European Union - English - EMA (European Medicines Agency)

astrazeneca ab - metformin hydrochloride, saxagliptin, dapagliflozin - diabetes mellitus, type 2 - drugs used in diabetes - qtrilmet is indicated in adults aged 18 years and older with type 2 diabetes mellitus:to improve glycaemic control when metformin with or without sulphonylurea (su) and either saxagliptin or dapagliflozin does not provide adequate glycaemic control.when already being treated with metformin and saxagliptin and dapagliflozin.

Australia - English - Department of Health (Therapeutic Goods Administration)

astrazeneca pty ltd - metformin hydrochloride, quantity: 500 mg; saxagliptin, quantity: 5 mg - tablet, modified release - excipient ingredients: microcrystalline cellulose; carmellose sodium; hypromellose; magnesium stearate; titanium dioxide; purified talc; polyvinyl alcohol; macrogol 3350; iron oxide yellow; iron oxide red; propylene glycol; butan-1-ol; isopropyl alcohol; strong ammonia solution; indigo carmine aluminium lake; ethanol; shellac; sulfuric acid - kombiglyze xr is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate (see clinical trials and dosing and administration for data on combinations studied).

Australia - English - Department of Health (Therapeutic Goods Administration)

astrazeneca pty ltd - metformin hydrochloride, quantity: 1000 mg; saxagliptin, quantity: 5 mg - tablet, modified release - excipient ingredients: hypromellose; carmellose sodium; magnesium stearate; propylene glycol; butan-1-ol; isopropyl alcohol; strong ammonia solution; indigo carmine aluminium lake; ethanol; shellac; sulfuric acid; titanium dioxide; purified talc; iron oxide red; polyvinyl alcohol; macrogol 3350 - kombiglyze xr is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate (see clinical trials and dosing and administration for data on combinations studied).

Australia - English - Department of Health (Therapeutic Goods Administration)

astrazeneca pty ltd - metformin hydrochloride, quantity: 1000 mg; saxagliptin, quantity: 2.5 mg - tablet, modified release - excipient ingredients: hypromellose; magnesium stearate; carmellose sodium; titanium dioxide; purified talc; polyvinyl alcohol; macrogol 3350; propylene glycol; butan-1-ol; isopropyl alcohol; strong ammonia solution; indigo carmine aluminium lake; ethanol; shellac; sulfuric acid; iron oxide yellow - kombiglyze xr is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate (see clinical trials and dosing and administration for data on combinations studied).

United States - English - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - dapagliflozin (unii: 1ull0qj8uc) (dapagliflozin - unii:1ull0qj8uc), saxagliptin hydrochloride (unii: z8j84yix6l) (saxagliptin anhydrous - unii:8i7io46ivq), metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - qternmet xr (dapagliflozin, saxagliptin, and metformin hydrochloride) extended-release tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. limitations of use qternmet xr is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. qternmet xr initiation is intended only for patients currently taking metformin. qternmet xr is contraindicated in patients with: risk summary based on animal data showing adverse renal effects, from dapagliflozin, qternmet xr is not recommended during the second and third trimesters of pregnancy. the limited available data with qternmet xr or components (dapagliflozin and saxagliptin) in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see data ). there are risks to the moth

United States - English - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - saxagliptin hydrochloride (unii: z8j84yix6l) (saxagliptin anhydrous - unii:8i7io46ivq), metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - saxagliptin anhydrous 2.5 mg - kombiglyze xr is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate [see clinical studies (14) ]. kombiglyze xr is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. kombiglyze xr is contraindicated in patients with: limited available data with kombiglyze xr or saxagliptin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see data ]. no adverse developmental effects independent of maternal toxicity were observed when saxagliptin and metformin were administered separately or in combination to pregnant rats and rabbits during the period of organogenesis [see data ]. the estimated background risk of major birth defects is 6 to 10% in women w

Israel - English - Ministry of Health

astrazeneca (israel) ltd - metformin hydrochloride; saxagliptin - film coated tablets - extended release - saxagliptin 5 mg; metformin hydrochloride 1000 mg - metformin - kombiglyze xr is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate.

Israel - English - Ministry of Health

astrazeneca (israel) ltd - metformin hydrochloride; saxagliptin - film coated tablets - extended release - saxagliptin 2.5 mg; metformin hydrochloride 1000 mg - metformin - kombiglyze xr is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate.

United States - English - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - dapagliflozin propanediol (unii: 887k2391vh) (dapagliflozin - unii:1ull0qj8uc), metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - dapagliflozin 10 mg - xigduo xr is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. dapagliflozin is indicated to reduce limitations of use xigduo xr is contraindicated in patients with: risk summary based on animal data showing adverse renal effects, xigduo xr is not recommended during the second and third trimesters of pregnancy. limited data with xigduo xr or dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see data) . there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see clinical considerations) . in animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see data) . the estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a hba1c greater than 7% and has been reported to be as high as 20 to 25% in women with hba1c greater than 10%. the estimated background risk of miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryofetal risk poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. data human data published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. however, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. animal data dapagliflozin dapagliflozin dosed directly to juvenile rats from postnatal day (pnd) 21 until pnd 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on auc). the renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. in a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. increased incidence or severity of renal pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on auc). dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on auc). no adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on auc). these outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development. in embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. in rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on auc). dose related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on auc), which were associated with maternal toxicity. no developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on auc). metformin hcl metformin hcl did not cause adverse developmental effects when administered to pregnant sprague dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. this represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m2 ) for rats and rabbits, respectively. determination of fetal concentrations demonstrated a partial placental barrier to metformin. risk summary there is no information regarding the presence of xigduo xr or dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. limited published studies report that metformin is present in human milk (see data) . however, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. dapagliflozin is present in the milk of lactating rats (see data) . however, due to species specific differences in lactation physiology, the clinical relevance of these data is not clear. since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. because of the potential for serious adverse reactions in breastfed infants, advise women that use of xigduo xr is not recommended while breastfeeding. data dapagliflozin dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. metformin hcl published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. however, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women. safety and effectiveness of xigduo xr in pediatric patients under 18 years of age have not been established. xigduo xr no xigduo xr dosage change is recommended based on age. more frequent assessment of renal function is recommended in elderly patients. dapagliflozin a total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. after controlling for level of renal function (egfr), efficacy was similar for patients under age 65 years and those 65 years and older. in patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin for glycemic control had adverse reactions of hypotension [see warnings and precautions (5.3) and adverse reactions (6.1)] . in both the dapa-hf and dapa-ckd studies, safety and efficacy were similar for patients age 65 years and younger and those older than 65 in both the overall population and the patients with type 2 diabetes mellitus. in the dapa-hf study, 2714 (57%) out of 4744 patients with heart failure with reduced ejection fraction (hfref) were older than 65 years. out of 2139 patients with hfref and type 2 diabetes mellitus, 1211 (57%) were older than 65 years. in the dapa-ckd study, 1818 (42%) out of 4304 patients with chronic kidney disease were older than 65 years. out of 2906 patients with chronic kidney disease and type 2 diabetes mellitus, 1399 (48%) were older than 65 years. metformin hcl controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. assess renal function more frequently in elderly patients [see warnings and precautions (5.1)] . initiation of xigduo xr is not recommended in patients with an egfr below 45 ml/min/1.73 m2 and is contraindicated in patients with severe renal impairment (egfr less than 30 ml/min/1.73 m2 ), end-stage renal disease or patients on dialysis [see dosage and administration (2.4), contraindications (4) and  warnings and precautions  (5.1, 5.3)] . dapagliflozin dapagliflozin 10 mg was evaluated in 4304 patients with chronic kidney disease (egfr 25 to 75 ml/min/1.73 m2 ) in the dapa-ckd study. dapagliflozin 10 mg was also evaluated in 1926 patients with an egfr of 30 to 60 ml/min/1.73 m2 in the dapa-hf study. the safety profile of dapagliflozin across egfr subgroups was consistent with the known safety profile [see adverse reactions (6.1) and clinical studies  (14.3 and 14.4)] . dapagliflozin 10 mg was evaluated in two glycemic control studies that included patients with moderate renal impairment (an egfr of 45 to less than 60 ml/min/1.73 m2 , and an egfr of 30 to less than 60 ml/min/1.73 m2 ) [see clinical studies (14.1)] . patients with diabetes and renal impairment using dapagliflozin 10 mg are more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. in the study of patients with an egfr 30 to less than 60 ml/min/1.73 m2 , 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo. use of dapagliflozin 10 mg for glycemic control in patients without established cv disease or cv risk factors is not recommended when egfr is less than 45 ml/min/1.73 m2  [see dosage and administration (2.4)] . metformin hcl metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. xigduo xr is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (egfr) below 30 ml/min/1.73 m2 [see dosage and administration (2.4), contraindications (4), warnings and precautions (5.1), and clinical pharmacology  (12.3)]. use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. xigduo xr is not recommended in patients with hepatic impairment [see warnings and precautions (5.1)] .

United States - English - NLM (National Library of Medicine)

mylan pharmaceuticals inc. - saxagliptin hydrochloride dihydrate (unii: 4n19on48zn) (saxagliptin anhydrous - unii:8i7io46ivq), metformin hydrochloride (unii: 786z46389e) (metformin - unii:9100l32l2n) - saxagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate [see clinical studies (14) ]. saxagliptin and metformin hydrochloride extended-release tablets are not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with: limited available data with saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see data ]. no adverse developmental effects independent of maternal toxicity were observed when saxagliptin and metformin were administered separately or in combination to pregnant rats and rabbits during the period of organogenesis [see data ]. the estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an hba1c greater than 7 and has been reported to be as high as 20 to 25% in women with an hba1c greater than 10. the estimated background risk of miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. in embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. no adverse developmental effects were observed in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on auc. saxagliptin crosses the placenta into the fetus following dosing in pregnant rats. in a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical dose, based on auc. metformin hydrochloride did not cause adverse developmental effect when administered to pregnant sprague dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. this represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m2 ) for rats and rabbits, respectively. saxagliptin and metformin coadministered to pregnant rats and rabbits during the period of organogenesis did not result in adverse developmental effects considered clinically relevant in either species. doses tested in rats provided exposure up to 100- and 10-times clinical exposure, and doses tested in rabbits provided exposure up to 249- and 1-times clinical exposure relative to the clinical dose of 5 mg saxagliptin and 2000 mg metformin. minor skeletal abnormalities associated with maternal toxicity were observed in rats. in rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. however, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29, associated with fetal body weight decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid bone. there is no information regarding the presence of saxagliptin and metformin or saxagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. limited published studies report that metformin is present in human milk [see data ]. however, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. saxagliptin is present in the milk of lactating rats [see data ]. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for saxagliptin and metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from saxagliptin and metformin hydrochloride extended-release tablets or from the underlying maternal condition. published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. however, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. no studies in lactating animals have been conducted with the combined components of saxagliptin and metformin hydrochloride extended-release tablets. in studies performed with the individual components, both saxagliptin and metformin are secreted in the milk of lactating rats. saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. safety and effectiveness of saxagliptin and metformin hydrochloride extended-release tablets in pediatric patients under 18 years of age have not been established. additionally, studies characterizing the pharmacokinetics of saxagliptin and metformin hydrochloride extended-release tablets in pediatric patients have not been performed. elderly patients are more likely to have decreased renal function. assess renal function more frequently in the elderly [see warnings and precautions (5.1) and clinical pharmacology (12.3) ]. in the seven, double-blind, controlled clinical safety and efficacy trials of saxagliptin, a total of 4751 (42.0%) of the 11301 patients randomized to saxagliptin were 65 years and over, and 1210 (10.7%) were 75 years and over. no overall differences in safety or effectiveness were observed between subjects ≥ 65 years old and younger subjects. while this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. metformin is known to be substantially excreted by the kidney. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. assess renal function more frequently in elderly patients [see contraindications (4), warnings and precautions (5.1), and clinical pharmacology (12.3) ]. in a 12-week randomized placebo-controlled trial, saxagliptin 2.5 mg was administered to 85 subjects with moderate (n = 48) or severe (n = 18) renal impairment or end-stage renal disease (esrd) (n = 19) [see clinical studies (14) ]. the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo. the overall incidence of reported hypoglycemia was 20% among subjects treated with saxagliptin 2.5 mg and 22% among subjects treated with placebo. four saxagliptin-treated subjects (4.7%) and three placebo-treated subjects (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤ 50 mg/dl). metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (egfr) below 30 ml/min/1.73 m2 [see dosage and administration (2.3), contraindications (4), warnings and precautions (5.1) and clinical pharmacology (12.3) ]. use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. saxagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment [see warnings and precautions (5.1) ].