Ամերիկայի Միացյալ Նահանգներ - անգլերեն - 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)] .

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - naloxegol oxalate (unii: 65i14tnm33) (naloxegol - unii:44t7335bke) - naloxegol 12.5 mg - movantik® is indicated for the treatment of opioid-induced constipation (oic) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. movantik is contraindicated in: risk summary limited available data with movantik use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. movantik may precipitate opioid withdrawal in the pregnant women and the fetus (see clinical considerations) . in animal development studies, no effects on embryo-fetal development were observed following administration of naloxegol in pregnant rats during the period of organogenesis at doses up to 1452 times the human auc (area under the plasma concentration-time curve) at the maximum recommended human dose. no effects on embryo-fetal development were observed following administration of naloxegol in pregnant rabbits during the period of organogenesis at

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - 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 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. clinical considerations disease-associated maternal and/or embryo/fetal risk 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. data animal data saxagliptin 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 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 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. risk summar y there is no information regarding the presence of kombiglyze xr 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 kombiglyze xr and any potential adverse effects on the breastfed child from kombiglyze xr or from the underlying maternal condition. data human 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. animals no studies in lactating animals have been conducted with the combined components of kombiglyze xr. 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 kombiglyze xr in pediatric patients under 18 years of age have not been established. additionally, studies characterizing the pharmacokinetics of kombiglyze xr in pediatric patients have not been performed. kombiglyze xr 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) ]. saxagliptin 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. metformin hydrochloride 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) ]. saxagliptin 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 hydrochloride metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. kombiglyze 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 (2.3), 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. kombiglyze xr is not recommended in patients with hepatic impairment [see warnings and precautions (5.1) ].

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - saxagliptin hydrochloride (unii: z8j84yix6l) (saxagliptin anhydrous - unii:8i7io46ivq) - saxagliptin anhydrous 5 mg - onglyza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see clinical studies (14) ]. onglyza is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings. onglyza is contraindicated in patients with a history of a serious hypersensitivity reaction to onglyza, such as anaphylaxis, angioedema, or exfoliative skin conditions [see warnings and precautions (5.4) and adverse reactions (6.2) ]. limited data with onglyza in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriages. there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see clinical considerations ]. no adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the pre- and postnatal period [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. disease-associated maternal and/or embryo/fetal risk 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. animal data 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. there is no information regarding the presence of onglyza in human milk, the effects on the breastfed infant, or the effects 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 onglyza and any potential adverse effects on the breastfed infant from onglyza or from the underlying maternal condition. saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. safety and effectiveness of onglyza in pediatric patients under 18 years of age have not been established. additionally, studies characterizing the pharmacokinetics of onglyza in pediatric patients have not been performed. in the seven, double-blind, controlled clinical safety and efficacy trials of onglyza, a total of 4751 (42.0%) of the 11301 patients randomized to onglyza 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. saxagliptin and its active metabolite are eliminated in part by the kidney. because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function [see dosage and administration (2.2) and clinical pharmacology (12.3) ]. in a 12-week randomized placebo-controlled trial, onglyza 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 onglyza and placebo. the overall incidence of reported hypoglycemia was 20% among subjects treated with onglyza 2.5 mg and 22% among subjects treated with placebo. four onglyza-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).

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - durvalumab (unii: 28x28x9okv) (durvalumab - unii:28x28x9okv) - durvalumab 120 mg in 2.4 ml - imfinzi, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (es-sclc). imfinzi, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (btc). none. risk summary based on findings from animal studies and its mechanism of action, imfinzi can cause fetal harm when administered to a pregnant woman [see clinical pharmacology (12.1)] . there are no available data on the use of imfinzi in pregnant women. in animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (auc), resulted in an increase in premature delivery, fetal loss, and premature neonatal death (see data). human immunoglobulin g1 (igg1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. apprise pregnant women of the potential risk to a fetus. 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. data animal data as reported in the literature, the pd-1/pd-l1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. in mouse allogeneic pregnancy models, disruption of pd-l1 signaling was shown to result in an increase in fetal loss. the effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at a clinical dose of 10 mg/kg (based on auc). administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. durvalumab was detected in infant serum on postpartum day 1, indicating the presence of placental transfer of durvalumab. based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in pd-1 knockout mice. risk summary there are no data on the presence of durvalumab in human milk, its effects on the breastfed child, or the effects on milk production. maternal igg is known to be present in human milk. the effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to imfinzi are unknown. durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see data ). because of the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with imfinzi and for 3 months after the last dose. refer to the prescribing information for the agents administered in combination with imfinzi for recommended duration to not breastfeed, as appropriate. data in lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on auc). administration of durvalumab resulted in premature neonatal death. pregnancy testing verify pregnancy status of females of reproductive potential prior to initiating treatment with imfinzi. contraception females imfinzi can cause fetal harm when administered to a pregnant woman [see use in specific populations (8.1)] . advise females of reproductive potential to use effective contraception during treatment with imfinzi and for 3 months following the last dose of imfinzi. refer to the prescribing information for the agents administered in combination with imfinzi for recommended contraception duration, as appropriate. the safety and effectiveness of imfinzi have not been established in pediatric patients. of the 476 patients treated with imfinzi in the pacific study, 45% were 65 years or older, while 7.6% were 75 years or older. no overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. the pacific study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients. of the 265 patients with es-sclc treated with imfinzi in combination with chemotherapy 101 (38%) patients were 65 years or older and 19 (7.2%) patients were 75 years or older. there were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients. of the 330 patients with metastatic nsclc treated with imfinzi in combination with tremelimumab-actl and platinum-based chemotherapy, 143 (43%) patients were 65 years or older and 35 (11%) patients were 75 years or older. there were no clinically meaningful differences in safety or efficacy between patients 65 years or older and younger patients. of the 338 patients with btc treated with imfinzi in combination with chemotherapy in the topaz-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. no overall differences in safety or effectiveness of imfinzi have been observed between patients 65 years of age and older and younger adult patients. of the 393 patients with uhcc treated with imfinzi in combination with tremelimumab-actl, 50% of patients were 65 years of age or older and 13% of patients were 75 years of age or older. no overall differences in safety or effectiveness of imfinzi have been observed between patients 65 years of age and older and younger adult patients.

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - dapagliflozin (unii: 1ull0qj8uc) (dapagliflozin - unii:1ull0qj8uc), saxagliptin hydrochloride (unii: z8j84yix6l) (saxagliptin anhydrous - unii:8i7io46ivq) - dapagliflozin 10 mg - qtern is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. limitations of use qtern is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see warnings and precautions (5.1) ] . qtern is contraindicated in patients with: risk summary based on animal data showing adverse renal effects from dapagliflozin, qtern is not recommended during the second and third trimesters of pregnancy. the limited available data with qtern or its components (dapagliflozin and saxagliptin) in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. 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 tubular dilatations, that were not fully reversible, were observed in rats when dapagliflozin (a component of qtern) 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) . no adverse developmental effects were observed when saxagliptin was administered to pregnant rats and rabbits (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. 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 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 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 pup 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 than 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). saxagliptin in embryofetal 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. risk summary there is no information regarding the presence of qtern or its components (dapagliflozin and saxagliptin) in human milk, the effects on the breastfed infant, or the effects on milk production. dapagliflozin and saxagliptin are 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 a breastfed infant, advise women that use of qtern is not recommended while breastfeeding. data dapagliflozin dapagliflozin was present 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 a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. saxagliptin saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. safety and effectiveness of qtern in pediatric patients under 18 years of age have not been established. because elderly patients are more likely to have decreased renal function, care should be taken when using qtern in the elderly based on renal function [see dosage and administration (2.3) ] . 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), in clinical studies with dapagliflozin, efficacy was similar for patients under age 65 years and those 65 years and older. in patients 65 years and older, a higher proportion of patients treated with dapagliflozin had adverse reactions of hypotension [see warnings and precautions (5.4) ] . saxagliptin in the seven double-blind, controlled clinical safety and efficacy trials of saxagliptin, a total of 4751 (42.0%) of the 11,301 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. qtern is contraindicated in patients with moderate to severe renal impairment (egfr less than 45 ml/min/1.73 m2 ), esrd, or on dialysis [see dosage and administration (2.3) , contraindications (4) and warnings and precautions (5.4) ]. dapagliflozin dapagliflozin 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 ). patients with diabetes and renal impairment using dapagliflozin for glycemic control may be 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. qtern may be used in patients with hepatic impairment. however, the benefit-risk for the use of qtern in patients with severe hepatic impairment should be individually assessed since safety and efficacy have not been studied in this population [see clinical pharmacology (12.3) ].

Ամերիկայի Միացյալ Նահանգներ - անգլերեն - NLM (National Library of Medicine)

astrazeneca pharmaceuticals lp - exenatide (unii: 9p1872d4ol) (exenatide - unii:9p1872d4ol) - exenatide 2 mg in 0.85 ml - bydureon bcise is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus [see clinical studies (14)]. limitations of use bydureon bcise: bydureon bcise is contraindicated in patients with a: risk summary limited data with exenatide, the active ingredient in bydureon bcise, in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. there are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see clinical considerations) . based on animal reproduction studies, there may be risks to the fetus from exposure to bydureon bcise during pregnancy. bydureon bcise should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. animal reproduction studies identified increased adverse fetal and neonatal outcomes from exposure to exenatide extended-release during pregnancy or from exposure to exenatide during pregnancy and lactation, in association with maternal effects. in rats, exenatide extended-release, administered during the period of organogenesis, reduced fetal growth and produced skeletal ossification deficits at doses that approximate clinical exposures at the maximum recommended human dose (mrhd) of 2 mg/week. in mice, exenatide administered during gestation and lactation, caused increased neonatal deaths at doses that approximate clinical exposures at the mrhd (see data ). based on animal data, advise pregnant women of the potential risk to a fetus. the estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an hba1c >7 and has been reported to be as high as 20-25% in women with hba1c >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 2-4% and 15-20%, 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 animal data pregnant rats given subcutaneous doses of 0.3, 1, or 3 mg/kg exenatide extended-release every 3 days during organogenesis had systemic exposures 3-, 8-, and 19-times human exposure, respectively, at the mrhd of 2 mg/week bydureon bcise based on plasma exenatide exposure (auc) comparison. reduced fetal growth at all doses and skeletal ossification deficits at 1 and 3 mg/kg occurred at doses that decreased maternal food intake and body weight gain. in studies evaluating reproduction and development in pregnant mice and rabbits, maternal animals were administered exenatide, the active ingredient in bydureon bcise, by subcutaneous injection twice a day. differences in embryofetal developmental toxicity from subcutaneously injected exenatide extended-release and exenatide were not evaluated in mice, rats, or rabbits. in pregnant mice given 6, 68, 460, or 760 mcg/kg/day exenatide during fetal organogenesis, skeletal variations associated with slowed fetal growth, including changes in number of rib pairs or vertebral ossifications sites, and wavy ribs were observed at 760 mcg/kg/day, a dose that produced maternal toxicity and yielded systemic exposure 200-times the human exposure resulting from the mrhd of bydureon bcise based on auc comparison. in pregnant rabbits given 0.2, 2, 22, 156, or 260 mcg/kg/day exenatide during fetal organogenesis, irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a dose yielding systemic exposure up to 6-times the human exposure from the mrhd of bydureon bcise based on auc comparison. in maternal mice given 6, 68, or 760 mcg/kg/day exenatide from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths at 6 mcg/kg/day were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a dose yielding a systemic exposure equivalent to the human exposure from the mrhd of bydureon bcise based on auc comparison. risk summary there is no information regarding the presence of exenatide, in human milk, the effects of exenatide on the breastfed infant, or the effects of exenatide on milk production. exenatide, the active ingredient in bydureon bcise was present in the milk of lactating mice. however, due to species-specific differences in lactation physiology, the clinical relevance of these data is not clear (see data) . the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for exenatide and any potential adverse effects on the breastfed child from exenatide or from the underlying maternal condition. data in lactating mice subcutaneously injected twice a day with exenatide, the active ingredient in bydureon bcise, the concentration of exenatide in milk was up to 2.5% of the concentration in maternal plasma. the safety and effectiveness of bydureon bcise as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. use of bydureon bcise for this indication is supported by a 24-week placebo-controlled trial with bydureon with 28-week open-label uncontrolled extension (trial 9) in 82 pediatric patients 10 years of age and older with type 2 diabetes, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus [see clinical pharmacology (12.3) and clinical studies (14.2, 14.3, 14.4, 14.6)] . safety and effectiveness of bydureon bcise have not been established in pediatric patients less than 10 years of age. in two comparator-controlled 28-week trials, bydureon bcise was studied in 74 patients (18%) who were at least 65 years of age and 10 (2.4%) patients who were at least 75 years of age. in these studies, no meaningful differences in safety and effectiveness were observed between patients ≥65 years of age and younger adult patients, but these studies did not include sufficient numbers of patients ≥75 years of age to determine whether they respond differently from younger adult patients. in a large cardiovascular outcomes trial [see clinical studies (14.5)] , bydureon was studied in 2,959 patients (40%) who were at least 65 years old and of those, 605 patients (8%) were at least 75 years old. use caution when initiating bydureon bcise in geriatric patients because they are more likely to have decreased kidney function [see use in specific populations (8.6)]. pharmacokinetic studies of adult patients with renal impairment who received bydureon bcise indicate that there is an increase in exenatide exposure in those with mild and moderate renal impairment as compared to patients with normal kidney function. bydureon bcise may induce nausea and vomiting with transient hypovolemia and may worsen kidney function in patients with renal impairment. monitor patients with mild renal impairment for adverse reactions that may lead to hypovolemia. bydureon bcise is not recommended for use in patients with egfr below 45 ml/min/1.73 m2 or end-stage renal disease. if bydureon bcise is used in patients with renal transplantation, closely monitor for adverse reactions that may lead to hypovolemia [see warnings and precautions (5.4) and clinical pharmacology (12.3)]. bydureon bcise® (by-dur-ee-on b-cise) (exenatide) extended-release injectable suspension for subcutaneous use once-weekly read the instructions for use before you start using bydureon bcise. before using bydureon bcise, talk to your healthcare provider about how to use it the right way. caregivers should help children with mixing and injecting bydureon bcise. before you begin the autoinjector: before use supplies needed to give your injection: ● bydureon bcise autoinjector ● alcohol swab ● a clean, flat surface ● sharps container (see “disposal” instructions at the end of these instructions) step 1: prepare for injection a. let your autoinjector come to room temperature. remove 1 autoinjector from the refrigerator and rest it flat for 15 minutes. autoinjector can be kept at room temperature for up to 4 weeks. b. check the expiration date (labeled exp) printed on the autoinjector label. do not use the autoinjector past the expiration date. if the expiration date has passed, throw it away and get a new autoinjector. c. wash your hands. d. choose your injection site. you can inject into your stomach, thigh, or back of the upper arm, see figure d. each week you can use the same area of your body, but choose a different injection site in that area of your body. clean the area with an alcohol swab. figure d step 2: mix the medicine a. look in the window. you may see white medicine along the sides, bottom or top. this means the medicine is not mixed evenly. b. shake the autoinjector hard, in an up-and-down motion, until the medicine is mixed evenly and you do not see any white medicine along the sides, bottom or top. c. check the mix. hold the autoinjector up to the light and look through both sides and the bottom of the window. if not mixed well, repeat step 2 and check again. do not go to the next step unless your medicine is mixed well. to get a full dose, the medicine must be mixed well and look cloudy. if not mixed well, continue to shake hard. step 3: prepare the autoinjector important: after the medicine is fully mixed, you must complete the preparation steps right away , and inject to get the full dose. do not save it to use later. only unlock the autoinjector when you are ready to inject a. unlock the autoinjector. hold the autoinjector up straight with the orange cap toward the ceiling. turn the knob from the lock to the unlock position until you hear a click. b. while still holding the autoinjector straight up, firmly unscrew the orange cap. it is normal to see a few drops of liquid inside the cap. do not recap the autoinjector. throw away the cap. step 4: inject the dose a. inject and hold: b. make sure you received your full dose. after you receive your injection, you will see an orange rod in the window. after you lift the autoinjector from your skin, the green shield will move back up to lock over the needle. see the common questions and answers for what to do if you do not see the orange rod in the window after injection. step 4: inject the dose (continued) c. disposal. put your used autoinjector in a fda-cleared sharps disposal container right away after use. do not throw away (dispose of) loose needles and syringes into your household trash. if you do not have an fda-cleared sharps disposal container, you may use a household container that is: when your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. there may be state or local laws about how you should throw away used needles and syringes. for more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to fda’s website at: http://www.fda.gov/safesharpsdisposal. do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. do not recycle your used sharps disposal container. see “common questions and answers” for additional disposal information. please keep these instructions to use for your next dose. common questions and answers 1. where is the needle? the needle is attached to the autoinjector and covered by the orange cap. when you unscrew the orange cap, the green shield keeps the needle covered until you inject. for more information, please see figure n in step 3b in the instructions for use. 2. how do i know if the medicine is fully mixed? after shaking the autoinjector, look through both sides of the window. you should not see any white medicine along the bottom, top, or sides. if you see white medicine, it is unmixed. to mix, shake the autoinjector hard until the white medicine is no longer on the bottom, top, or sides. the medicine should look even throughout. 3. why do i need to hold the autoinjector upright while removing the orange cap? holding the autoinjector with the orange cap straight up helps prevent the medicine from leaking. it is normal to see a few drops of medicine inside the orange cap after you unscrew it. 4. why should i inject my medicine right away after mixing it? if you do not inject your medicine right away after mixing, the medicine may separate, and you will not get your full dose. you can re-mix your medicine if your autoinjector is in the locked position. however, after you unlock it, you must complete the preparation steps right away and inject to get the full dose. you cannot save it for later use. 5. how do i know i gave myself the full dose of medicine? to be sure you get your full dose, press and hold the autoinjector against your skin. you will feel the needle go into your skin. hold the needle against your skin for 15 seconds. this will allow enough time for all the medicine to go from the autoinjector to under your skin. after removing the needle, look for the orange rod in the window as a way to tell that the dose has been given. if the orange rod does not appear contact customer service at 1-800-236-9933. 6. why should i store my autoinjectors flat in the refrigerator? autoinjectors stored vertically (with the needle up or down) are more difficult to mix. the medicine can still be fully mixed, but it will take more shaking and more time. 7. what if i do not have an fda-cleared sharps disposal container? do not throw away (dispose of) the autoinjector in your household trash. if you do not have an fda-cleared sharps disposal container, you may use a household container that is: when your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. there may be state or local laws about how you should throw away used needles and autoinjectors. for more information about safe sharps disposal, and for specific information about sharps disposal in the state you live in, go to the fda’s website at: http://www.fda.gov/safesharpsdisposal. 8. what if i cannot unlock the autoinjector? review the instructions for use step 3 to make sure you are following the right instructions, then contact customer service, 1-800-236-9933 for help as needed. do not try to unlock with excessive force or tools. 9. what if i cannot remove the orange cap from the autoinjector? review the instructions for use step 3 to make sure you are following the right instructions. you should also check that the knob is fully in the unlocked position, then contact customer service, 1-800-236-9933 for help as needed. do not use tools or try to force the cap off. 10. for other questions about bydureon bcise: visit www.bydureonbcise.com. call customer service at 1-800-236-9933. how to store bydureon bcise autoinjector

Ավստրալիա - անգլերեն - Department of Health (Therapeutic Goods Administration)

astrazeneca pty ltd - water for injections -

Ավստրալիա - անգլերեն - Department of Health (Therapeutic Goods Administration)

astrazeneca pty ltd - water for injections -

Ավստրալիա - անգլերեն - Department of Health (Therapeutic Goods Administration)

astrazeneca pty ltd - sodium chloride -