- ġisem ma żdiedx mill- linja bażi bit- terapija b’ sitagliptin, la fi studju wieħed u l- anqas fl- ieħor mqabbel ma ’ tnaqqis żgħir f’ pazjenti bil- plaċebo.
In a study in patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance < 50 ml/ min), the safety and tolerability of reduced doses of sitagliptin were investigated and generally similar to placebo.
Fi studju f’ pazjenti bid- dijabete tat- tip 2 u insuffiċjenza kronika renali (tneħħija tal- kreatinina < 50 ml/ min), is- sigurtà u t- tollerabilità ta ’ dożi mnaqqsa ta ’ sitagliptin kienu nvestigati u ġeneralment kienu bħal tal- plaċebo.
In addition, the reductions in HbA1c and FPG with sitagliptin compared to placebo were generally similar to those observed in other monotherapy studies in patients with normal renal function (see section 5.2).
Ukoll, it- tnaqqis f’ HbA1C u FPG b’ sitagliptin meta mqabbel mal- plaċebo kien ġeneralment simili għal dak osservat fi studji oħra b’ terapija waħda f’ pazjenti b’ funzjoni renali normali (ara sezzjoni 5. 2).
The number of patients with moderate to severe renal insufficiency was too low to confirm safe use of sitagliptin in this type of patients.
In- numru ta ’ pazjenti b’ insuffiċjenza moderata jew severa renali kien baxx wisq biex l- użu mingħajr periklu ta 'sitagliptin jiġi kkonfermat f’ dan it- tip ta ’ pazjenti.
Sitagliptin 100 mg once daily provided significant improvements in glycaemic parameters compared with placebo in two 24-week studies of sitagliptin as add-on therapy, one in combination with metformin and one in combination with pioglitazone.
Sitagliptin 100 mg darba kuljum wassal għal titjib sinifikanti fil- parametri gliċemiċi meta mqabbel ma ’ plaċebo f’ żewġ studji ta ’ 24 ġimgħa ta ’ sitagliptin bħala terapija miżjuda, wieħed flimkien ma ’ metformin u l- ieħor flimkien ma ’ pioglitazone.
Change from baseline in body weight was similar for patients treated with sitagliptin relative to placebo.
Il- bidla mil- linja bażi tal- piż tal- ġisem kienet simili għal pazjenti kkurati b’ sitagliptin meta mqabbel mal- plaċebo.
In these studies there was a similar incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
F’ dawn l- istudji kien hemm inċidenza simili għall- ipogliċemija rrappurtata għal pazjenti kkurati bi sitagliptin jew plaċebo.
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin (100 mg once daily) added to glimepiride alone or glimepiride in combination with metformin.
Ġie mfassal studju ta ’ 24 ġimgħa b’ kontroll bi plaċebo biex jevalwa l- effikaċja u s- sigurtà ta ’ sitagliptin (100 mg darba kuljum) meta miżjud ma ’ glimepiride waħdu jew glimepiride flimkien ma ’ metformin.
The addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant improvements in glycaemic parameters.
Iż- żieda ta ’ sitagliptin ma ’ glimepiride waħdu jew glimepiride ma ’ metformin wassal għal titjib sinifikanti fil- parametri glikemiċi.
Patients treated with sitagliptin had a modest increase in body weight compared to those given placebo.
Pazjenti kkurati bi sitagliptin kellhom żieda żgħira fil- piż tal - ġisem meta mqabbla ma ’ dawk li ħadu l- plaċebo.
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in combination with metformin (500 mg or 1000 mg twice daily) provided significant improvements in glycaemic parameters compared with either monotherapy.
Fi studju fattorjali ta ’ 24 ġimgħa kkontrollat bi plaċebo ta ’ terapija inizjali, sitagliptin 50 mg darbtejn kuljum f’ kombinazzjoni ma ’ metformin (500 mg jew 1000 mg darbtejn kuljum) irriżulta f’ titjib sinifikanti fil- parametri gliċemiċi meta mqabbel ma ’ monoterapija waħda jew l- oħra.
The decrease in body weight with the combination of sitagliptin and metformin was similar to that observed with metformin alone or placebo; there was no change from baseline for patients on sitagliptin alone.
It- tnaqqis fil- piż tal- ġisem bil- kombinazzjoni ta ’ sitagliptin u metformin kien simili għal dak osservat b’ metformin waħdu jew bi plaċebo; ma kien hemm ebda bidla mil- linja bażi għal pazjenti fuq sitagliptin waħdu.
The incidence of hypoglycaemia was similar across treatment groups.
L - inċidenza ta ’ ipogliċemija kienet simili għall- gruppi ta ’ trattament kollha.
Table 2.
8 Tabella 2:
HbA1c results in placebo-controlled monotherapy and combination therapy studies*
Riżultati ta ’ HbA1c fi studji ta ’ monoterapija kkontrollata bi plaċebo u studji ta ’ terapija ta ’ kombinazzjoni *
Mean
Studju
Mean change from
Linja bażi
change in HbA1c (%) at
Bidla medja mil- linja
Study
Bidla medja kkoreġuta bi
baseline
medja HbA1c
baseline HbA1c (%)
bażi HbA1c (%)
Week 24†
plaċebo f’ HbA1c (%) f’ Ġimgħa 24 †
Monotherapy Studies
Studji ta ’ Monoterapija Sitagliptin 100 mg
at Week 24†
f’ Ġimgħa 24
CI)
(95% CI) - 0. 6 ‡
Sitagliptin 100 mg once daily§
darba kuljum§ (N= 193) Sitagliptin 100 mg
-0.6‡
(- 0. 8, - 0. 4) - 0. 8 ‡
(N= 193) Sitagliptin 100 mg once daily (N= 229) Combination Therapy Studies
darba kuljum (N= 229)
Week 24†
(- 1. 0, - 0. 6)
ongoing metformin therapy (N=453) Sitagliptin 100 mg once daily added to
Studji ta ’ Terapija ta ’ Kombinazzjoni Sitagliptin 100 mg darba kuljum miżjud - 0. 7 ‡ ma ’ terapija ta ’ metaformin għaddiena (N=453) Sitagliptin 100 mg darba kuljum miżjud
(-0.8, -0.5) -0.7‡
(- 0. 8, - 0. 5) - 0. 7 ‡
ongoing pioglitazone therapy (N=163) Sitagliptin 100 mg once daily added to
ma ’ terapija ta ’ pioglitazone għaddiena (N=163) Sitagliptin 100 mg darba kuljum miżjud
(-0.9, -0.5) -0.6‡
(- 0. 9, - 0. 5) - 0. 6 ‡
ongoing glimepiride therapy (N=102) Sitagliptin 100 mg once daily added to
ma ’ terapija bi glimepiride għaddiena (N=102) Sitagliptin 100 mg darba kuljum miżjud
(-0.8, -0.3)
(- 0. 8, - 0. 3)
ongoing glimepiride + metformin therapy (N=115) Initial therapy (twice daily):
ma ’ terapija bi glimepiride + metformin għaddiena (N=115) Terapija inizjali (darbtejn kuljum):
-0.9‡ (-1.1, -0.7) -1.6‡
- 0. 9 ‡ (- 1. 1, - 0. 7) - 1. 6 ‡
Sitagliptin 50 mg + metformin 500 mg (N=183) Initial therapy (twice daily):
Sitagliptin 50 mg + metformin 500 mg (N=183) Terapija inizjali (darbtejn kuljum):
* All Patients Treated Population (an intention-to-treat analysis). † Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value. ‡ p < 0.001 compared to placebo or placebo + combination treatment. § HbA1c (%) at week 18.
L- inqas kwadri tfisser aġġustament għal status ta ’ terapija anti- ipergliċemika preċedenti u valur tal- linja bażi. †
In a study comparing the efficacy and safety of the addition of Januvia 100 mg once daily or glipizide (a sulphonylurea agent) in patients with inadequate glycaemic control on metformin monotherapy, sitagliptin was similar to glipizide in reducing HbA1c.
Fi studju li qabbel l- effikaċja u s- sigurtà taż- żieda ta ’ Januvia 100 mg darba kuljum jew glipizide (aġent ta ’ sulphonylurea) f’ pazjenti li ma kellhomx kontroll gliċemiku tajjeb b’ kura ta ’ metformin biss, sitagliptin kien simili għal glipizide biex inaqqas l- HbA1c.
The mean glipizide dose used in the comparator group was 10 mg per day with approximately 40% of patients requiring a glipizide dose of ≤ 5 mg/ day throughout the study.
Id- doża medja ta ’ glipizide użata fil - 9 grupp imqabbel kienet ta ’ 10 mg kuljum b’ madwar 40% tal- pazjenti li kienu jeħtieġu doża ta ’ glipizide ta ’ < 5 mg kuljum għal kemm dam l- istudju.
However, more patients in the sitagliptin group discontinued due to lack of efficacy than in the glipizide group.
Madankollu, kien hemm iktar pazjenti fil- grupp ta ’ sitagliptin li waqfu minħabba nuqqas ta ’ effikaċja milli mill- grupp ta ’ glipizide.
Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 vs. +1.1 kg).
Pazjenti ttrattati b ’ sitagliptin urew tnaqqis medju sinifikanti mil- linja bażi fil- piż tal- ġisem meta mqabbla ma ’ żieda fil - piż sinifikanti f’ pazjenti mogħtija glipizide (- 1. 5 vs. +1. 1 kg).
In this study, the proinsulin to insulin ratio, a marker of efficiency of insulin synthesis and release, improved with sitagliptin and deteriorated with glipizide treatment.
F’ dan l- istudju, il- proporzjon bejn il - proinsulina u l- insultina, li hu indikatur ta ’ l- effiċjenza tas- sinteżi u r- rilaxx ta ’ l- insulina, tjieb b’ kura b’ sitagliptin u ddeterjora b’ kura bi glipizide.
The incidence of hypoglycaemia in the sitagliptin group (4.9%) was significantly lower than that in the glipizide group (32.0%).
L- inċidenza ta ’ ipogliċemija fil- grupp li kien qed jieħu sitagliptin (4. 9%) kienet inqas b’ mod sinifikanti minn dik tal- grupp fuq glipizide (32. 0%).
The absolute bioavailability of sitagliptin is approximately 87%.
Assorbiment Wara l- amministrazzjoni orali ta ’ doża ta ’ 100 mg f’ suġġetti f’ saħħithom, sitagliptin kien assorbit malajr; b’ konċentrazzjonijiet massimi fil- plażma (Tmax medju) jintlaħqu minn siegħa sa 4 sigħat wara d- doża, il- plażma medja AUC ta ’ sitagliptin kienet ta ’ 8. 52 μM• hr, Cmax kien 950 nM Il - bijodisponibiltà assoluta ta ’ sitagliptin hija bejn wieħed u ieħor 87%.
Since coadministration of a high-fat meal with Januvia had no effect on the pharmacokinetics, Januvia may be administered with or without food.
Billi t- teħid ta ’ ikla b’ ammont għoli ta ’ xaħam ma ’ Januvia ma kellu l- ebda effett fuq l- effetti farmakokinetiċi, Januvia tista ’ tingħata ma ’ l- ikel jew mingħajru l- ikel..
Plasma AUC of sitagliptin increased in a dose-proportional manner.
L- AUC tal- plażma ta ’ sitagliptin tkattar b’ mod proporzjonali għad- doża.
Dose-proportionality was not established for Cmax and C24hr (Cmax increased in a greater than dose-proportional manner and C24hr increased in a less than dose-proportional manner).
Il- proporzjonalità mad- doża ma ġietx stabbilita għal Cmax u C24hr (Cmax tkattar b’ mod ikbar mill- proporzjon mad- doża u C24hr tkattar b’ mod inqas mill- proporzjon mad- doża).
Distribution The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters.
Distribuzzjoni Il- volum medju ta ’ distribuzzjoni fi stat fiss wara doża waħda fil- vina ta ’ 100 mg ta ’ sitagliptin f’ suġġetti f’ saħħithom hija bejn wieħed u ieħor ta ’ 198 litru.
The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Il- frazzjoni ta ’ sitagliptin li hi marbuta b’ mod reversibbli mal- proteini tal- plażma hija baxx (38%).
9 Metabolism Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Metaboliżmu Sitagliptin primarjament jitneħħa ma ’ l- urina bla ma jinbidel, u l- metaboliżmu huwa mogħdija minuri.
Approximately 79% of sitagliptin is excreted unchanged in the urine.
Bejn wieħed u ieħor 79% ta ’ sitagliptin jitneħħa ma ’ l- urina bla ma jinbidel.
Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin.
Wara doża orali ta ’ [14C] sitagliptin, bejn wieħed u ieħor 16% tar- radjuattività tneħħiet bħala metabolit ta ’ sitagliptin.
Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin.
Ġew identifikati sitt metaboliti fil- livell ta ’ traċċa u mhux mistennija li jikkontribwixxu għall- attività inibitorja tal- plażma DPP- 4 ta ’ sitagliptin.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Studji in vitro indikaw li l- enżima li hi primarjament responsabbli għall- metaboliżmu limitat ta ’ sitagliptin kienet CYP3A4, b’ kontribuzzjoni minn CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Tagħrif in vitro wera li sitagliptin mhux inibitur ta ’ CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 jew 2B6, and ma huwiex stimulatur ta ’ CYP3A4 u CYP1A2.
Elimination Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in faeces (13%) or urine (87%) within one week of dosing.
Tneħħija Wara l- amministrazjoni ta ’ doża orali ta ’ [14C] sitagliptin lil suġġetti f’ saħħithom, bejn wieħed u ieħor 100% tar- radjuattività li ġiet amministrata tneħħiet fil- ħmieġ (13%) jew l- urina (87%) fi żmien ġimgħa mid- dożaġġ.
The apparent terminal t1/ 2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours.
Il- half- life terminali t1/ 2 apparenti wara doża oral ta ’ 100 mg ta ’ sitagliptin kienet bejn wieħed u ieħor 12. 4- il siegħa.
Sitagliptin accumulates only minimally with multiple doses.
Sitagliptin jakkumula bl- inqas mod b’ dożi multipli.
The renal clearance was approximately 350 ml/ min.
It- neħħija renali hija bejn wieħed u ieħor 350 ml/ min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
L- eliminazzjoni ta ’ sitagliptin sseħħ primarjament permezz ta ’ eskrezzjoni renali u tinvolvi eskrezzjoni attivi mit- tubi.
Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin.
Sitagliptin huwa sustrat għat- trasportatur- 3 uman ta ’ l- anion organiku (hOAT- 3), li jista ’ jkun involut fl- eliminazzjoni renali ta ’ sitagliptin.
The clinical relevance of hOAT-3 in sitagliptin transport has not been established.
Ma ġietx stabbilita r- relevanza klinika ta ’ hOAT- 3 fit- trasport ta ’ sitagliptin.
Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin.
Sitagliptin huwa wkoll sustrat ta ’ p- glycoprotein, li jista ’ jkun ukoll hija mdaħħla fl- eleminiazzjoni renali ta ’ sitagliptin.
However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.
Madankollu, cyclosporine, li hu inibitur ta ’ p- glycoprotein, ma naqqasx it- tneħħija renali ta ’ sitagliptin.
Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/ 2 transporters.
Sitagliptin mhux sustrat għat- trasportaturi OCT2 jew OAT1 jew PEPT1/ 2.
In vitro, sitagliptin did not inhibit OAT3 (IC50=160 μ M) or p-glycoprotein (up to 250 μ M) mediated transport at therapeutically relevant plasma concentrations.
In vitro, sitagliptin ma kienx jinibixxi transport permezz ta ’ OAT3 10 (IC50=160 μM) jew p- glycoprotein (sa 250 μM) f’ konċentrazzjonijiet fil- plażma terapewtikament relevanti.
In a clinical study sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild inhibitor of p-glycoprotein.
Fi studju kliniku sitagliptin kellu effett żgħir fuq il- konċentrazzjonijiet ta ’ digoxin fil - plażma, li jindika li sitagliptin jista` jkun inibitur ħafif ta ’ p- glycoprotein.
Characteristics in patients The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Karatteristiċi fil- pazjenti Il- karatteristiċi farmakokinetiċi ta ’ sitagliptin ġeneralment kienu simili f’ suġġetti f’ saħħithom u f’ pazjenti b’ dijabete tat- tip 2.
The study included patients with renal insufficiency classified on the basis of creatinine clearance as mild (50 to < 80 ml/ min), moderate (30 to < 50 ml/ min), and severe (< 30 ml/ min), as well as patients with end-stage renal disease (ESRD) on hemodialysis.
Insuffiċjenza renali Sar studju bil- mediċina magħrufa u b’ doża waħda biex jevalwa l- effetti farmakokinetiċi ta ’ doża mnaqqsa ta’ sitagliptin (50 mg) f’ pazjenti b’ insuffiċjenza renali kronika fi stadji differenti, ikklassifikati skond it- tneħħija tal- kreatinina bħala ħafifa (50 sa < 80 ml/ min), moderata (30 sa < 50 ml/ min), u qawwija (< 30 ml/ min), kif ukoll pazjenti b’ mard renali fl- aħħar stadju tiegħu (ESRD) li kienu qed jieħdu l- emodijalisi.
Patients with mild renal insufficiency did not have a clinically meaningful increase in the plasma concentration of sitagliptin as compared to normal healthy control subjects.
Il- pazjenti b’ insuffiċjenza renali ħafifa ma kellhomx żieda klinikament sinifikanti fil- konċentrazzjoni fil- plażma ta ’ sitagliptin meta mqabbla ma ’ suġġetti normali f’ saħħithom bħala ’ kontroll.
An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal insufficiency, and an approximately 4-fold increase was observed in patients with severe renal insufficiency and in patients with ESRD on hemodialysis, as compared to normal healthy control subjects.
F’ pazjenti b’ insuffiċjenza renali moderata ġie osservat bejn wieħed u ieħor l- irduppjar ta ’ l- AUC fil- plażma ta ’ sitagliptin, u ż- żieda kienet ta ’ 4 darbiet għal pażjenti b’ insuffiċjenza renali qawwija u pazjenti b’ ESRD li kienu qed jieħdu l- emodijalisi, meta mqabbla ma ’ suġġetti normali f’ saħħithom bħala kontroll.
Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours postdose).
Sitagliptin tneħħa xi ftit bl- emodijalisi (13. 5% wara sessjoni ta ’ emodijalisi ta ’ bejn 3 u 4 sigħat li bdiet 4 sigħat wara d- dożaġġ).
(See section 4.2.)
Januvia mhux rakkomandat għall- użu f’ pazjenti b’ insuffiċjenza renali moderata jew severa inkluż dawk b’ ESRD billi l- esperjenza f ’ dawn il- pazjenti hija limitati wisq (ara sezzjoni 4. 2).
Hepatic insufficiency No dosage adjustment for Januvia is necessary for patients with mild or moderate hepatic insufficiency (Child-Pugh score ≤ 9).
Insuffiċjenza epatika M’ hemmx għalfejn aġġustment fid- doża għal Januvia għal pazjenti b’ insuffiċjenza epatika ħafifa jew moderata (Punteġġ Child- Pugh ≤ 9).
There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score > 9).
M’ hemmx esperjenza klinika f’ pazjenti b’ insuffiċjenza epatika qawwija (Punteġġ Child- Pugh > 9).
However, because sitagliptin is primarily renally eliminated, severe hepatic insufficiency is not expected to affect the pharmacokinetics of sitagliptin.
Madankollu billi sitagliptin jitneħħa primarjament mill- kliewi, insuffiċjenza epatika qawwija mhix mistennija li taffetwa l- effett farmakokinetiku ta ’ sitagliptin.
10 Elderly No dosage adjustment is required based on age.
Anzjani M’ hemmx bżonn aġġustament tad- doża skond l- età.
Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data.
Meta wieħed iqis l- analiżi farmakokinetika fil - popolazzjoni tat- tagħrif ta ’ Fażi I u Fażi II, l- età ma kellhiex impatt kliniku sinifikanti fuq l- effett farmakokinetiku ta ’ sitagliptin.