natgillin/translations-raw huggingface dataset:
Patienter med mild nyreinsufficiens havde ikke en klinisk relevant stigning i plasmakoncentrationen af sitagliptin sammenlignet med de normale raske kontrolpersoner.
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.
Der blev observeret en stigning til ca. det dobbelte i sitagliptins plasma- AUC hos patienter med moderat nyreinsufficiens, og en stigning til ca. det firdobbelte blev observeret hos patienter med svær nyreinsufficiens og hos patienter med ESRD i hæmodialyse sammenlignet med normale raske kontrolpersoner.
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 haemodialysis, as compared to normal healthy control subjects.
Sitagliptin elimineredes moderat ved hæmodialyse (13, 5% over en 3- 4 timers hæmodialysesession med start 4 timer efter dosering).
Sitagliptin was modestly removed by haemodialysis (13.5% over a 3- to 4-hour haemodialysis session starting 4 hours post-dose).
4. 2.).
Sitagliptin is not recommended for use in patients with moderate or severe renal insufficiency including those with ESRD since experience in these patients is too limited (see section 4.2).
Leverinsufficiens Dosisjustering af sitagliptin er ikke nødvendig hos patienter med mild eller moderat leverinsufficiens (Child- Pugh score ≤9).
Hepatic insufficiency No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic insufficiency (Child-Pugh score ≤ 9).
Der er ingen klinisk erfaring fra patienter med svær leverinsufficiens (Child - Pugh score > 9), men da sitagliptin primært elimineres renalt, forventes leverinsufficiens ikke at påvirke sitagliptins farmakokinetik.
However, because sitagliptin is primarily renally eliminated, severe hepatic insufficiency is not expected to affect the pharmacokinetics of sitagliptin.
Ældre Dosisjustering er ikke nødvendig på basis af alder.
Elderly No dose adjustment is required based on age.
Alder havde ingen klinisk relevant indflydelse på sitagliptins farmakokinetik baseret på en farmakokinetisk populationsanalyse af fase I - og fase II- data.
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.
19% højere sitagliptinplasmakoncentrationer sammenlignet med yngre patienter.
Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
13 Der er ikke udført undersøgelser med anvendelse af sitagliptin til børn.
Paediatric No studies with sitagliptin have been performed in paediatric patients.
Andre patientkarakteristika Dosisjustering er ikke nødvendig på basis af køn, race eller body mass index (BMI).
Other patient characteristics No dose adjustment is necessary based on gender, race, or body mass index (BMI).
Disse karakteristika havde ingen klinisk relevant virkning på sitagliptins farmakokinetik på basis af en sammensat analyse af fase I farmakokinetiske data og en farmakokinetisk populationsanalyse af fase I - og fase II- data.
These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a 13 composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Metformin Absorption Efter en oral dosis metformin nås tmax efter 2, 5 timer.
Metformin Absorption After an oral dose of metformin, tmax is reached in 2.5 h.
50- 60% hos raske forsøgspersoner.
Absolute bioavailability of a 500 mg metformin tablet is approximately 50-60% in healthy subjects.
Efter en oral dosis var den ikke - absorberede fraktion i fæces 20- 30%.
After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
Ved de normale metformindoser og doseringsregimer nås steady state plasmakoncentrationer inden for 24- 48 timer og er generelt under 1 µg/ ml.
At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1 µg/ ml.
I kontrollerede kliniske undersøgelser oversteg metformins maksimale plasmakoncentrationer (Cmax) ikke 4 µg/ ml, selv ved maksimale doser.
In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 µg/ ml, even at maximum doses.
Efter administration af en dosis på 850 mg sås en 40% lavere plasma peakkoncentration, 25% fald i AUC og en forlængelse af tiden op til plasma peakkoncentration på 35 minutter.
Following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC and a 35 min prolongation of time to peak plasma concentration was observed.
Distribution Plasmaproteinbindingen er ubetydelig.
Distribution Plasma protein binding is negligible.
Gennemsnitligt fordelingsvolumen (Vd) lå på 63- 276 l.
The mean Vd ranged between 63 – 276 l.
Metabolisme Metformin udskilles uændret i urinen.
Metabolism Metformin is excreted unchanged in the urine.
Elimination Metformins renale clearance er > 400 ml/ min, hvilket tyder på, at metformin elimineres ved glomerulær filtration og tubulær sekretion.
Elimination Renal clearance of metformin is > 400 ml/ min, indicating that metformin is eliminated by glomerular filtration and tubular secretion.
6, 5 timer.
Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 h.
I 16- ugers undersøgelser, hvor hunde blev behandlet med enten metformin alene eller en kombination af metformin og sitagliptin, sås ikke øget toksicitet med kombinationsbehandlingen.
In 16-week studies in which dogs were treated with either metformin alone or a combination of metformin and sitagliptin, no additional toxicity was observed from the combination.
6 og 2, 5 gange højere end hos mennesker.
The NOEL in these studies was observed at exposures to sitagliptin of approximately 6 times the human exposure and to metformin of approximately 2.5 times the human exposure.
Sitagliptin Der blev observeret nyre - og levertoksicitet hos gnavere ved systemiske eksponeringsniveauer, der var 58 gange højere end eksponeringsniveauet hos mennesker, mens no- effect- niveauet fandtes ved et niveau, der var 19 gange højere end eksponeringsniveauet hos mennesker.
Sitagliptin 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.
No- effect- niveauet for dette fund var 58 gange højere på basis af 14- ugers -
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.
Vejrtrækning med åben mund, spytafsondring, hvid skummende opkastning, ataksi, skælven, nedsat aktivitet og/ eller krum stilling.
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.
23 gange højere end hos mennesker.
In addition, very slight to slight skeletal muscle degeneration was also observed histologically at doses resulting in systemic exposure levels of approximately 23 times
No- effect- niveauet for disse fund var til stede ved en eksponering, der var 6 gange højere end i klinikken.
A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level.
Eftersom hepatotoksicitet har vist sig at korrelere med induktion af hepatisk neoplasi hos rotter, var denne øgede forekomst af hepatiske tumorer sandsynligvis sekundær til kronisk hepatisk toksicitet ved denne høje dosis.
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.
På grund af den høje sikkerhedsmargin (19 gange på dette no- effect- niveau), anses disse neoplastiske ændringer ikke som relevante for situationen hos mennesker.
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.
Der blev ikke observeret bivirkninger i fertiliteten hos han - og hunrotter, der blev behandlet med sitagliptin før og under parringsperioden.
No treatment related effects on fertility were observed in male and female rats given sitagliptin prior to and throughout mating.
Sitagliptin viste ingen bivirkninger i en præ - og postnatal udviklingsundersøgelse udført med rotter.
In a pre-/ postnatal development study performed in rats sitagliptin showed no adverse effects.
Reproduktive toksicitetsundersøgelser viste en let behandlingsrelateret øget forekomst af føtale ribbensdefekter (manglende, hypoplastiske og takkede ribben) hos rotteafkom ved en systemisk eksponering på mere end 29 gange eksponeringen hos mennesker.
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.
Sitagliptin udskilles i betydelige mængder i modermælken hos diegivende rotter (mælk/ plasma- ratio:
Sitagliptin is secreted in considerable amounts into the milk of lactating rats (milk/ plasma ratio:
Metformin De prækliniske data for metformin viser ingen særlig fare for mennesker på basis af traditionelle undersøgelser af sikkerhedsfarmakologi, gentagen dosistoksicitet, genotoksicitet, karcinogenicitet, og toksicitet i forbindelse med reproduktion.
Metformin Preclinical data for metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
Mikrokrystallinsk cellulose (E460) Povidon K29/ 32 (E1201) Natriumlaurilsulfat Natriumstearylfumarat
Tablet core: microcrystalline cellulose (E460) povidone K29/ 32 (E1201) sodium lauril sulfate sodium stearyl fumarate
Polyvinylalkohol Macrogol 3350 Talcum (E553b) Titandioxid (E171) Rød jernoxid (E172) Sort jernoxid (E172)
Film coating: polyvinyl alcohol macrogol 3350 talc (E553b) titanium dioxide (E171) iron oxide red (E172) iron oxide black (E172)
Uigennemsigtig blister (PVC/ PE/ PVDC og aluminium).
Opaque blisters (PVC/ PE/ PVDC and aluminum).
Pakninger med 14, 28, 56, 112, 168, 196 filmovertrukne tabletter, multipakning indeholdende 196 (2 x 98) filmovertrukne tabletter.
Packs of 14, 28, 56, 112, 168, 196 film-coated tablets, multi-packs containing 196 (2 packs of 98) film-coated tablets.
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Efficib 50 mg/ 1000 mg filmovertrukne tabletter.
Efficib 50 mg/ 1000 mg film-coated tablets
Hver tablet indeholder 50 mg sitagliptin (som phosphatmonohydrat) og 1000 mg metforminhydrochlorid.
Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 1,000 mg of metformin hydrochloride.
Kapselformet, rød filmovertrukken tablet med "577" præget på den ene side.
Capsule-shaped, red film-coated tablet with “ 577” debossed on one side.
17 Til de forskellige metformindoser findes Efficib i styrker på 50 mg sitagliptin og 850 mg metforminhydrochlorid eller 1. 000 mg metforminhydrochlorid.
17 For the different doses on metformin, Efficib is available in strengths of 50 mg sitagliptin and 850 mg metformin hydrochloride or 1,000 mg metformin hydrochloride.
18 hos patienter på metformin er primært opstået hos diabetespatienter med betydelig nyreinsufficiens.
18 risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any conditions associated with hypoxia.
Der bør udvises særlig forsigtighed i situationer, hvor nyrefunktionen kan svækkes, f. eks. ved initiering af antihypertensiv eller diuretikabehandling, eller når behandling med et nonsteroid antiinflammtorisk stof (NSAID) påbegyndes.
Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug (NSAID).
Ændring i klinisk status hos patienter med tidligere velbehandlet type 2- diabetes En patient med type 2- diabetes, der tidligere var velbehandlet på Efficib, og som udvikler unormale laboratorieværdier eller klinisk sygdom (især vagt eller uklart defineret sygdom) bør vurderes hurtigt med henblik på tegn på ketoacidose eller laktacidose.
19 Change in clinical status of patients with previously controlled type 2 diabetes A patient with type 2 diabetes previously well controlled on Efficib who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis.
ACE- hæmmere sænke blodglucoseniveauet.
ACE-inhibitors may decrease the blood glucose levels.
In vitro- undersøgelser tyder på, at CYP3A4 primært er ansvarlig for sitagliptins begrænsede metabolisme, og at CYP2C8 medvirker hertil.
20 In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin is CYP3A4, with contribution from CYP2C8.
20 itraconazol, ritonavir, clarithromycin) muligvis ændre sitagliptins farmakokinetik hos patienter med svær nyreinsufficiens eller 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.
Samtidig administration af af OAT3- hæmmere er ikke vurderet in vivo.
Concomitant administration of OAT3 inhibitors has not been evaluated in vivo.
Sitagliptin havde en lille effekt på digoxinkoncentrationen i plasma og kan være en mild hæmmer af p- glycoprotein in vivo.
Sitagliptin had a small effect on plasma digoxin concentrations, and may be a mild inhibitor of p-glycoprotein in vivo.
Der er ikke tilstrækkelige data for anvendelse af sitagliptin til gravide.
There are no adequate data from the use of sitagliptin in pregnant women.
4. 8 Bivirkninger
21 4.8 Undesirable effects
Til sammenligning var bivirkningsincidensen 7, 1% hos de patienter, der blev behandlet med placebo og glimepirid/ metformin.
22 with glimepiride and metformin was 18.1% compared to treatment with the addition of placebo to the ongoing treatment with glimepiride and metformin which was 7.1%.
4. 4).
During post-marketing experience of Efficib or sitagliptin, one of the active substances of Efficib, the following additional adverse reactions 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).
Data fra kliniske undersøgelser og efter markedsføring
Clinical Trial Data and Post-marketing data
23 Tabel 2.
Table 2.
Mave- tarmkanalen Symptomer fra mave- tarmkanalena
23 Adverse reaction
Meget almindelig
Frequency
Urticaria, erythema, pruritus
gastrointestinal symptomsa
Metabolisme og ernæring Laktacidose B12- vitaminmangelb
Skin and subcutaneous disorders urticaria, erythema, pruritis
B
Metabolism and nutrition disorders
Meget sjælden
lactic acidosis vitamin B12 deficiencyb
forekommer hyppigst ved initiering af behandlingen og forsvinder spontant i de fleste tilfælde. b Langvarig behandling med metformin er blevet associeret med nedsat absorption af B12- vitamin, som meget sjældent kan medføre kliniks signifikant B12- vitaminmangel (f. eks. megaloblastær anæmi).
Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e. g., megaloblastic anaemia).
I fase- I flerdosisundersøgelser blev der ikke observeret dosisrelaterede kliniske bivirkninger med sitagliptin med doser op til 600 mg/ dag i 10 dage og 400 mg/ dag i perioder op til 28 dage.
In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for 10 days and 400 mg per day for periods of up to 28 days.
Efficib er en kombination af to antihyperglykæmiske præparater med komplementære virkningsmekanismer til forbedring af glykæmisk kontrol hos patienter med type 2- diabetes: sitagliptinphosphat, en dipeptylpeptidase- 4- hæmmer (DPP- 4), og metforminhydrochlorid, der tilhører biguanidklassen.
Efficib combines two antihyperglycaemic agents with complementary mechanisms of action to improve glycaemic control in patients with type 2 diabetes: sitagliptin phosphate, a dipeptidyl peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Sitagliptin Sitagliptinphosphat er en oralt aktiv, potent og højselektiv hæmmer af DPP- 4- enzymet til behandling af type 2- diabetes.
24 Sitagliptin Sitagliptin phosphate is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes.
Når blodglucosekoncentrationen er normal eller forhøjet, bevirker GLP- 1 og GIP en øget insulinsyntese og frigørelsen af insulin fra de pankreatiske betaceller.
When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells.
25 Undersøgelse af sitagliptin i kombination med metformin og et sulfonylurinstof En 24- ugers placebo- kontrolleret undersøgelse blev designet til at vurdere effekt og sikkerhed af sitagliptin (100 mg én gang dagligt) som supplement til glimepirid (alene eller i kombination med metformin).
Study of sitagliptin in combination with metformin and a sulphonylurea 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 in combination with metformin).
Tabel 3:
25 Table 3:
HbA1c resultater in placebokontrollerede undersøgelser af kombinationsbehandling med sitagliptin og metformin *
HbA1c results in placebo-controlled combination therapy studies of sitagliptin and metformin*
- ved forsinkelse af intestinal glucoseabsorption.
- by delaying intestinal glucose absorption
Den prospektive, randomiserede undersøgelse (UKPDS) har fastslået den langvarige, gunstige effekt af intensiv blodglucosekontrol ved type 2- diabetes.
26 The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes.
metformingruppen (29, 8 hændelser/ 1. 000 patientår) versus diæt alene (43, 3 hændelser/ 1000 patientår), p=0, 0023, og versus den kombinerede sulfonylurinstof/ insulinmonoterapigruppe (40, 1 hændelser/ 1. 000 patientår), p=0, 0034.
group (29.8 events/ 1,000 patient-years) versus diet alone (43.3 events/ 1,000 patient-years), p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups (40.1 events/ 1,000 patient-years), p=0.0034
hændelser/ 1000 patientår, diæt alene 12, 7 hændelser/ 1. 000 patientår, p=0, 017.
7.5 events/ 1,000 patient-years, diet alone 12.7 events/ 1,000 patient-years, p=0.017
100% af den administrerede radioaktivitet i fæces (13%) eller urin (87%) inden for en uge efter dosering.
27 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.
Der blev observeret en stigning til ca. det dobbelte i sitagliptins plasma AUC hos patienter med moderat nyreinsufficiens, og en stigning til ca. det firdobbelte blev observeret hos patienter med svær nyreinsufficiens og hos patienter med ESRD i hæmodialyse sammenlignet med normale raske kontrolpersoner.
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 haemodialysis, as compared to normal healthy control subjects.
28 Der er ikke udført undersøgelser med anvendelse af sitagliptin til børn.
Paediatric No studies with sitagliptin have been performed in paediatric patients.
Disse karakteristika havde ingen klinisk relevant virkning på sitagliptins farmakokinetik på basis af en sammensat analyse af fase I farmakokinetiske data og en farmakokinetisk populationsanalyse af fase I - og fase II- data.
These characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a 28 composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.
Abnormiteter af fortænderne observeredes hos rotter ved en eksponering, der var 67 gange højere end det kliniske eksponeringsniveau.
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.
No- effect- niveauet for dette fund var 58 gange højere på basis af 14- ugers -
The relevance of these findings for humans is unknown.
29 rotteundersøgelsen.
29 the human exposure level.
Nogle af disse tyder på neural toksicitet:
A no-effect level for these findings was found at an exposure 6-fold the clinical exposure level.
30 6. 3 Opbevaringstid
6.3 Shelf life
6. 4 Særlige opbevaringsforhold
30 6.4 Special precautions for storage
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Via Compultense 140 ES- 28805 Alcala de Henares – Madrid Spanien
Via Complutense 140 ES-28805 Alcala de Henares - Madrid Spain
Pharmacovigilance Indehaveren af markedsføringstilladelsen skal sikre, at pharmacovigilancesystemet, som beskrevet i version 4, og som fremgår af Modul 1. 8. 1 i ansøgningen om markedsføringstilladelse, er på plads og fungerer, før og mens dette produkt er på markedet.
Pharmacovigilance system The MAH must ensure that the system of pharmacovigilance, as described in version 4 presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and whilst the product is on the market.
Risk Management Plan Indehaveren af markedsføringstilladelsen forpligter sig til at gennemføre de undersøgelser og yderligere pharmacovigilanceaktiviteter, som er beskrevet i Pharmacovigilanceplanen, og som fremgår af version 1. 1 af Risk Management Planen (RMP) i Modul 1. 8. 2 i ansøgningen om markedsføringstilladelse og alle følgende opdateringer af RMP, der er vedtaget af CHMP.
Risk Management Plan The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 1.1 of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP agreed by the CHMP.