qanastek/EMEA-V3 huggingface dataset:
For both GLP-1 and GIP, stimulation of insulin release is enhanced as glucose rises above normal concentrations.
Kemm g al GLP- 1 kif ukoll g al GIP, ir- rilaxx ta ’ l- insulin ji i stimulat aktar hekk kif glucose jog la iktar mill - kon entrazzjonijiet normali.
Further, GLP-1 does not impair the normal glucagon response to hypoglycaemia.
Apparti dan, GLP- 1 ma jfixkilx ir- respons normali tal- glucagon g all - ipogli emija.
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- en ima DPP- 4, li malajr tidroli a l- ormoni incretin biex tipprodu i 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 jipprevjeni l- idroli i ta ’ l- ormoni incretin mill - DPP- 4, u dan ghalkekk iwassal g al ieda fil- kon entrazzjonijiet ta ’ forom attivi ta ’ GLP- 1 u GIP fil - pla ma.
By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose- dependent manner.
Billi jkattar il- livelli ta ’ incretin attiv, sitgliptin jwassal biex tintre a iktar insulina u jonqsu l - livelli ta ’ glucagon b’ mod li jiddependi mill- 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- ipergli emija, dawn il- bidliet fil- livelli ta ’ l- insulina u glucagon inaqqsu l- emoglobina A1c (HbA1c) u jnaqqsu l- livelli ta ’ kon entrazzjonijiet ta ’ glucose meta sajjem u wara l- ikel.
The glucose-dependent mechanism of sitagliptin is distinct from the mechanism of sulphonylureas, which increase insulin secretion even when glucose levels are low and can lead to hypoglycaemia in patients with type 2 diabetes and in normal subjects.
Il- mekkani mu ta ’ sitagliptin li jiddependi mill- glucose huwa distint mill- mekkani mu ta ’ sulphonylureas, li j idu s- sekrezzjoni ta ’ l - insulina anke meta l- livelli ta ’ glucose huma baxxi u jista ’ jwassal g al ipogli emija f’ pazjenti ta ’ dijabete tat- tip 2 u f’ individwi normali.
Sitagliptin is a potent and 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 afna ta ’ l- en ima DPP- 4 u ma jra anx l- en imi DPP- 8 u DPP- 9 li huma relatati mill- qrib, f’ kon entrazzjonijiet terapewti i.
7 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 enerali, sitagliptin tejjeb il- kontroll gli emiku meta mog ti b ala monoterapija, meta w at f’ kombinazzjoni ma ’ metformin (terapija inizjali jew mi juda), u f’ kombinazzjoni ma ’ sulphonylurea (bi jew ming ajr metformin), u f’ kombinazzjoni ma ’ thiazolidinedione, kif imkejla bi tnaqqis klinikament relevanti f’ HbA1c mil- linja ba i fi tmiem l- istudju (ara t- Tabella 2).
Two studies were conducted to evaluate the efficacy and safety of TESAVEL monotherapy.
Saru ew studji biex jevalwaw l- effika ja u s- sigurtà ta ’ terapija b’ TESAVEL wa du.
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 b ala monoterapija wasslet g al titjib sinifikanti fil- HbA1c, fil- livell
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 ta - elluli beta, inklu HOMA - (Mudell Omeostatiku ta ’ Assessjar -), il- proporzjon bejn proinsulina u insulina, u l- kejl tar- respons ta - elluli beta minn kampjuni me uda frekwentament fit- test tat- tolleranza g all- ikel ew osservati.
The observed incidence of hypoglycaemia in patients treated with TESAVEL was similar to placebo.
L- in idenza li iet osservata ta ’ ipogli emija f’ pazjenti li ew ikkurati b’ TESAVEL kienet b al tal- pla ebo.
Body weight did not increase from baseline with sitagliptin therapy in either study, compared to a small reduction in patients given placebo.
Il- pi tal - isem ma diedx mill- linja ba i bit- terapija b’ sitagliptin, la fi studju wie ed u l- anqas fl- ie or mqabbel ma ’ tnaqqis g ir f’ pazjenti bil- pla ebo.
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 insuffi jenza renali kronika (tne ija tal- kreatinina < 50 ml/ min), is- sigurtà u t- tollerabilità ta ’ do i mnaqqsa ta ’ sitagliptin kienu nvestigati u eneralment kienu b al tal- pla ebo.
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- pla ebo eneralment kien simili g al dak osservat fi studji o ra b’ terapija wa da 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’ insuffi jenza renali moderata jew severa kien baxx wisq biex l- u u ming ajr periklu ta '
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
Change from baseline in body weight was similar for patients treated with sitagliptin relative to placebo.
ma ’ pla ebo f ’ ew studji ta ’ 24 img a ta ’ sitagliptin b ala terapija mi juda, wie ed flimkien ma ’ metformin u l- ie or flimkien ma ’ pioglitazone.
In these studies there was a similar incidence of hypoglycaemia reported for patients treated with sitagliptin or placebo.
F’ dawn l- istudji kien hemm in idenza simili g all- ipogli emija rrappurtata g al pazjenti kkurati b’ sitagliptin jew bil- pla ebo.
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.
ie mfassal studju ta ’ 24 img a b’ kontroll bi pla ebo biex jevalwa l- effika ja u s- sigurtà ta ’ sitagliptin (100 mg darba kuljum) meta mi jud ma ’ glimepiride wa du jew glimepiride flimkien ma ’ metformin.
The addition of sitagliptin to either glimepiride alone or to glimepiride and metformin provided significant improvements in glycaemic parameters.
I - ieda ta ’ sitagliptin ma ’ glimepiride wa du jew glimepiride ma ’ metformin wassal g al titjib sinifikanti fil- parametri gli emi i.
Patients treated with sitagliptin had a modest increase in body weight compared to those given placebo.
Pazjenti kkurati b’ sitagliptin kellhom ieda g ira fil- pi tal - isem meta mqabbla ma ’ dawk li adu l- pla ebo.
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 img a kkontrollat bi pla ebo ta ’ terapija inizjali, sitagliptin 50 mg darbtejn kuljum f’ kombinazzjoni ma ’ metformin (500 mg jew 1000 mg darbtejn kuljum) irri ulta f’ titjib sinifikanti fil- parametri gli emi i meta mqabbel ma ’ monoterapija wa da jew l- o ra.
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- pi tal - isem bil- kombinazzjoni ta ’ sitagliptin u metformin kien simili g al dak osservat b’ metformin wa du jew bi pla ebo; ma kien hemm ebda bidla mil- linja ba i g al pazjenti fuq sitagliptin wa du.
The incidence of hypoglycaemia was similar across treatment groups.
L - in idenza ta ’ ipogli emija kienet simili g all- gruppi ta ’ trattament kollha.
Table 2.
9 Tabella 2:
HbA1c results in placebo-controlled monotherapy and combination therapy studies*
Ri ultati ta ’ HbA1c fi studji ta ’ monoterapija kkontrollati bi pla ebo u studji ta ’ terapija kkombinata *
change in HbA1c (%) at
Linja ba i medja HbA1c
baseline HbA1c (%)
Bidla medja mil- linja ba i HbA1c (%)
baseline HbA1c (%) † at Week 24
Bidla medja kkore uta bi pla ebo f’ HbA1c (%) f ’ img a 24 †
Monotherapy Studies Sitagliptin 100 mg once daily§
Studji ta ’ Monoterapija Sitagliptin 100 mg
-0.5
f ’ img a 24
-0.6‡
(95% CI) - 0. 6 ‡
(N= 193) Sitagliptin 100 mg once daily (N= 229) Combination Therapy Studies Sitagliptin 100 mg once daily added to
darba kuljum§ (N= 193) Sitagliptin 100 mg
-0.6
- 0. 5
(-0.8, -0.4) -0.8‡ (-1.0, -0.6) -0.7‡
(- 0. 8, - 0. 4) - 0. 8 ‡
ongoing metformin therapy (N=453)
darba kuljum (N= 229)
-0.7
- 0. 6
(-0.8, -0.5)
(- 1. 0, - 0. 6)
Placebo-corrected mean
Studji ta ’ Terapija Kkombinata Sitagliptin 100 mg darba kuljum mi jud - 0. 7 ‡ ma ’ terapija ta ’ metaformin g addiena (N=453) Sitagliptin 100 mg darba kuljum mi jud
Study
- 0. 7
Week 24† (95% CI)
(- 0. 8, - 0. 5) - 0. 7 ‡
Sitagliptin 100 mg once daily added to -0.7‡ ongoing pioglitazone therapy (N=163) Sitagliptin 100 mg once daily added to
ma ’ terapija ta ’ pioglitazone g addiena (N=163) Sitagliptin 100 mg darba kuljum mi jud
ongoing glimepiride therapy (N=102) Sitagliptin 100 mg once daily added to
ma ’ terapija bi glimepiride g addiena (N=102) Sitagliptin 100 mg darba kuljum mi jud
ongoing glimepiride + metformin therapy (N=115) Initial therapy (twice daily):
ma ’ terapija bi glimepiride + metformin g addiena (N=115) 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.
* Il- Popolazzjoni tal- Pazjenti Kollha Trattati (anali i ta ’ l- intenzjoni biex isir trattament). † L- inqas kwadri tfisser a ustament g al status ta ’ terapija anti- ipergli emika pre edenti u valur tal - linja ba i. ‡ p < 0. 001 meta mqabbel ma ’ pla ebo jew pla ebo + trattament ikkombinat. § HbA1c (%) f ’ img a 18.
In a study comparing the efficacy and safety of the addition of TESAVEL 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- effika ja u s- sigurtà ta - ieda ta ’ TESAVEL 100 mg darba kuljum jew glipizide (sustanza ta ’ sulphonylurea) f’ pazjenti li ma kellhomx kontroll gli emiku tajjeb b’ kura ta ’ metformin
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- do a medja ta ’ glipizide u ata fil - grupp imqabbel kienet ta ’ 10 mg kuljum b’ madwar 40% tal- pazjenti li kienu je tie u do a ta ’ glipizide ta ’ < 5 mg kuljum g al 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 min abba nuqqas ta ’ effika ja 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 ba i fil- pi tal - isem meta mqabbla ma ’ ieda fil - pi sinifikanti f’ pazjenti mog tija 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- effi jenza tas- sinte i 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- in idenza ta ’ ipogli emija fil- grupp li kien qed jie u 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 ’ do a ta ’ 100 mg f’ individwi f’ sa ithom, sitagliptin kien assorbit malajr; b’ kon entrazzjonijiet massimi fil- pla ma (Tmax medju) jintla qu minn sieg a sa 4 sig at wara d- do a, il- pla ma medja AUC ta ’ sitagliptin kienet ta ’ 8. 52 µM• hr, Cmax kien 950 nM Il - bijodisponibiltà assoluta ta ’ sitagliptin hija bejn wie ed u ie or 87%.
Since coadministration of a high-fat meal with TESAVEL had no effect on the pharmacokinetics, TESAVEL may be administered with or without food.
Billi t- te id ta ’ ikla b’ ammont g oli ta ’ xa am ma ’ TESAVEL ma kellu l- ebda effett fuq il- farmakokinetika, TESAVEL jista ’ jing ata ma ’ l- ikel jew ming ajr l- ikel..
Plasma AUC of sitagliptin increased in a dose-proportional manner.
L- AUC ta ’ sitagliptin fil- pla ma tkattar b’ mod proporzjonali g ad- do a.
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- do a ma ietx stabbilita g al Cmax u C24hr (Cmax tkattar b’ mod ikbar mill- proporzjon mad- do a u C24hr tkattar b’ mod inqas mill- proporzjon mad- do a).
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 ta ’ distribuzzjoni medju fi stat fiss wara do a wa da fil- vina ta ’ 100 mg ta ’ sitagliptin f’ individwi f’ sa ithom hija bejn wie ed u ie or ta ’ 198 litru.
The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).
Il- frazzjoni ta ’ sitagliptin li hi marbuta b’ mod riversibbli mal- proteini tal- pla ma hija baxx (38%).
9 Metabolism Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Metaboli mu Sitagliptin primarjament jitne a ma ’ l- urina bla ma jinbidel, u l- metaboli mu huwa mog dija minuri.
Approximately 79% of sitagliptin is excreted unchanged in the urine.
Bejn wie ed u ie or 79% ta ’ sitagliptin jitne a ma ’ l- urina bla ma jinbidel.
Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin.
Wara do a orali ta ’ [14C] sitagliptin, bejn wie ed u ie or 16% tar- radjuattività tne iet b ala metabolit ta ’ sitagliptin. ew identifikati sitt metaboliti fil- livell ta ’ tra a u mhux mistennija li jikkontribwixxu g all- attività inibitorja ta ’ sitagliptin fuq DPP- 4 fil- pla ma.
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- en ima li hi primarjament responsabbli g all- metaboli mu 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.
Tag rif in vitro wera li sitagliptin mhux inibitur ta ’ l- iso imi CYP 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.
Eliminazzjoni Wara l- g oti ta ’ do a orali ta ’ [14C] sitagliptin lill - individwi f’ sa ithom, bejn wie ed u ie or 100% tar- radjuattività li ng atat tne iet ma ’ l- ippurgar (13%) jew l- urina (87%) fi mien img a mid - do a.
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 do a oral ta ’ 100 mg ta ’ sitagliptin kienet bejn wie ed u ie or 12. 4 sig at.
Sitagliptin accumulates only minimally with multiple doses.
Sitagliptin jakkumula bl- inqas mod b’ do i multipli.
The renal clearance was approximately 350 ml/ min.
It- ne ija renali hija bejn wie ed u ie or 350 ml/ min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
L- eliminazzjoni ta ’ sitagliptin sse primarjament permezz ta ’ eskrezzjoni renali u tinvolvi eskrezzjoni attiva 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 substrat g at- trasportatur- 3 uman ta ’ l- enajin 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 ietx 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 substrat ta ’ p- glycoprotein, li jista ’ jkun ukoll li hija mda la 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- tne ija renali ta ’ sitagliptin.
Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/ 2 transporters.
Sitagliptin mhux substrat g at- 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.
11 permezz ta ’ OAT3 (IC50=160 µM) jew p- glycoprotein (sa 250 µM) f’ kon entrazzjonijiet fil- pla ma 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 g ir fuq il- kon entrazzjonijiet ta ’ digoxin fil- pla ma, li jindika li sitagliptin jista` jkun inibitur afif ta ’ p- glycoprotein.
Characteristics in patients The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.
Karatteristi i fil- pazjenti Il- farmakokinetika ta ’ sitagliptin eneralment kienet simili f’ individwi f’ sa b’ dijabete tat- tip 2.
Renal insufficiency A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin (50-mg) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects.
Sar studju open- label u b’ do a wa da biex jevalwa l- farmakokinetika ta ’ do a mnaqqsa ta’ sitagliptin (50 mg) f’ pazjenti b’ insuffi jenza renali kronika fi stadji differenti, kkomparati ma ’ individwi f’ sa ithom b ala kontroll.
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.
L- istudju inkluda pazjenti b’ insuffi jecza renali ikklassifikata skond it - tne ija tal- kreatinina b ala afifa (50 sa < 80 ml/ min), moderata (30 sa < 50 ml/ min), u qawwija (< 30 ml/ min), kif ukoll pazjenti b’ mard renali fl- a ar stadju tieg u (ESRD) li kienu fuq 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’ insuffi jenza renali afifa ma kellhomx ieda klinikament sinifikanti fil- kon entrazzjoni ta ’ sitagliptin fil- pla ma meta mqabbla ma ’ individwi normali f’ sa ithom b ala 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’ insuffi jenza renali moderata ie osservat bejn wie ed u ie or l- irduppjar ta ’ l- AUC fil- pla ma ta ’ sitagliptin, u - ieda kienet ta ’ 4 darbiet g al pa jenti b’ insuffi jenza renali qawwija u pazjenti b’ ESRD li kienu fuq l- emodijalisi, meta mqabbla ma ’ individwi normali f’ sa ithom b ala kontroll.
Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours postdose).
Sitagliptin tne a xi ftit bl- emodijalisi (13. 5% wara sessjoni ta ’ emodijalisi ta ’ bejn 3 u 4 sig at li bdiet 4 sig at wara d- do a).
(See section 4.2.)
TESAVEL mhux rakkomandat g all- u u f’ pazjenti b’ insuffi jenza renali moderata jew severa inklu dawk b’ ESRD billi l- esperjenza f ’ dawn il- pazjenti hija limitati wisq (Ara sezzjoni 4. 2).
Hepatic insufficiency No dosage adjustment for TESAVEL is necessary for patients with mild or moderate hepatic insufficiency (Child-Pugh score ≤ 9).
Insuffi jenza epatika M’ hemmx g alfejn a ustment fid- do a ta ’ TESAVEL g al pazjenti b’ insuffi jenza epatika afifa jew moderata (Punte 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’ insuffi jenza epatika qawwija (Punte 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 jitne a primarjament mill - kliewi, insuffi jenza epatika qawwija mhix mistennija li taffetwa l- farmakokinetika ta ’ sitagliptin.
10 Elderly No dosage adjustment is required based on age.
Anzjani M’ hemmx b onn a ustament tad- do a min abba 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 wie ed iqis l- anali i farmakokinetika fil- popolazzjoni tat- tag rif ta ’ Fa i I u Fa i II, l- età ma kellhiex impatt kliniku sinifikanti fuq il - farmakokinetika ta ’ sitagliptin.
Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
Individwi anzjani (65 sa 80 sena) kellhom kon entrazzjonijiet ta ’ sitagliptin fil- pla ma li kienu bejn wie ed u ie or 19% og la meta mqabbla ma ’ individwi i g ar.
Paediatric No studies with TESAVEL have been performed in paediatric patients.
Pedjatri i Ma sarux studji b’ TESAVEL fuq pazjenti pedjatri i.
Other patient characteristics No dosage adjustment is necessary based on gender, race, or body mass index (BMI).
Karatterisiti i o ra tal- pazjenti M’ hemmx b onn bidla fid- do a min abba sess, razza jew l- indi i tal- massa tal - isem (BMI).
These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Dawn il - karatteristi i m’ g andhom l- ebda effett kliniku sinifikanti fuq il- farmakokinetika ta ’ sitagliptin skond l- anali i komposta tat- tag rif farmakokinetku ta ’ Fa i I u skond l- anali i farmakokinetika fil - popolazzjoni tat- tag rif ta ’ Fa i I u Fa i II.
5.3 Preclinical safety data
5. 3 Tag rif ta' qabel l- u u kliniku dwar is- sigurtà tal- medi ina
Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human exposure level, while the no-effect level was found at 19 times the human exposure level.
Tossi ità renali u fil- fwied ew osservati fl- annimali gerriema li kienu esposti g al valuri 58 darba iktar mill- livell ta ’ espo izzjoni fl- umani.
Incisor teeth abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no- effect level for this finding was 58-fold based on the 14-week rat study.
Fil- waqt li l- livell li fih ma jkunx hemm effett instab li kien ta 19- il darba l- livell ta ’ espo izzjoni fl- umani. ew osservati anormalitajiet fis- snien in i uri ta ’ firien li ew esposti g al livelli 67 darba ikbar mill- livell kliniku ta ’ espo izzjoni; g al din is- sejba l - livell ta ’ ming ajr effett kien 58 darba ibba at fuq studju fuq il- firien ta ’ 14- il img a.
The relevance of these findings for humans is unknown.
Mhix mag rufa r- relevanza ta ’ dawn is- sejbiet g all- bnedmin.
Transient treatment-related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/ or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level.
Fi klieb li ew esposti g al bejn wie ed u ie or 23 darba l- livell kliniku ta ’ espo izzjoni ew osservati sinjali fi i i li jg addu relatati mal- kura, li xi w ud minnhom jissu gerixxu tossi ità newrali, b al li jittie ed in- nifs bil - alq miftu, ru tal - 12 b ieq, rimettar abjad bir- rag wa, nuqqas ta ’ ko- ordinament tal- muskoli, trehid, attività mnaqqsa, u/ jew po izzjoni m atba.
In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level.
Ukoll, b’ do i li wasslu g al livelli ta ’ espo izzjoni sistemika 23 darba l - livell ta ’ espo izzjoni umana, ie osservat istolo ikament de enerazzjoni fil- muskoli skeletali minn ftit sa ftit afna.
A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level.
Il- livell g al dawn is- sejbiet li fih ma kienx hemm effett instab li kien espo izzjoni 6 darbiet il- livell kliniku.
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies.
Fi studji ta ’ qabel l- u u kliniku sitagliptin ma ntweriex li g andu effett tossiku fuq il - eni.
Sitagliptin was not carcinogenic in mice.
Sitagliptin ma kienx iwassal g al riskju ta ’ kan er fil - rieden.
In rats, there was an increased incidence of hepatic adenomas and carcinomas at systemic exposure levels 58 times the human exposure level.
Fil- firien, kien hemm in idenza ikbar ta ’ adenoma u kar inoma fil- fwied b’ espo izzjoni sistemika li kienet 58 darba iktar minn dik fl- umani.
Since hepatotoxicity has been shown to correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumors in rats was likely secondary to chronic hepatic toxicity at this high dose.
Billi l- livell tossiku epatiku ntwera li jikkorelata ma ’ l- induzzjoni ta ’ neopla ja epatika fil- firien, din l- in idenza ikbar ta ’ tumuri epati i fil- firien aktarx li kienet sekondarja g at- tossi ità epatika kronika f’ din id - do a g olja.
Because of the high safety margin (19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation in humans.
Min abba l- mar ini g oli ta ’ sigurtà (19- il darba f’ dan il- livell ta ’ ming ajr effett), dawn il- bidliet neoplasti i m’ humiex ikkonsidrati relevanti g all- bnedmin.
No adverse effects upon fertility were observed in male and female rats given sitagliptin prior to and throughout mating.
Ma ewx osservati effetti avversi fuq il- fertilità tal- firien nisa u r iel li ng ataw sitagliptin qabel u waqt l- akkoppjament.
In a pre-/ postnatal development study performed in rats sitagliptin showed no adverse effects.
Fi studju dwar l- i vilupp qabel u wara t- twelid li sar fuq il- firien sitagliptin ma wera l- ebda effett avvers
Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels more than 29 times the human exposure levels.
Studji ta ’ tossi ità fir- riproduzzjoni wrew li kien hemm in idenza kemmxejn ikbar marbuta mal- kura ta ’ malformazzjonijiet fil- kustilji tal- fetu (kustilji neqsin, ipoplasti i jew immew in) fil- frieg tal - firien li kienu esposti g al do i sistemi i iktar minn 29 darba l- livell uman.
Maternal toxicity was seen in rabbits at more than 29 times the human exposure levels.
Fil- fniek kien hemm tossi ita materna fl- livelli ta’ espo izzjoni ta ’ aktar minn 29 darba dawk umani.
Because of the high safety margins, these findings do not suggest a relevant risk for human reproduction.
Min abba l- mar ini g olja ta ’ sigurtà, dan it- tag rif ma jissu erix li hemm riskju relevanti g ar- riproduzzjoni umana.
Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk/ plasma ratio:
Sitagliptin jo ro f’ ammonti konsiderevoli fil - alib ta ’ firien li qed ireddg u (proporzjon alib/ pla ma:
11 calcium hydrogen phosphate, anhydrous (E341) croscarmellose sodium (E468) magnesium stearate (E470b) sodium stearyl fumarate
Qalba tal- pillola: microcrystalline cellulose (E460) calcium hydrogen phosphate, anhydrous (E341) croscarmellose sodium (E468) magnesium stearate (E470b) sodium stearyl fumarate
6.4 Special precautions for storage
13 6. 4 Prekawzjonijiet spe jali g all - a na
This medicinal product does not require any special storage conditions.
Dan il - prodott medi inali m’ g andux b onn ta’ kundizzjonijiet spe jali ta ’ a na.
Packs of 14, 28, 56, 84 or 98 film-coated tablets and 50 x 1 film-coated tablets in perforated unit dose blisters.
Pakketti ta ’ 14, 28, 56, 84 jew 98 pillola miksija b’ rita u 50 x 1 pillola miksija b’ rita f’ folji perforati ta ’ do i uni i.
Any unused product or waste material should be disposed of in accordance with local requirements.
Kull fdal tal- prodott li ma jkunx intu a jew skart li jibqa ’ wara l- u u tal- prodott g andu jintrema kif jitolbu l- li ijiet lokali.
MARKETING AUTHORISATION HOLDER
I D- DETENTUR TA’ L- AWTORIZZAZZJONI GHAT- TQEG ID FIS- SUQ
10.
DATA TA ’ META
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) web site: http: / /www. emea. europa. eu/.
Informazzjoni dettaljata dwar dan il- prodott medi inali tinsab fis- sit ta ’ l- internet ta ’ l- A enzija Ewropea tal- Medi ini (EMEA) sit: http: // www. emea. europa. eu /.
TESAVEL 50 mg film-coated tablets
TESAVEL pilloli miksija b’ rita tal- 50 mg
Each tablet contains sitagliptin phosphate monohydrate, equivalent to 50 mg sitagliptin.
Kull pillola fiha sitagliptin phosphate monohydrate, ekwivalenti g al 50 mg ta ’ sitagliptin.
Round, light beige film-coated tablet with “ 112” on one side.
Pillola miksija b’ rita tonda u beige ar bi “ 112 ” fuq na a wa da.
14 Patients with renal insufficiency For patients with mild renal insufficiency (creatinine clearance [CrCl] ≥ 50 ml/ min), no dosage adjustment for TESAVEL is required.
15 Pazjenti b’ insuffi jenza renali ija tal- krejatinina [CrCl] ≥50 ml/ min,, m’ hemmx G al pazjenti b’ insuffi jenza renali afifa (tne b onn bidla fid- do a ta ’ TESAVEL.
TESAVEL has not been studied in patients with severe hepatic insufficiency.
TESAVEL ma iex studjat f’ pazjenti b’ insuffi jenza epatika.
Limited safety data is available in patients ≥ 75 years of age and care should be exercised.
Hemm tag rif limitat dwar sigurtà f’ pazjenti ta ’ 75 sena u g andhatigi ezercitata attenzjoni
Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 4.8).
Sensittività e essiva g as- sustanza attiva jew g al xi sustanzi mhux attivi (ara sezzjonijiet 4. 4 u 4. 8)
Renal insufficiency As the experience is limited, patients with moderate to severe renal insufficiency should not be treated with TESAVEL (see section 5.2).
Insuffi jenza renali Min abba li l- esperjenza hi limitata, pazjenti b’ insuffi jenza moderata renali jew severa m’ g andhomx ji u kkurati b’ TESAVEL (ara sezzjoni 5. 2).
4.5 Interaction with other medicinal products and other forms of interaction
16 4. 5 Prodotti medi inali o ra li ma jaqblux ma ’ dan il- prodott u affarjiet o ra li jistg u jibdlu l- effett farma ewtiku tal- prodott
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- kon entrazzjonijiet ta ’ digoxin fil- pla ma, u jista ’ jkun inibitur afif ta ’ p- glycoprotein in vivo.
Following administration of 0.25 mg digoxin concomitantly with 100 mg of TESAVEL 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 ing ata flimkien ma ’ 100 mg ta’ TESAVEL kuljum g al 10 ijiem, l- AUC ta ’ digoxin fil - pla ma kibret b’ medja ta ’ 11%, u Cmax fil- pla ma b’ medja ta ’ 18%.
No dosage adjustment of digoxin is recommended.
Mhux rakkomandat li tinbidel id - do a ta ’ digoxin.
However, patients at risk of digoxin toxicity should be monitored for this when sitagliptin and digoxin are administered concomitantly.
Madankollu, pazjenti li g andhom riskju ta ’ tossi ità b’ digoxin g andhom jit allew ta t sorveljanza g al dan meta sitagliptin u digoxin jing ataw flimkien.
Studies in animals have shown reproductive toxicity at high doses (see section 5.3).
Studji fuq l- annimali urew tossi ità fis- sistema riproduttiva f’ dozi g oljin( ara sezzjoni 5. 3).
Lactation It is unknown whether sitagliptin is excreted in human breast milk.
17 Treddig Mhux nag ruf jekk sitagliptin jitne iex mal - alib tas- sider fil- bniedem.
Animal studies have shown excretion of sitagliptin in breast milk.
Studji fl- annimali urew li sitagliptin jitne a mal - alib tas- sider.
TESAVEL should not be used during breast-feeding.
TESAVEL m’ g andux jintu a waqt treddigh ta ’ trab ’.
However, when driving or operating machines, it should be taken into account that dizziness and somnolence have been reported.
Madankollu, meta ssuq jew t addem magni, jrid jigi ikkunsidrat li sturdament u - ng as gew irrappurtati.
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 adu sitagliptin ma kellhomx iktar reazzjonijiet avversi kkunsidrati relatati mal medi ina (> 0. 2% u differenza ta ’ > pazjent 1) meta mqabbla ma ’ pazjenti li adu kura ta ’ kontroll.
Table 1.
18 Tabella 1.
Sitagliptin with Sitagliptin with Sitagliptin with 1 2
Frekwenza tar- reazzjoni avversa skond Sitagliptin ma ’ Sitagliptin ma ’ Metformin1 Sulfonylurea2
Metformin and a a PPARγ Agent Sulfonylurea3 (pioglitazone)4
ir- re imen tat- trattament Sitagliptin ma ’ Sitagliptin ma ’ Metformin u sustanza ta ’ Sulfonylurea3 γ PPARγ (pioglitazone) 4
Very common
Komuni afna
Very common Common
Komuni afna Komuni
Nervous system disorders somnolence
Disturbi fis - sistema nervu a ng as Mhux komuni
In clinical trials of TESAVEL 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.
Investigazzjonijiet livell imnaqqas ta ’ Mhux komuni glucose fid- demm * Fi provi klini i ta ’ TESAVEL b ala monoterapija u sitagliptin b ala parti minn terapija kkombinata ma ’ metformin jew pioglitazone, rati ta ’ ipogli emija rrapportati b’ sitagliptin kienu simili g al rati f’ pazjenti li kienu qed jie du pla ebo.
17 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 ttie ed flimkien ma ’ metformin, l- in idenza ta ’ reazzjonijiet avversi kkunsidrati relatati mal- medi ina f’ pazjenti li adu sitagliptin/ metformin meta mqabbla ma ’ sulphonylurea/ metformin kienet ta ’ 14. 5% u 30. 3%, rispettivament.
In pooled studies of up to 1 year in duration comparing sitagliptin/ metformin to a sulphonylurea agent/ metformin, adverse reactions considered as drug-related reported in patients treated with sitagliptin 100 mg occurring in excess (> 0.2% and difference > 1 patient) of that in patients receiving the sulphonylurea agent are as follows: anorexia (Metabolism and nutritional disorders; frequency uncommon) and weight decreased (Investigations; frequency uncommon).
Fi studji mi bura flimkien li damu sa sena u li qabblu sitagliptin/ metformin ma ’ sustanza ta ’ sulphonylurea/ metformin, ir- reazzjonijiet avversi kunsidrati relatati mal- medi ina li dehru aktar (> 0. 2% u differenza ta ’ > pazjent 1) f’ pazjenti li adu sitagliptin 100 mg minn f’ pazjenti li adu sustanza ta ’ sulphonylurea, huma kif ejjin: anoressija (Disturbi fil- metaboli mu u n- nutrizzjoni; frekwenza mhux komuni) u tnaqqis fil- pi (Investigazzjonijiet; frekwenza mhux komuni) 2 F’ dan l- istudju ta ’ 24 img a ta ’ 100 mg ta ’ sitagliptin darba kuljum flimkien ma ’ glimepiride, l - in idenza ta ’ reazzjonijiet avversi li setg u jitqiesu li kienu relatati mal- medi ina f’ pazjenti kkurati
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.
19 b ’ sitagliptin/ glimepiride meta mqabbla ma ’ kura bi pla ebo/ glimepiride kienet ta ’ 11. 3% u 6. 6% rispettivament.
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 img a ta ’ terapija kkombinata inizjali b ’ sitagliptin u metformin mog tija darbtejn kuljum (sitagliptin/ metformin 50 mg/ 500 mg jew 50 mg/ 1000 mg), l- in idenza totali ta ’ reazzjonijiet avversi meqjusin relatati mal- medi ina f’ pazjenti ttratti b’ kombinazzjoni ta ’ sitagliptin u metformin meta mqabbla ma ’ pazjenti ttrattati bi pla ebo kienet ta ’ 14. 0% u 9. 7%, rispettivament.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed with TESAVEL treatment.
F’ kura b’ TESAVEL ma ewx osservati bidliet b’ relevanza klinika fis- sinjali vitali jew fl- ECG (inklu l- intervall QTc).
18 Post-marketing Experience:
Esperjenza ta ’ Wara t- Tqeg id 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- tqeg id fis- suq ew irrappurtati l- effetti sekondarji o ra li ejjin (il - frekwenza mhix mag rufa): reazzjonijiet ipersensittivi, inklu anafilassi, an joedema, raxx, urtikarja u kundizzjonijiet ta ’ ilda li titqaxxar inklu is- sindromu ta ’ Stevens- Johnson (ara sezzjoni 4. 4).
Minimal increases in QTc, not considered to be clinically relevant, were observed in one study at a dose of 800 mg sitagliptin.
I - idiet minimi fi QTc, li ma tqisux klinikament relevanti, kienu osservati fi studju wie ed b’ do a ta ’ 800 mg ta ’ sitagliptin.
There is no experience with doses above 800 mg in humans.
M’ hemmx esperjenza b’ do i 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.
20 Fil- ka ta ’ do a e essiva, ikun ra onevoli li jintu aw il- mi uri ta ’ appo tas- soltu, ng idu a na jitne a materjal mhux assorbit mill- apparat gastro- intestinali, isir monitora kliniku (inklu elettrokardjogramma), u tinbeda terapija ta ’ appo g jekk hemm b onn.
19 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 enerali, sitagliptin tejjeb il- kontroll gli emiku meta mog ti b ala monoterapija, meta w at f’ kombinazzjoni ma ’ metformin (terapija inizjali jew mi juda), u f’ kombinazzjoni ma ’ sulphonylurea (bi jew ming ajr metformin), u f’ kombinazzjoni ma ’ thiazolidinedione, kif imkejla bi tnaqqis klinikament relevanti f’ HbA1c mil- linja ba i fi tmiem l- istudju (ara t- Tabella 2).
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 b ala monoterapija wasslet g al titjib sinifikanti fil- HbA1c, fil- livell ta ’ glucose fil- pla ma meta sajjem (FPG), u fil- livell ta ’ glucose sag tjen wara l- ikel (PPG ta ’ sag tejn), meta mqabbel mal- pla ebo f ’ ew studji, wie ed ta ’ 18- il img a u l- ie or ta ’ 24 img a.
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.
21 Assessjar -), il- proporzjon bejn proinsulina u insulina, u l- kejl tar- respons ta - elluli beta minn kampjuni me uda frekwentament fit- test tat- tolleranza g all- ikel ew osservati.
Table 2.
22 Tabella 2:
Week 24†
Bidla medja kkore uta bi pla ebo f’ HbA1c (%) f ’ img a 24 †
at Week 24†
f ’ img a 24
Sitagliptin 100 mg once daily§ (N= 193) Sitagliptin 100 mg once daily (N= 229) Combination Therapy Studies Sitagliptin 100 mg once daily added to
darba kuljum§ (N= 193) Sitagliptin 100 mg
-0.6‡ (-0.8, -0.4) -0.8‡ (-1.0, -0.6) -0.7‡
(- 0. 8, - 0. 4) - 0. 8 ‡
Sitagliptin 100 mg once daily added to
Studji ta ’ Terapija Kkombinata Sitagliptin 100 mg darba kuljum mi jud - 0. 7 ‡ ma ’ terapija ta ’ metaformin g addiena (N=453) Sitagliptin 100 mg darba kuljum mi jud
HbA1c (%)
8. 0
at Week 24†
- 0. 7
(95% CI) -0.7‡
(- 0. 8, - 0. 5) - 0. 7 ‡
ongoing pioglitazone therapy (N=163) Sitagliptin 100 mg once daily added to
ma ’ terapija ta ’ pioglitazone g addiena (N=163) Sitagliptin 100 mg darba kuljum mi jud
The absolute bioavailability of sitagliptin is approximately 87%.
Assorbiment Wara l- amministrazzjoni orali ta ’ do a ta ’ 100 mg f’ individwi f’ sa ithom, sitagliptin kien assorbit malajr; b 'entrazzjonijiet massimi fil- pla ma (Tmax medju) jintla qu minn sieg a sa 4 sig at wara kon d- do a, il- pla ma medja AUC ta ’ sitagliptin kienet ta ’ 8. 52 µM• hr, Cmax kien 950 nM Il - bijodisponibiltà assoluta ta ’ sitagliptin hija bejn wie ed u ie or 87%.
Since coadministration of a high-fat meal with TESAVEL had no effect on the pharmacokinetics, TESAVEL may be administered with or without food.
Billi t- te id ta ’ ikla b’ ammont g oli ta ’ xa am ma ’ TESAVEL ma kellu l- ebda effett fuq il- farmakokinetika, TESAVEL jista ’ jing ata ma ’ l- ikel jew ming ajr l- ikel.
21 Metabolism Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Metaboli mu Sitagliptin primarjament jitne a ma ’ l- urina bla ma jinbidel, u l- metaboli mu huwa mog dija minuri.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.
Wara do a orali ta ’ [14C] sitagliptin, bejn wie ed u ie or 16% tar- radjuattività tne iet b ala metabolit ta ’ sitagliptin. ew identifikati sitt metaboliti fil- livell ta ’ tra a u mhux mistennija li jikkontribwixxu g all- attività inibitorja ta ’ sitagliptin fuq DPP- 4 fil- pla ma Studji in vitro indikaw li l- en ima li hi primarjament responsabbli g all- metaboli mu limitat ta ’ sitagliptin kienet CYP3A4, b’ kontribuzzjoni minn CYP2C8.
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.
Eliminazzjoni Wara l- g oti ta ’ do a orali ta ’ [14C] sitagliptin lill- individwi f’ sa ithom, bejn wie ed u ie or 100% tar- radjuattività li ng atat tne iet ma ’ l- ippurgar (13%) jew l- urina (87%) fi mien img a mid - do a.
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 g at- trasportatur- 3 uman ta ’ l- enajin organiku (hOAT- 3), li jista ’ jkun involut fl- eliminazzjoni renali ta ’ sitagliptin.
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.
24 permezz ta ’ OAT3 (IC50=160 µM) jew p- glycoprotein (sa 250 µM) f’ kon entrazzjonijiet fil- pla ma terapewtikament relevanti.
Renal insufficiency A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of sitagliptin (50-mg) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects.
Sar studju open- label u b’ do a wa da biex jevalwa l- farmakokinetika ta ’ do a mnaqqsa ta ’ sitagliptin (50 mg) f’ pazjenti b’ insuffi jenza renali kronika fi stadji differenti, kkomparati ma ’ individwi f’ sa ithom b ala kontroll.
However, because sitagliptin is primarily renally eliminated, severe hepatic insufficiency is not expected to affect the pharmacokinetics of sitagliptin.
Madankollu billi sitagliptin jitne a primarjament mill - kliewi, insuffi jenza epatika qawwija mhix mistennija li taffetw l- farmakokinetika ta ’ sitagliptin.
22 Elderly No dosage adjustment is required based on age.
Anzjani M’ hemmx b onn a ustament tad- do a min abba l- età.
Transient treatment-related physical signs, some of which suggest neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling, decreased activity, and/ or hunched posture were observed in dogs at exposure levels approximately 23 times the clinical exposure level.
Fi klieb li ew esposti g al bejn wie ed u ie or 23 darba l- livell kliniku ta ’ espo izzjoni ew osservati sinjali fi i i li jg addu relatati mal- kura, li xi w ud minnhom jissu gerixxu tossi ità newrali, b al li jittie ed in- nifs bil - alq miftu, ru tal- b ieq, 25 rimettar abjad bir- rag wa, nuqqas ta ’ ko- ordinament tal- muskoli, trehid, attività mnaqqsa, u/ jew po izzjoni m atba.
In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times the human exposure level.
Ukoll, b’ do i li wasslu g al livelli ta ’ espo izzjoni sistemika 23 darba l- livell ta ’ espo izzjoni umana, ie osservat istolo ikament de enerazzjoni fil- muskoli skeletali minn ftit sa ftit afna.
A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level.
Il- livell g al dawn is- sejbiet li fih ma kienx hemm effett instab li kien espo izzjoni 6 darbiet il - livell kliniku.