CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Glycemic Control in Patients with Type Diabetes Mellitus. Overview of Clinical Studies of dapagliflozin for Type Diabetes Mellitus. Dapagliflozin has been studied as monotherapy, in combination with metformin, pioglitazone, sulfonylurea (glimepiride), sitagliptin (with or without metformin), metformin plus sulfonylurea, or insulin (with or without other oral antidiabetic therapy), compared to sulfonylurea (glipizide), and in combination with GLP-1 receptor agonist (exenatide extended-release) added-on to metformin. Dapagliflozin has also been studied in patients with type diabetes mellitus and moderate renal impairment.Treatment with dapagliflozin as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control. Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).. Monotherapy. total of 840 treatment-naive patients with inadequately controlled type diabetes mellitus participated in placebo-controlled studies to evaluate the safety and efficacy of monotherapy with dapagliflozin.In monotherapy study, total of 558 treatment-naive patients with inadequately controlled diabetes participated in 24-week study (NCT00528372). Following 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c >=7% and <=10% were randomized to dapagliflozin mg or dapagliflozin 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo.At Week 24, treatment with dapagliflozin 10 mg QAM provided significant improvements in HbA1c and the fasting plasma glucose (FPG) compared with placebo (see Table 8). Table 8: Results at Week 24 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) in Placebo-Controlled Study of Dapagliflozin Monotherapy in Patients with Type Diabetes Mellitus (Main Cohort AM Doses)Efficacy ParameterDapagliflozin10 mgN=70All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.Dapagliflozin5 mgN=64PlaceboN=75HbA1c (%) Baseline (mean)8.07.87.8 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)-0.9-0.8-0.2 Difference from placebo (adjusted mean) (95% CI)-0.7p-value <0.0001 versus placebo. Sensitivity analyses yielded smaller estimates of treatment difference with placebo. (-1.0, -0.4)-0.5(-0.8, -0.2) Percent of patients achieving HbA1c <7% adjusted for baseline50.8%Not evaluated for statistical significance as result of the sequential testing procedure for the secondary endpoints. 44.2% 31.6%FPG (mg/dL) Baseline (mean)166.6157.2159.9 Change from baseline (adjusted mean)-28.8-24.1-4.1 Difference from placebo (adjusted mean) (95% CI)-24.7 (-35.7, -13.6)-19.9(-31.3, -8.5). Initial Combination Therapy with Metformin XR. total of 1236 treatment-naive patients with inadequately controlled type diabetes mellitus (HbA1c >=7.5% and <=12%) participated in active-controlled studies of 24-week duration to evaluate initial therapy with dapagliflozin mg (NCT00643851) or 10 mg (NCT00859898) in combination with metformin extended-release (XR) formulation.In study, 638 patients randomized to of treatment arms following 1-week lead-in period received: dapagliflozin 10 mg plus metformin XR (up to 2000 mg per day), dapagliflozin 10 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with median dose achieved of 2000 mg.The combination treatment of dapagliflozin 10 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table and Figure 2). Dapagliflozin 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin alone and was non-inferior to metformin XR monotherapy in lowering HbA1c.Table 9: Results at Week 24 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) in an Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XREfficacy ParameterDapagliflozin10 mg+ Metformin XRDapagliflozin 10 mgMetforminXRN=211All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.N=219N=208HbA1c (%) Baseline (mean)9.19.09.0 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)-2.0-1.5-1.4 Difference from dapagliflozin (adjusted mean) (95% CI)-0.5p-value <0.0001. (-0.7, -0.3) Difference from metformin XR (adjusted mean) (95% CI)-0.5 (-0.8, -0.3)0.0Non-inferior versus metformin XR. (-0.2, 0.2) Percent of patients achieving HbA1c <7% adjusted for baseline46.6%p-value <0.05. 31.7%35.2%FPG (mg/dL) Baseline (mean)189.6197.5189.9 Change from baseline (adjusted mean)-60.4-46.4-34.8 Difference from dapagliflozin (adjusted mean) (95% CI)-13.9 (-20.9, -7.0) Difference from metformin XR (adjusted mean) (95% CI)-25.5 (-32.6, -18.5)-11.6 (-18.6, -4.6)Body Weight (kg) Baseline (mean)88.688.587.2 Change from baseline (adjusted mean)-3.3-2.7-1.4 Difference from metformin XR (adjusted mean) (95% CI)-2.0 (-2.6, -1.3)-1.4 (-2.0, -0.7)Figure 2: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in 24-Week Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XRIn second study, 603 patients were randomized to of treatment arms following 1-week lead-in period: dapagliflozin mg plus metformin XR (up to 2000 mg per day), dapagliflozin mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with median dose achieved of 2000 mg.The combination treatment of dapagliflozin mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 10).Table 10: Results at Week 24 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) in an Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XREfficacy ParameterDapagliflozin5 mg+ Metformin XRDapagliflozin5 mgMetforminXRN=194All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.N=203N=201HbA1c (%) Baseline (mean)9.29.19.1 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)-2.1-1.2-1.4 Difference from dapagliflozin (adjusted mean) (95% CI)-0.9p-value <0.0001. (-1.1, -0.6) Difference from metformin XR (adjusted mean) (95% CI)-0.7 (-0.9, -0.5) Percent of patients achieving HbA1c <7% adjusted for baseline52.4%p-value <0.05. 22.5%34.6%FPG (mg/dL) Baseline (mean)193.4190.8196.7 Change from baseline (adjusted mean)-61.0-42.0-33.6 Difference from dapagliflozin (adjusted mean) (95% CI)-19.1 (-26.7, -11.4) Difference from metformin XR (adjusted mean) (95% CI)-27.5 (-35.1, -19.8)Body Weight (kg) Baseline (mean)84.286.285.8 Change from baseline (adjusted mean)-2.7-2.6-1.3 Difference from metformin XR (adjusted mean) (95% CI)-1.4 (-2.0, -0.7). Figure2. Add-On to Metformin. total of 546 patients with type diabetes mellitus with inadequate glycemic control (HbA1c >=7% and <=10%) participated in 24-week, placebo-controlled study to evaluate dapagliflozin in combination with metformin (NCT00528879). Patients on metformin at dose of at least 1500 mg per day were randomized after completing 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin mg, dapagliflozin 10 mg, or placebo in addition to their current dose of metformin.As add-on treatment to metformin, dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 11 and Figure 3). Statistically significant (p <0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus metformin were -4.5 mmHg and -5.3 mmHg with dapagliflozin mg and 10 mg plus metformin, respectively.Table 11: Results of 24-Week (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) Placebo-Controlled Study of Dapagliflozin in Add-On Combination with MetforminEfficacy ParameterDapagliflozin 10 mg+ MetforminN=135All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.Dapagliflozin mg+ MetforminN=137Placebo+ MetforminN=137HbA1c (%) Baseline (mean) 7.98.28.1 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)-0.8-0.7-0.3 Difference from placebo (adjusted mean) (95% CI)-0.5p-value <0.0001 versus placebo metformin. (-0.7, -0.3)-0.4 (-0.6, -0.2) Percent of patients achieving HbA1c <7% adjusted for baseline40.6%p-value <0.05 versus placebo metformin. 37.5% 25.9% FPG (mg/dL) Baseline (mean)156.0169.2165.6 Change from baseline at Week 24 (adjusted mean) -23.5-21.5-6.0 Difference from placebo (adjusted mean) (95% CI)-17.5 (-25.0, -10.0)-15.5 (-22.9, -8.1) Change from baseline at Week (adjusted mean)-16.5 (N=115)-12.0 (N=121)1.2(N=126)Body Weight (kg) Baseline (mean) 86.384.787.7 Change from baseline (adjusted mean) -2.9-3.0-0.9 Difference from placebo (adjusted mean) (95% CI)-2.0 (-2.6, -1.3)-2.2 (-2.8, -1.5)Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in 24-Week Placebo-Controlled Study of Dapagliflozin in Combination with Metformin. Figure3. Active Glipizide-Controlled Study Add-On to Metformin. total of 816 patients with type diabetes mellitus with inadequate glycemic control (HbA1c >6.5% and <=10%) were randomized in 52-week, glipizide-controlled, non-inferiority study to evaluate dapagliflozin as add-on therapy to metformin (NCT00660907). Patients on metformin at dose of at least 1500 mg per day were randomized following 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin led to similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating non-inferiority (see Table 12). Dapagliflozin treatment led to statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was -5.0 mmHg with dapagliflozin plus metformin.Table 12: Results at Week 52 (LOCFLOCF: last observation carried forward.) in an Active-Controlled Study Comparing Dapagliflozin to Glipizide as Add-On to MetforminEfficacy ParameterDapagliflozin+ MetforminN=400Randomized and treated patients with baseline and at least post-baseline efficacy measurement.Glipizide+ MetforminN=401HbA1c (%) Baseline (mean)7.77.7 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)-0.5-0.5 Difference from glipizide metformin (adjusted mean) (95% CI)0.0Non-inferior to glipizide metformin. (-0.1, 0.1)Body Weight (kg) Baseline (mean)88.487.6 Change from baseline (adjusted mean)-3.21.4 Difference from glipizide metformin (adjusted mean) (95% CI)-4.7p-value <0.0001. (-5.1, -4.2). Add-On Combination Therapy with Other Antidiabetic Agents. Add-On Combination Therapy with Sulfonylurea. total of 597 patients with type diabetes mellitus and inadequate glycemic control (HbA1c >=7% and <=10%) were randomized in this 24-week, placebo-controlled study to evaluate dapagliflozin in combination with glimepiride (a sulfonylurea) (NCT00680745).Patients on at least half the maximum recommended dose of glimepiride as monotherapy (4 mg) for at least weeks lead-in were randomized to dapagliflozin mg, dapagliflozin 10 mg, or placebo in addition to glimepiride mg per day. Down-titration of glimepiride to mg or mg was allowed for hypoglycemia during the treatment period; no up-titration of glimepiride was allowed.In combination with glimepiride, dapagliflozin 10 mg provided statistically significant improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in body weight compared with placebo plus glimepiride at Week 24 (see Table 13). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus glimepiride were -2.8 mmHg and -3.8 mmHg with dapagliflozin mg and 10 mg plus glimepiride, respectively.. Add-on Combination Therapy with Metformin and Sulfonylurea. total of 218 patients with type diabetes mellitus and inadequate glycemic control (HbA1c >=7% and <=10.5%) participated in 24-week, placebo-controlled study to evaluate dapagliflozin in combination with metformin and sulfonylurea (NCT01392677). Patients on stable dose of metformin (immediate- or extended-release formulations) >=1500 mg/day plus maximum tolerated dose, which must be at least half the maximum dose, of sulfonylurea for at least weeks prior to enrollment were randomized after an 8-week placebo lead-in period to dapagliflozin 10 mg or placebo. Dose-titration of dapagliflozin or metformin was not permitted during the 24-week treatment period. Down-titration of the sulfonylurea was permitted to prevent hypoglycemia, but no up-titration was permitted. As add-on treatment to combined metformin and sulfonylurea, treatment with dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG and statistically significant reduction in body weight compared with placebo at Week 24 (Table 13). statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with metformin and sulfonylurea was -3.8 mmHg with dapagliflozin 10 mg in combination with metformin and sulfonylurea at Week 8.. Add-On Combination Therapy with Thiazolidinedione. total of 420 patients with type diabetes mellitus with inadequate glycemic control (HbA1c >=7% and <=10.5%) participated in 24-week, placebo-controlled study to evaluate dapagliflozin in combination with pioglitazone (a thiazolidinedione [TZD]) alone (NCT00683878). Patients on stable dose of pioglitazone of 45 mg per day (or 30 mg per day, if 45 mg per day was not tolerated) for 12 weeks were randomized after 2-week lead-in period to or 10 mg of dapagliflozin or placebo in addition to their current dose of pioglitazone. Dose titration of dapagliflozin or pioglitazone was not permitted during the study.In combination with pioglitazone, treatment with dapagliflozin 10 mg provided statistically significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7%, and statistically significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (see Table 13) at Week 24. statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with pioglitazone was -4.5 mmHg with dapagliflozin 10 mg in combination with pioglitazone.. Add-On Combination Therapy with DPP4 Inhibitor. total of 452 patients with type diabetes mellitus who were drug naive, or who were treated at entry with metformin or DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c >=7.0% and <=10.0% at randomization), participated in 24-week, placebo-controlled study to evaluate dapagliflozin in combination with sitagliptin (a DPP4 inhibitor) with or without metformin (NCT00984867).Eligible patients were stratified based on the presence or absence of background metformin (>=1500 mg per day), and within each stratum were randomized to either dapagliflozin 10 mg plus sitagliptin 100 mg once daily, or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for dapagliflozin 10 mg versus placebo for the total study group (sitagliptin with and without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on DPP4 inhibitor alone, and 18% were on DPP4 inhibitor plus metformin. Dose titration of dapagliflozin, sitagliptin, or metformin was not permitted during the study.In combination with sitagliptin (with or without metformin), dapagliflozin 10 mg provided statistically significant improvements in HbA1c, FPG, and statistically significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (see Table 13). These improvements were also seen in the stratum of patients who received dapagliflozin 10 mg plus sitagliptin alone (placebo-corrected mean change for HbA1c -0.56%; n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received dapagliflozin 10 mg plus sitagliptin and metformin (placebo-corrected mean change for HbA1c -0.40; n=113) compared with placebo plus sitagliptin with metformin (n=113).. Add-On Combination Therapy with Insulin. total of 808 patients with type diabetes mellitus who had inadequate glycemic control (HbA1c >=7.5% and <=10.5%) were randomized in 24-week, placebo-controlled study to evaluate dapagliflozin as add-on therapy to insulin (NCT00673231). Patients on stable insulin regimen, with mean dose of at least 30 IU of injectable insulin per day, for period of at least weeks prior to enrollment and on maximum of oral antidiabetic medications (OADs), including metformin, were randomized after completing 2-week enrollment period to receive either dapagliflozin mg, dapagliflozin 10 mg, or placebo in addition to their current dose of insulin and other OADs, if applicable. Patients were stratified according to the presence or absence of background OADs. Up- or down-titration of insulin was only permitted during the treatment phase in patients who failed to meet specific glycemic goals. Dose modifications of blinded study medication or OAD(s) were not allowed during the treatment phase, with the exception of decreasing OAD(s) where there were concerns over hypoglycemia after cessation of insulin therapy.In this study, 50% of patients were on insulin monotherapy at baseline, while 50% were on or OADs in addition to insulin. At Week 24, dapagliflozin 10 mg dose provided statistically significant improvement in HbA1c and reduction in mean insulin dose, and statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to OADs (see Table 13); the effect of dapagliflozin on HbA1c was similar in patients treated with insulin alone and patients treated with insulin plus OAD. Statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with insulin was -3.0 mmHg with dapagliflozin 10 mg in combination with insulin.At Week 24, dapagliflozin mg (-5.7 IU, difference from placebo) and 10 mg (-6.2 IU, difference from placebo) once daily resulted in statistically significant reduction in mean daily insulin dose (p<0.0001 for both doses) compared to placebo in combination with insulin, and statistically significantly higher proportion of patients on dapagliflozin 10 mg (19.6%) reduced their insulin dose by at least 10% compared to placebo (11.0%).Table 13: Results of 24-Week (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) Placebo-Controlled Studies of Dapagliflozin in Combination with Antidiabetic AgentsEfficacy ParameterDapagliflozin 10 mgDapagliflozin mgPlaceboIn Combination with Sulfonylurea (Glimepiride)Intent-to-Treat PopulationN=151Randomized and treated patients with baseline and at least post-baseline efficacy measurement.N=142N=145HbA1c (%) Baseline (mean) 8.18.18.2 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value based on an ANCOVA model. )-0.8-0.6-0.1 Difference from placebo (adjusted mean) (95% CI)-0.7p-value <0.0001 versus placebo. (-0.9, -0.5)-0.5 (-0.7, -0.3)Percent of patients achieving HbA1c <7% adjusted for baseline31.7% 30.3% 13.0%FPG (mg/dL) Baseline (mean)172.4174.5172.7 Change from baseline (adjusted mean) -28.5-21.2-2.0 Difference from placebo (adjusted mean) (95% CI)-26.5 (-33.5, -19.5)-19.3 (-26.3, -12.2)2-hour PPG2-hour PPG level as response to 75-gram oral glucose tolerance test (OGTT). (mg/dL) Baseline (mean)329.6322.8324.1 Change from baseline (adjusted mean)-60.6-54.5-11.5 Difference from placebo (adjusted mean) (95% CI)-49.1 (-64.1, -34.1)-43.0 (-58.4, -27.5)Body Weight (kg) Baseline (mean) 80.681.080.9 Change from baseline (adjusted mean)-2.3-1.6-0.7 Difference from placebo (adjusted mean) (95% CI)-1.5 (-2.2, -0.9)-0.8 (-1.5, -0.2)In Combination with Metformin and SulfonylureaIntent-to-Treat PopulationN=108-N=108HbA1c (%) Baseline (mean) 8.08-8.24 Change from baseline (adjusted mean Least squares mean adjusted for baseline value based on longitudinal repeated measures model.)-0.86--0.17 Difference from placebo (adjusted mean (95% CI)-0.69 (-0.89, -0.49)- Percent of patients achieving HbA1c <7% adjusted for baseline31.8% -11.1% FPG (mg/dL) Baseline (mean)167.4-180.3 Change from baseline (adjusted mean)-34.2--0.8 Difference from placebo (adjusted mean) (95% CI)-33.5 (-43.1, -23.8)-Body Weight (kg) Baseline (mean) 88.57-90.07 Change from baseline (adjusted mean)-2.65--0.58 Difference from placebo (adjusted mean) (95% CI)-2.07 (-2.79, -1.35)-In Combination with Thiazolidinedione (Pioglitazone)Intent-to-Treat PopulationN=140All randomized patients who took at least one dose of double-blind study medication during the short-term, double-blind period.N=141N=139HbA1c (%) Baseline (mean)8.48.48.3 Change from baseline (adjusted mean)-1.0-0.8-0.4 Difference from placebo (adjusted mean) (95% CI)-0.6 (-0.8, -0.3)-0.4 (-0.6, -0.2) Percent of patients achieving HbA1c <7% adjusted for baseline38.8%p-value <0.05 versus placebo. 32.5% 22.4%FPG (mg/dL) Baseline (mean)164.9168.3160.7 Change from baseline (adjusted mean)-29.6-24.9-5.5 Difference from placebo (adjusted mean) (95% CI)-24.1 (-32.2, -16.1)-19.5 (-27.5, -11.4)2-hour PPG (mg/dL) Baseline (mean)308.0284.8293.6 Change from baseline (adjusted mean)-67.5-65.1-14.1 Difference from placebo (adjusted mean) (95% CI)-53.3 (-71.1, -35.6)-51.0 (-68.7, -33.2)Body Weight (kg) Baseline (mean)84.887.886.4 Change from baseline (adjusted mean)-0.10.11.6 Difference from placebo (adjusted mean) (95% CI)-1.8 (-2.6, -1.0)-1.6 (-2.3, -0.8)In Combination with DPP4 Inhibitor (Sitagliptin) with or without MetforminIntent-to-Treat PopulationN=223-N=224HbA1c (%) Baseline (mean)7.90-7.97 Change from baseline (adjusted mean)-0.45-0.04 Difference from placebo (adjusted mean) (95% CI)-0.48 (-0.62, -0.34)- Patients with HbA1c decrease >=0.7% (adjusted percent)35.4%-16.6%FPG (mg/dL) Baseline (mean)161.7-163.1 Change from baseline at Week 24 (adjusted mean)-24.1-3.8 Difference from placebo (adjusted mean) (95% CI)-27.9 (-34.5, -21.4)-Body Weight (kg) Baseline (mean) 91.02-89.23 Change from baseline (adjusted mean)-2.14--0.26 Difference from placebo (adjusted mean) (95% CI)-1.89 (-2.37, -1.40)-In Combination with Insulin with or without up to Oral Antidiabetic TherapiesIntent-to-Treat PopulationN=194N=211N=193HbA1c (%) Baseline (mean) 8.68.68.5 Change from baseline (adjusted mean)-0.9-0.8-0.3 Difference from placebo (adjusted mean) (95% CI)-0.6 (-0.7, -0.5)-0.5 (-0.7, -0.4)FPG (mg/dL) Baseline (mean)173.7NTNT: Not formally tested because of failing to achieve statistically significant difference in an endpoint that was earlier in the testing sequence. 170.0 Change from baseline (adjusted mean)-21.7NT 3.3 Difference from placebo (adjusted mean) (95% CI) -25.0 (-34.3, -15.8)NT Body Weight (kg) Baseline (mean) 94.693.294.2 Change from baseline (adjusted mean)-1.7-1.00.0 Difference from placebo (adjusted mean) (95% CI)-1.7 (-2.2, -1.2)-1.0 (-1.5, -0.5). Combination Therapy with Exenatide-Extended Release as Add-On to Metformin. total of 694 adult patients with type diabetes mellitus and inadequate glycemic control (HbA1c >=8.0 and <=12.0%) on metformin, were evaluated in 28-week double-blind, active-controlled study to compare dapagliflozin in combination with exenatide extended-release (a GLP-1 receptor agonist) to dapagliflozin alone and exenatide extended-release alone, as add-on to metformin (NCT02229396). Patients on metformin at dose of at least 1,500 mg per day were randomized following 1-week placebo lead-in period to receive either dapagliflozin 10 mg once daily (QD) in combination with exenatide extended-release mg once weekly (QW), dapagliflozin 10 mg QD, or exenatide extended-release mg QW. At Week 28, dapagliflozin in combination with exenatide extended-release provided statistically significantly greater reductions in HbA1c (-1.77%) compared to dapagliflozin alone (-1.32%, p=0.001) and exenatide extended-release alone (-1.42%, p=0.012). Dapagliflozin in combination with exenatide extended-release provided statistically significantly greater reductions in FPG (-57.35 mg/dL) compared to dapagliflozin alone (-44.72 mg/dL, p=0.006) and exenatide extended-release alone (-40.53, <0.001).. Use in Patients with Type Diabetes Mellitus and Moderate Renal Impairment. Dapagliflozin was assessed in two placebo-controlled studies of patients with type diabetes mellitus and moderate renal impairment.Patients with type diabetes mellitus and an eGFR between 45 to less than 60 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in 24-week, double-blind, placebo-controlled clinical study (NCT02413398). Patients were randomized to either Dapagliflozin 10 mg or placebo, administered orally once daily. At Week 24, dapaliflozin provided statistically significant reductions in HbA1c compared with placebo (Table 14).Table 14: Results at Week 24 of Placebo-Controlled Study for Dapagliflozin in Patients with Type Diabetes Mellitus and Renal Impairment (eGFR 45 to less than 60 mL/min/1.73 m2)Dapagliflozin 10 mgPlaceboNumber of patients:N=160N=161HbA1c (%) Baseline (mean)8.38.0 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value; at Week 24, HbA1c was missing for 5.6% and 6.8% of individuals treated with dapagliflozin and placebo, respectively. Retrieved dropouts, i.e. observed HbA1c at Week 24 from subjects who discontinued treatment, were used to impute missing values in HbA1c. )-0.4-0.1 Difference from placebo (adjusted mean) (95% CI)-0.3p-value =0.008 versus placebo. (-0.5, 0.1). 14.2 Cardiovascular Outcomes in Patients with Type Diabetes Mellitus Dapagliflozin Effect on Cardiovascular Events (DECLARE, NCT01730534) was an international, multicenter, randomized, double-blind, placebo-controlled, clinical study conducted to determine the effect of dapagliflozin relative to placebo on cardiovascular (CV) outcomes when added to current background therapy. All patients had type diabetes mellitus and either established CV disease or two or more additional CV risk factors (age >=55 years in men or >=60 years in women and one or more of dyslipidemia, hypertension, or current tobacco use). Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases. Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186 (59.4%) did not have established CV disease. total of 8582 patients were randomized to dapagliflozin 10 mg, 8578 to placebo, and patients were followed for median of 4.2 years.Approximately 80% of the trial population was White, 4% Black or African American, and 13% Asian. The mean age was 64 years, and approximately 63% were male. Mean duration of diabetes was 11.9 years and 22.4% of patients had diabetes for less than years. Mean eGFR was 85.2 mL/min/1.73 m2. At baseline, 23.5% of patients had microalbuminuria (UACR >=30 to <=300 mg/g) and 6.8% had macroalbuminuria (UACR >300 mg/g). Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m2. At baseline, 10% of patients had history of heart failure. Most patients (98.1%) used one or more antihyperglycemic medications at baseline. 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with sulfonylurea, 16.8% with DPP4 inhibitor, and 4.4% with GLP-1 receptor agonist.Approximately 81.3% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics, and 10.5% with loop diuretics.A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio (HR) of the composite of CV death, myocardial infarction (MI), or ischemic stroke (MACE) and if non-inferiority was demonstrated, to test for superiority on the two primary endpoints: 1) the composite of hospitalization for heart failure or CV death, and 2) MACE.The incidence rate of MACE was similar in both treatment arms: 2.30 MACE events per 100 patient-years on dapagliflozin vs 2.46 MACE events per 100 patient-years on placebo. The estimated hazard ratio of MACE associated with dapagliflozin relative to placebo was 0.93 with 95% CI of (0.84, 1.03). The upper bound of this confidence interval, 1.03, excluded the pre-specified non-inferiority margin of 1.3. Dapagliflozin was superior to placebo in reducing the incidence of the primary composite endpoint of hospitalization for heart failure or CV death (HR 0.83 [95% CI 0.73, 0.95]). The treatment effect was due to significant reduction in the risk of hospitalization for heart failure in subjects randomized to Dapagliflozin (HR 0.73 [95% CI 0.61, 0.88]), with no change in the risk of CV death (Table 15 and Figures and 5).Table 15: Treatment Effects for the Primary EndpointsFull analysis set. and their Components in the DECLARE StudyPatients with events (%)Efficacy Variable(time to first occurrence)Dapagliflozin 10 mgN=8582PlaceboN=8578Hazard ratio(95% CI)Primary EndpointsComposite of Hospitalization for Heart Failure, CV Deathp-value =0.005 versus placebo.417 (4.9)496 (5.8)0.83 (0.73, 0.95)Composite Endpoint of CV Death, MI, Ischemic Stroke756 (8.8)803 (9.4)0.93 (0.84, 1.03)Components of the composite endpointsTotal number of events presented for each component of the composite endpoints. Hospitalization for Heart Failure212 (2.5)286 (3.3)0.73 (0.61, 0.88) CV Death245 (2.9)249 (2.9)0.98 (0.82, 1.17) Myocardial Infarction393 (4.6)441 (5.1)0.89 (0.77, 1.01) Ischemic Stroke235 (2.7)231 (2.7)1.01 (0.84, 1.21)N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction.Figure 4: Time to First Occurrence of Hospitalization for Heart Failure or CV Death in the DECLARE StudyFigure 5: Time to First Occurrence of Hospitalization for Heart Failure in the DECLARE Study. Figure4. Figure5. 14.3 Chronic Kidney Disease The Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA-CKD, NCT03036150) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with chronic kidney disease (CKD) (eGFR between 25 and 75 mL/min/1.73 m2) and albuminuria (urine albumin creatinine ratio [UACR] between 200 and 5000 mg/g) who were receiving standard of care background therapy, including maximally tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The trial excluded patients with autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis and patients requiring cytotoxic, immunosuppressive, or immunomodulatory therapies in the preceding months.The primary objective was to determine whether dapagliflozin reduces the incidence of the composite endpoint of >=50% sustained decline in eGFR, progression to end-stage kidney disease (ESKD) (defined as sustained eGFR <15 mL/min/1.73 m2, initiation of chronic dialysis treatment or renal transplant), CV or renal death.A total of 4304 patients were randomized equally to dapagliflozin 10 mg or placebo and were followed for median of 28.5 months. The mean age of the study population was 62 years and 67% were male. The population was 53% White, 4% Black or African American, and 34% Asian; 25% were of Hispanic or Latino ethnicity.At baseline, mean eGFR was 43 mL/min/1.73 m2, 44% of patients had an eGFR 30 mL/min/1.73 m2 to less than 45 mL/min/1.73 m2, and 15% of patients had an eGFR less than 30 mL/min/1.73 m2. Median UACR was 950 mg/g. total of 68% of the patients had type diabetes mellitus at randomization. The most common etiologies of CKD were diabetic nephropathy (58%), ischemic/hypertensive nephropathy (16%), and IgA nephropathy (6%).At baseline, 97% of patients were treated with ACEi or ARB. Approximately 44% were taking antiplatelet agents, and 65% were on statin.Dapagliflozin reduced the incidence of the primary composite endpoint of >=50% sustained decline in eGFR, progression to ESKD, CV or renal death (HR 0.61 [95% CI 0.51,0.72]; p<0.0001). The dapagliflozin and placebo event curves separate by Month and continue to diverge over the study period. The treatment effect reflected reduction in >=50% sustained decline in eGFR, progression to ESKD, and CV death. There were few renal deaths during the trial (Table 16, Figure 6).Dapagliflozin also reduced the incidence of the composite endpoint of CV death or hospitalization for heart failure (HR 0.71 [95% CI 0.55, 0.92], p=0.0089) and all-cause mortality (HR 0.69 [95% CI 0.53, 0.88], p=0.0035).Table 16: Treatment Effect for the Primary Composite Endpoint, its Components, and Secondary Composite Endpoints, in the DAPA-CKD StudyPatients with events (event rate)Efficacy Variable(time to first occurrence)Dapagliflozin 10 mgN=2152PlaceboN=2152Hazard ratio(95% CI)p-valueComposite of >=50% sustained eGFR decline, ESKD, CV or renal death197 (4.6)312 (7.5)0.61(0.51, 0.72)<0.0001 >=50% sustained eGFR decline112 (2.6)201 (4.8)0.53(0.42, 0.67) ESKDESKD is defined as sustained eGFR <15 mL/min/1.73 m2, initiation of chronic dialysis treatment, or transplant. 109 (2.5)161 (3.8)0.64(0.50, 0.82) CV Death65 (1.4)80 (1.7)0.81(0.58, 1.12) Renal Death2 (<0.1)6 (0.1)>=50% sustained eGFR decline, ESKD or renal death142 (3.3)243 (5.8)0.56(0.45, 0.68)<0.0001CV death or Hospitalization for Heart Failure100 (2.2)138 (3.0)0.71(0.55, 0.92)0.0089 Hospitalization for Heart Failure37 (0.8)71 (1.6)0.51(0.34, 0.76)All-Cause Mortality101 (2.2)146 (3.1)0.69(0.53, 0.88)0.0035N=Number of patients, CI=Confidence interval, CV=Cardiovascular, ESKD=End stage kidney disease.NOTE: Time to first event was analyzed in Cox proportional hazards model. Event rates are presented as the number of subjects with event per 100 patient years of follow-up.There were too few events of renal death to compute reliable hazard ratio.Figure 6: Time to First Occurrence of the Primary Composite Endpoint, >=50% Sustained Decline in eGFR, ESKD, CV or Renal Death (DAPA-CKD Study)Patients at risk is the number of subjects at risk at the beginning of the period. month corresponds to 30 days. 2-sided p-value is displayed. HR, CI and p-value are from the Cox proportional hazard model. HR=hazard ratio; CI=confidence interval; eGFR=estimated glomerular filtration rate; ESKD=end stage kidney disease; CV=cardiovascular; vs=versus.The results of the primary composite endpoint were consistent across the subgroups examined, including CKD patients with and without type diabetes mellitus, causes of CKD, age, biological sex, race, UACR, and eGFR.DAPA-CKD enrolled population with relatively advanced CKD at high risk of progression. Exploratory analyses of randomized, double-blind, placebo-controlled trial conducted to determine the effect of dapagliflozin on CV outcomes (the DECLARE trial) support the conclusion that dapagliflozin is also likely to be effective in patients with less advanced CKD.. Figure6. 14.4 Heart Failure The efficacy and safety of dapagliflozin 10 mg were assessed independently in two Phase studies in patients with heart failure.Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF, NCT03036124) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with heart failure (New York Heart Association [NYHA] functional class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] 40% or less) to determine whether dapagliflozin reduces the risk of cardiovascular death and hospitalization for heart failure. Of 4744 patients, 2373 were randomized to dapagliflozin 10 mg and 2371 to placebo and were followed for median of 18 months. Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure (DELIVER, NCT03619213) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients aged >=40 years with heart failure (NYHA class II-IV) with LVEF >40% and evidence of structural heart disease to determine whether dapagliflozin reduces the risk of cardiovascular death, hospitalization for heart failure or urgent heart failure visits. Of 6263 patients, 3131 were randomized to dapagliflozin 10 mg and 3132 to placebo and were followed for median of 28 months. The study included 654 (10%) heart failure patients who were randomized during hospitalization for heart failure or within 30 days of discharge. In DAPA-HF, at baseline, 94% of patients were treated with ACEi, ARB or angiotensin receptor-neprilysin inhibitor (ARNI, including sacubitril/valsartan 11%), 96% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 93% with diuretic, and 26% had an implantable device.In DELIVER, at baseline, 77% of patients were treated with ACEi, ARB or ARNI, 83% with beta-blocker, 43% with MRA, 98% with diuretic.In both studies, dapagliflozin reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit (see Table 17). Table 17: Treatment Effect for the Primary Composite EndpointFull analysis set., its Components in the DAPA-HF and DELIVER StudiesDAPA-HF StudyDELIVER StudyPatients with events(event rate)Hazard ratio(95% CI)p-valueTwo-sided p-values.Patients with events(event rate)Hazard ratio(95% CI)p-valueEfficacy Variable(Time to first occurrence)Dapagliflozin 10 mgN=2373PlaceboN=2371Dapagliflozin 10 mgN=3131PlaceboN=3132Composite of Hospitalization for Heart Failure, CV DeathIn DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause. or Urgent Heart Failure Visit386(11.6)502(15.6)0.74(0.65, 0.85)<0.0001512(7.8)610(9.6)0.82(0.73, 0.92)0.0008Components of the composite endpointsCV Death 227(6.5)273(7.9)0.82(0.69, 0.98)231(3.3)261(3.8)0.88(0.74, 1.05)Hospitalization for Heart Failure or Urgent Heart Failure Visit237(7.1)326(10.1)0.70(0.59, 0.83)368(5.6)455(7.2)0.79(0.69, 0.91)Hospitalization for Heart Failure231(6.9)318(9.8)0.70(0.59, 0.83)329(5.0)418(6.5)0.77(0.67, 0.89)Urgent Heart Failure Visit10(0.3)23(0.7)0.43(0.20, 0.90)60(0.9)78(1.1)0.76(0.55, 1.07)N=Number of patients, CI=Confidence interval, CV=Cardiovascular.NOTE: Time to first event was analyzed in Cox proportional hazards model. The number of first events for the single components are the actual number of first events for each component and does not add up to the number of events in the composite endpoint. Event rates are presented as the number of subjects with event per 100 patient years of follow-up.In both studies, all three components of the primary composite endpoint individually contributed to the treatment effect. In both studies, the dapagliflozin and placebo event curves separated early and continued to diverge over the study period (see Figures and 9).Figure 7: Time to the First Occurrence of the Composite of Cardiovascular Death, Hospitalization for Heart Failure or Urgent Heart Failure VisitA) DAPA-HF StudyB) DELIVER StudyNOTE: An urgent heart failure visit was defined as an urgent, unplanned, assessment by physician, e.g., in an Emergency Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics). In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.+ Patients at risk is the number of patients at risk at the beginning of the period.HR=Hazard ratio, CI=Confidence interval, CV=Cardiovascular.Figure 8: Time to Cardiovascular DeathA) DAPA-HF StudyB) DELIVER Study In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.+ Patients at risk is the number of patients at risk at the beginning of the period.HR=Hazard ratio, CI=Confidence interval, CV=Cardiovascular.Figure 9: Time to the First Occurrence of Hospitalization for Heart Failure or Urgent Heart Failure VisitA) DAPA-HF StudyB) DELIVER Study Patients at risk is the number of patients at risk at the beginning of the period. HR=Hazard ratio, CI=Confidence interval.In DAPA-HF, dapagliflozin reduced the total number of hospitalizations for heart failure (first and recurrent) events and CV death, with 567 and 742 total events in the dapagliflozin-treated vs placebo group (Rate Ratio 0.75 [95% CI 0.65, 0.88]; p=0.0002).In DELIVER, dapagliflozin reduced the total number of heart failure events (first and recurrent hospitalization for heart failure or urgent heart failure visit) and CV death, with 815 and 1057 total events in the dapagliflozin treated vs placebo group (Rate Ratio 0.77 [95% CI 0.67, 0.89]; p=0.0003).In both studies, the results of the primary composite endpoint were consistent across the subgroups examined (see Figure 10).Figure 10: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and Heart Failure Events) Subgroup Analysis A) DAPA-HF Studya Hazard ratio estimates are not presented for subgroups with less than 15 events in total, both arms combined.n/N Number of subjects with event/number of subjects in the subgroup.NT-proBNP N-terminal pro b-type natriuretic peptide, HF Heart failure, MRA mineralocorticoid receptor antagonist, ECG electrocardiogram, eGFR estimated glomerular filtration rate.Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.B) DELIVER Studya Subacute patient defined as randomized during hospitalization for heart failure or within 30 days of discharge.b Defined as history of type diabetes mellitus. This analysis does not include type diabetes mellitus as stratification factor.n/N Number of subjects with event/number of subjects in the subgroup.NT-proBNP N-terminal pro b-type natriuretic peptide, HF Heart failure, ECG electrocardiogram, eGFR estimated glomerular filtration rate, BMI body mass index, SBP systolic blood pressure, T2DM type diabetes mellitus.NOTE: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.The treatment effect of dapagliflozin on the composite endpoint of cardiovascular death, hospitalization for heart failure or urgent heart failure was consistent across the LVEF range as evaluated in DAPA-HF and DELIVER studies (Figure 11).Figure 11: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and Heart Failure Events) by LVEF (DAPA-HF and DELIVER Studies) patient in DAPA-HF study had LVEF >40. patients in DELIVER study had LVEF<=40.In DAPA-HF study, the 5% and 95% percentiles of LVEF were 20 and 40 respectively. In DELIVER study, the 5% and 95% percentiles of LVEF were 42 and 70, respectively.. Figure7a. Figure-7b. Figure-8a. Figure8b. Figure-9a. Figure-9b. Figure10a. Figure10b. Figure11.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling:oDiabetic Ketoacidosis in Patients with Type Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.1)]oVolume Depletion [see Warnings and Precautions (5.2)]oUrosepsis and Pyelonephritis [see Warnings and Precautions (5.3)]oHypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4)]oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see Warnings and Precautions (5.5)] oGenital Mycotic Infections [see Warnings and Precautions (5.6)]. oDiabetic Ketoacidosis in Patients with Type Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.1)]. oVolume Depletion [see Warnings and Precautions (5.2)]. oUrosepsis and Pyelonephritis [see Warnings and Precautions (5.3)]. oHypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.4)]. oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see Warnings and Precautions (5.5)] oGenital Mycotic Infections [see Warnings and Precautions (5.6)]. oMost common adverse reactions (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oMost common adverse reactions (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. (6.1). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Dapagliflozin has been evaluated in clinical trials in patients with type diabetes mellitus, in patients with heart failure, and in patients with chronic kidney disease. The overall safety profile of dapagliflozin was consistent across the studied indications. Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus.Clinical Trials in Patients with Type Diabetes MellitusPool of 12 Placebo-Controlled Studies for Dapagliflozin and 10 mg for Glycemic ControlThe data in Table is derived from 12 glycemic control placebo-controlled studies in patients with type diabetes mellitus ranging from 12 to 24 weeks. In studies dapagliflozin was used as monotherapy, and in studies dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14.1)]. These data reflect exposure of 2338 patients to dapagliflozin with mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin mg (N=1145), or dapagliflozin 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of years, had mean hemoglobin A1c (HbA1c) of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m2).Table shows common adverse reactions associated with the use of dapagliflozin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin mg or dapagliflozin 10 mg.Table 2: Adverse Reactions in Placebo-Controlled Studies of Glycemic Control Reported in >=2% of Patients Treated with DapagliflozinAdverse Reaction% of PatientsPool of 12 Placebo-Controlled StudiesPlaceboN=1393Dapagliflozin mgN=1145Dapagliflozin 10 mgN=1193Female genital mycotic infectionsGenital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin mg=581, dapagliflozin 10 mg=598). 1.58.46.9Nasopharyngitis6.26.66.3Urinary tract infectionsUrinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis. 3.75.74.3Back pain3.23.14.2Increased urinationIncreased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. 1.72.93.8Male genital mycotic infectionsGenital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, and posthitis. (N for males: Placebo=716, dapagliflozin mg=564, dapagliflozin 10 mg=595). 0.32.82.7Nausea2.42.82.5Influenza2.32.72.3Dyslipidemia1.52.12.5Constipation1.52.21.9Discomfort with urination 0.71.62.1Pain in extremity1.42.01.7Pool of 13 Placebo-Controlled Studies for Dapagliflozin 10 mg for Glycemic ControlDapagliflozin 10 mg was also evaluated in larger glycemic control placebo-controlled study pool in patients with type diabetes mellitus. This pool combined 13 placebo-controlled studies, including monotherapy studies, add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg for mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of years, had mean HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR 82 mL/min/1.73 m2).Volume DepletionDapagliflozin causes an osmotic diuresis, which may lead to reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) in patients with type diabetes mellitus for the 12-study and 13-study, short-term, placebo-controlled pools and for the DECLARE study are shown in Table [see Warnings and Precautions (5.2)]. Table 3: Adverse Reactions Related to Volume DepletionVolume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. in Clinical Studies in Patients with Type Diabetes Mellitus with DapagliflozinPool of 12 Placebo-ControlledStudiesPool of 13 Placebo-ControlledStudiesDECLARE StudyPlaceboDapagliflozin5 mgDapagliflozin10 mgPlaceboDapagliflozin10 mgPlaceboDapagliflozin10 mgOverall population (%)N=13935(0.4%)N=11457(0.6%)N=11939(0.8%)N=229517(0.7%)N=236027(1.1%)N=8569207(2.4%)N=8574213 (2.5%)Patient Subgroup (%)Patients on loop diureticsn=551 (1.8%)n=400 n=313 (9.7%)n=2674 (1.5%)n=2366 (2.5%)n=93457(6.1%)n=86657(6.6%)Patients with moderate renal impairment with eGFR >=30 and <60 mL/min/1.73 m2 n=1072(1.9%)n=1071(0.9%)n=891(1.1%)n=2684(1.5%)n=2655(1.9%)n=65830(4.6%)n=60435(5.8%)Patients >=65 years of agen=2761(0.4%)n=2161(0.5%)n=2043(1.5%)n=7116(0.8%)n=66511(1.7%)n=3950121(3.1%)n=3948117(3.0%)HypoglycemiaThe frequency of hypoglycemia by study in patients with type diabetes mellitus [see Clinical Studies (14.1)] is shown in Table 4. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see Warnings and Precautions (5.4)].Table 4: Incidence of Severe HypoglycemiaSevere episodes of hypoglycemia were defined as episodes of severe impairment in consciousness or behavior, requiring external (third party) assistance, and with prompt recovery after intervention regardless of glucose level. and Hypoglycemia with Glucose 54 mg/dLEpisodes of hypoglycemia with glucose <54 mg/dL (3 mmol/L) were defined as reported episodes of hypoglycemia meeting the glucose criteria that did not also qualify as severe episode. in Controlled Glycemic Control Clinical Studies in Patients with Type Diabetes MellitusPlacebo/Active ControlDapagliflozin5 mgDapagliflozin10 mgMonotherapy (24 weeks)N=75N=64N=70 Severe [n (%)]000 Glucose <54 mg/dL [n (%)]000Add-on to Metformin (24 weeks)N=137N=137N=135 Severe [n (%)]000 Glucose <54 mg/dL [n (%)]000Add-on to Glimepiride (24 weeks)N=146N=145N=151 Severe [n (%)]000 Glucose <54 mg/dL [n (%)]1 (0.7)3 (2.1)5 (3.3)Add-on to Metformin and Sulfonylurea (24 Weeks)N=109-N=109 Severe [n (%)]0-0 Glucose <54 mg/dL [n (%)]3 (2.8)-7 (6.4)Add-on to Pioglitazone (24 weeks)N=139N=141N=140 Severe [n (%)]000 Glucose <54 mg/dL [n (%)]01 (0.7)0Add-on to DPP4 inhibitor (24 weeks)N=226-N=225 Severe [n (%)]0-1 (0.4) Glucose <54 mg/dL [n (%)]1 (0.4)-1 (0.4)Add-on to Insulin with or without other OADsOAD oral antidiabetic therapy. (24 weeks)N=197N=212N=196 Severe [n (%)]1 (0.5)2 (0.9)2 (1.0) Glucose <54 mg/dL [n (%)]43 (21.8)55 (25.9)45 (23.0)In the DECLARE study [see Clinical Studies (14.2)], severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 patients treated with dapagliflozin and 83 (1.0%) out of 8569 patients treated with placebo. Genital Mycotic InfectionsIn the glycemic control trials, genital mycotic infections were more frequent with dapagliflozin treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin mg, and 4.8% on dapagliflozin 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 2). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with history of genital mycotic infections were more likely to have genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin mg, and dapagliflozin 10 mg, respectively). In the DECLARE study [see Clinical Studies (14.2)], serious genital mycotic infections were reported in <0.1% of patients treated with dapagliflozin and <0.1% of patients treated with placebo. Genital mycotic infections that caused study drug discontinuation were reported in 0.9% of patients treated with dapagliflozin and <0.1% of patients treated with placebo. Hypersensitivity ReactionsHypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. In glycemic control studies, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of dapagliflozin-treated patients. If hypersensitivity reactions occur, discontinue use of DAPAGLIFLOZIN TABLETS; treat per standard of care and monitor until signs and symptoms resolve.Ketoacidosis in Patients with Diabetes Mellitus In the DECLARE study [see Clinical Studies (14.2)], events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 patients in the dapagliflozin-treated group and 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period. Laboratory TestsIncreases in Serum Creatinine and Decreases in eGFRInitiation of SGLT2 inhibitors, including dapagliflozin causes small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions (5.2)]. In two studies that included patients with type diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play role in the renal function changes observed with dapagliflozin.Increase in HematocritIn the pool of 13 placebo-controlled studies of glycemic control, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg-treated patients.Increase in Low-Density Lipoprotein CholesterolIn the pool of 13 placebo-controlled studies of glycemic control, changes from baseline in mean lipid values were reported in dapagliflozin-treated patients compared to placebo-treated patients. Mean percent changes from baseline at Week 24 were 0.0% versus 2.5% for total cholesterol, and -1.0% versus 2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively. In the DECLARE study [see Clinical Studies (14.2)], mean changes from baseline after years were 0.4 mg/dL versus -4.1 mg/dL for total cholesterol, and -2.5 mg/dL versus -4.4 mg/dL for LDL cholesterol, in dapagliflozin-treated and the placebo groups, respectively.Decrease in Serum BicarbonateIn study of concomitant therapy of dapagliflozin 10 mg with exenatide extended-release (on background of metformin), four patients (1.7%) on concomitant therapy had serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the dapagliflozin and exenatide-extended release treatment groups [see Warnings and Precautions (5.1)].DAPA-HF and DELIVER Heart Failure StudiesNo new adverse reactions were identified in the DAPA-HF and DELIVER heart failure studies.DAPA-CKD Chronic Kidney Disease StudyNo new adverse reactions were identified in the DAPA-CKD study in patients with chronic kidney disease.. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of dapagliflozin in patients with diabetes mellitus. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Infections: Necrotizing fasciitis of the perineum (Fourniers Gangrene), urosepsis and pyelonephritisMetabolism and Nutrition Disorders: KetoacidosisRenal and Urinary Disorders: Acute kidney injurySkin and Subcutaneous Tissue Disorders: Rash.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72-times (males) and 105-times (females) the clinical dose of 10 mg per day, based on AUC exposure. In rats, the highest dose was approximately 131-times (males) and 186-times (females) the clinical dose of 10 mg per day, based on AUC exposure.Dapagliflozin was negative in the Ames mutagenicity assay and was positive in series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations greater than or equal to 100 ug/mL. Dapagliflozin was negative for clastogenicity in series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples greater than 2100-times the clinical dose.There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent genotoxic risk to humans.Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples less than or equal to 1708-times and 998-times the maximum recommended human dose in males and females, respectively.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Sodium-glucose cotransporter (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion.Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.. 12.2 Pharmacodynamics. General. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of or 10 mg per day in patients with type diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions (6.1)]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about days for the 10 mg dose.Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type Diabetes Mellitus (T2DM) (Semi-Log Plot). Figure1. Cardiac Electrophysiology. Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15-times the recommended maximum dose) in study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum dose) of dapagliflozin in healthy subjects.. 12.3 Pharmacokinetics. Absorption. Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of 10 mg dose is 78%. Administration of dapagliflozin with high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.. Distribution. Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.. Metabolism. The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.. Elimination. Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t 1/2 for dapagliflozin is approximately 12.9 hours following single oral dose of dapagliflozin 10 mg.. Specific Populations. Renal Impairment. At steady-state (20 mg once daily dapagliflozin for days), patients with type diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100%, and 200% higher, respectively, as compared to patients with type diabetes mellitus with normal renal function. There was no meaningful difference in exposure between patients with chronic kidney disease with and without type diabetes. Higher systemic exposure of dapagliflozin in patients with type diabetes mellitus with renal impairment did not result in correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type diabetes mellitus with normal renal function.The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.2) Warnings and Precautions (5.2) Use in Specific Populations (8.6), and Clinical Studies (14)].. Hepatic Impairment. In subjects with mild and moderate hepatic impairment (Child-Pugh classes and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [see Use in Specific Populations (8.7)].. Effects of Age, Gender, Race, and Body Weight on Pharmacokinetics. Based on population pharmacokinetic analysis, age, gender, race, and body weight do not have clinically meaningful effect on the pharmacokinetics of dapagliflozin and thus, no dose adjustment is recommended.. Pediatric. Pharmacokinetics in the pediatric population has not been studied.. Drug Interactions. In Vitro Assessment of Drug Interactions. In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.. Effects of Other Drugs on Dapagliflozin. Table shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. No dose adjustments are recommended for dapagliflozin.Table 6: Effects of Coadministered Drugs on Dapagliflozin Systemic ExposureCoadministered Drug(Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)Effect on Dapagliflozin Exposure(% Change [90% CI])Cmax AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.No dosing adjustments required for the following:Oral Antidiabetic Agents Metformin (1000 mg)20 mg<-><-> Pioglitazone (45 mg)50 mg<-><-> Sitagliptin (100 mg)20 mg<-><-> Glimepiride (4 mg)20 mg<-><-> Voglibose (0.2 mg three times daily)10 mg<-><->Other Medications Hydrochlorothiazide (25 mg)50 mg<-><-> Bumetanide (1 mg)10 mg once dailyfor days<-><-> Valsartan (320 mg)20 mg12%[3%, 20%]<-> Simvastatin (40 mg)20 mg<-><->Anti-infective Agent Rifampin (600 mg once daily for days)10 mg7%[22%, 11%]22%[27%, 17%]Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every hours)10 mg13%[3%, 24%]51%[44%, 58%]<-> no change (geometric mean ratio of test: reference within 0.80 to 1.25); or parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25). Effects of Dapagliflozin on Other Drugs. Table shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.Table 7: Effects of Dapagliflozin on the Systemic Exposures of Coadministered DrugsCoadministered Drug(Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)Effect on Coadministered Drug Exposure(% Change [90% CI])Cmax AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.No dosing adjustments required for the following:Oral Antidiabetic Agents Metformin (1000 mg)20 mg<-><-> Pioglitazone (45 mg)50 mg7%[25%, 15%]<-> Sitagliptin (100 mg)20 mg<-><-> Glimepiride (4 mg)20 mg<->13%[0%, 29%]Other Medications Hydrochlorothiazide (25 mg)50 mg<-><-> Bumetanide (1 mg)10 mg once dailyfor days13%[2%, 31%]13%[1%, 30%] Valsartan (320 mg)20 mg6%[24%, 16%]5%[15%, 29%] Simvastatin (40 mg)20 mg<->19% Digoxin (0.25 mg)20 mg loading dosethen 10 mg once dailyfor days<-><-> Warfarin (25 mg)20 mg loading dosethen 10 mg once dailyfor days<-><-><-> no change (geometric mean ratio of test: reference within 0.80 to 1.25); or parameter was lower or higher, respectively, with coadministration compared to the other medicine administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. oHistory of serious hypersensitivity reaction to dapagliflozin, such as anaphylactic reactions or angioedema [see Adverse Reactions (6.1)].. oHistory of serious hypersensitivity reaction to dapagliflozin, such as anaphylactic reactions or angioedema [see Adverse Reactions (6.1)].. oHistory of serious hypersensitivity reaction to dapagliflozin. (4). oHistory of serious hypersensitivity reaction to dapagliflozin. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Dapagliflozin, an inhibitor of SGLT2, is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical formula is C21H25ClO6oC3H8O2oH2O and the molecular weight is 502.98. The structural formula is:DAPAGLIFLOZIN TABLETS are available as film-coated tablets for oral administration containing the equivalent of mg dapagliflozin as dapagliflozin propanediol or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide.. Dapagliflozin Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oAssess volume status and correct volume depletion before initiating. (2.1)eGFR (mL/min/1.73 m2)Recommended DoseeGFR 45 or greaterTo improve glycemic control, the recommended starting dose is mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control.For all other indications, the recommended starting dose is 10 mg orally once daily.eGFR 25 to less than 4510 mg orally once dailyeGFR less than 25Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF.oWithhold DAPAGLIFLOZIN TABLETS for at least days, if possible, prior to major surgery or procedures associated with prolonged fasting. (2.3). oAssess volume status and correct volume depletion before initiating. (2.1). oWithhold DAPAGLIFLOZIN TABLETS for at least days, if possible, prior to major surgery or procedures associated with prolonged fasting. (2.3). 2.1 Prior to Initiation of DAPAGLIFLOZIN TABLETS Assess renal function prior to initiation of DAPAGLIFLOZIN TABLETS therapy and then as clinically indicated [see Warnings and Precautions (5.2) ]. Assess volume status. In patients with volume depletion, correct this condition before initiating DAPAGLIFLOZIN TABLETS [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)].. 2.2 Recommended Dosage See Table for dosage recommendations based on estimated glomerular filtration rate (eGFR).Table 1: Recommended DosageeGFR (mL/min/1.73 m2)Recommended DoseeGFR 45 or greaterTo improve glycemic control, the recommended starting dose is mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic controlDAPAGLIFLOZIN TABLETS are not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. DAPAGLIFLOZIN TABLETS are likely to be ineffective in this setting based upon its mechanism of action..For all other indications, the recommended starting dose is 10 mg orally once daily.eGFR 25 to less than 4510 mg orally once daily.eGFR less than 25Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF.hHF: hospitalization for heart failure, CV: Cardiovascular, ESKD: End Stage Kidney Disease.. 2.3 Temporary Interruption for Surgery. Withhold DAPAGLIFLOZIN TABLETS for at least days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume DAPAGLIFLOZIN TABLETS when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. oDAPAGLIFLOZIN TABLETS mg are yellow, biconvex, round, film-coated tablets with 5 engraved on one side and 1427 engraved on the other side.oDAPAGLIFLOZIN TABLETS 10 mg are yellow, biconvex, diamond-shaped, film-coated tablets with 10 engraved on one side and 1428 engraved on the other side.. oDAPAGLIFLOZIN TABLETS mg are yellow, biconvex, round, film-coated tablets with 5 engraved on one side and 1427 engraved on the other side.. oDAPAGLIFLOZIN TABLETS 10 mg are yellow, biconvex, diamond-shaped, film-coated tablets with 10 engraved on one side and 1428 engraved on the other side.. oTablets: mg and 10 mg (3). oTablets: mg and 10 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Table 5: Clinically Relevant Interactions with DAPAGLIFLOZIN TABLETSInsulin or Insulin SecretagoguesClinical ImpactThe risk of hypoglycemia may be increased when DAPAGLIFLOZIN TABLETS are used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions (5.4)].InterventionConcomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.LithiumClinical ImpactConcomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.InterventionMonitor serum lithium concentration more frequently during DAPAGLIFLOZIN TABLETS initiation and dosage changes.Positive Urine Glucose TestClinical ImpactSGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.InterventionMonitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.Interference with 1,5-anhydroglucitol (1,5-AG) AssayClinical ImpactMeasurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.InterventionMonitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.. See full prescribing information for information on drug interactions and interference of DAPAGLIFLOZIN TABLETS with laboratory tests. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. No DAPAGLIFLOZIN TABLETS dosage change is recommended based on age. 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 pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control in type diabetes mellitus. 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, higher proportion of patients treated with dapagliflozin for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].In the DAPA-CKD, DAPA-HF and DELIVER studies, safety and efficacy were similar for patients age 65 years and younger and those older than 65. In the DAPA-HF study, 2714 (57%) out of 4744 patients with HFrEF were older than 65 years. In the DELIVER study, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with CKD were older than 65 years.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-7056NDC: 50090-7056-0 30 TABLET, FILM COATED in BOTTLE, PLASTIC.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DAPAGLIFLOZIN TABLETS are indicated:oTo reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.oTo reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure.oTo reduce the risk of hospitalization for heart failure in adults with type diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.oAs an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. Limitations of Use oDAPAGLIFLOZIN TABLETS are not recommended for use to improve glycemic control in patients with type diabetes mellitus [see Warnings and Precautions (5.1)].oDAPAGLIFLOZIN TABLETS are not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. DAPAGLIFLOZIN TABLETS are likely to be ineffective in this setting based upon its mechanism of action.oDAPAGLIFLOZIN TABLETS are not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with recent history of immunosuppressive therapy for kidney disease. DAPAGLIFLOZIN TABLETS are not expected to be effective in these populations.. oTo reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.. oTo reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure.. oTo reduce the risk of hospitalization for heart failure in adults with type diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.. oAs an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.. oDAPAGLIFLOZIN TABLETS are not recommended for use to improve glycemic control in patients with type diabetes mellitus [see Warnings and Precautions (5.1)].. oDAPAGLIFLOZIN TABLETS are not recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. DAPAGLIFLOZIN TABLETS are likely to be ineffective in this setting based upon its mechanism of action.. oDAPAGLIFLOZIN TABLETS are not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with recent history of immunosuppressive therapy for kidney disease. DAPAGLIFLOZIN TABLETS are not expected to be effective in these populations.. DAPAGLIFLOZIN TABLETS, sodium-glucose cotransporter (SGLT2) inhibitor, are indicated:oTo reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression. (1)oTo reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure. (1)oTo reduce the risk of hospitalization for heart failure in adults with type diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. (1)oAs an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. (1) Limitations of use:oNot recommended for use to improve glycemic control in patients with type diabetes mellitus. (1)oNot recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. DAPAGLIFLOZIN TABLETS are likely to be ineffective in this setting based upon its mechanism of action. (1)oNot recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with recent history of immunosuppressive therapy for the treatment of kidney disease. DAPAGLIFLOZIN TABLETS are not expected to be effective in these populations. (1). oTo reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression. (1). oTo reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure. (1). oTo reduce the risk of hospitalization for heart failure in adults with type diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. (1). oAs an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. (1). oNot recommended for use to improve glycemic control in patients with type diabetes mellitus. (1). oNot recommended for use to improve glycemic control in adults with type diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. DAPAGLIFLOZIN TABLETS are likely to be ineffective in this setting based upon its mechanism of action. (1). oNot recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with recent history of immunosuppressive therapy for the treatment of kidney disease. DAPAGLIFLOZIN TABLETS are not expected to be effective in these populations. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).Diabetic Ketoacidosis in Patients with Type Diabetes Mellitus and Other KetoacidosisIn patients with type diabetes mellitus, inform them that using DAPAGLIFLOZIN TABLETS can increase their risk of life-threatening diabetic ketoacidosis. For all other patients, inform them that DAPAGLIFLOZIN TABLETS can cause potentially fatal ketoacidosis and that type diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors. Educate all patients on precipitating factors (such as insulin dose reduction or missed insulin doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis.Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue DAPAGLIFLOZIN TABLETS and seek medical attention immediately [see Warnings and Precautions (5.1) ].Volume DepletionInform patients that symptomatic hypotension may occur with DAPAGLIFLOZIN TABLETS and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.2)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.Serious Urinary Tract Infections Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.3) ].Hypoglycemia with Concomitant Use with Insulin and Insulin SecretagoguesInform patients that the incidence of hypoglycemia may increase when DAPAGLIFLOZIN TABLETS are added to an insulin secretagogue (e.g., sulfonylurea) and/or insulin. Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)].Necrotizing Fasciitis of the Perineum (Fourniers Gangrene)Inform patients that necrotizing infections of the perineum (Fourniers Gangrene) have occurred with dapagliflozin in patients with diabetes mellitus. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with fever above 100.4F or malaise [see Warnings and Precautions (5.5) ].Genital Mycotic Infections in Females (e.g., Vulvovaginitis)Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6) ].Genital Mycotic Infections in Males (e.g., Balanitis)Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.6) ].Hypersensitivity ReactionsInform patients that serious hypersensitivity reactions (e.g., urticaria, anaphylactic reactions, and angioedema) have been reported with dapagliflozin. Advise patients to immediately report any signs or symptoms suggesting allergic reaction or angioedema, and to take no more of the drug until they have consulted prescribing physicians.PregnancyAdvise pregnant patients of the potential risk to fetus with treatment with DAPAGLIFLOZIN TABLETS. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see Use in Specific Populations (8.1)].LactationAdvise patients that use of DAPAGLIFLOZIN TABLETS is not recommended while breastfeeding [see Use in Specific Populations (8.2)]. Laboratory Tests Due to its mechanism of action, patients taking DAPAGLIFLOZIN TABLETS will test positive for glucose in their urine.Missed DoseIf dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of DAPAGLIFLOZIN TABLETS at the same time.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere is no information regarding the presence of dapagliflozin in human milk, the effects on the breastfed infant, or the effects 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 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 DAPAGLIFLOZIN TABLETS is not recommended while breastfeeding.DataDapagliflozin was present in rat milk at milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at 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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Sodium-glucose cotransporter (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion.Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72-times (males) and 105-times (females) the clinical dose of 10 mg per day, based on AUC exposure. In rats, the highest dose was approximately 131-times (males) and 186-times (females) the clinical dose of 10 mg per day, based on AUC exposure.Dapagliflozin was negative in the Ames mutagenicity assay and was positive in series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations greater than or equal to 100 ug/mL. Dapagliflozin was negative for clastogenicity in series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples greater than 2100-times the clinical dose.There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent genotoxic risk to humans.Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples less than or equal to 1708-times and 998-times the maximum recommended human dose in males and females, respectively.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There were no reports of overdose during the clinical development program for dapagliflozin.In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ supportive measures as dictated by the patients clinical status. The removal of dapagliflozin by hemodialysis has not been studied.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

DAPAGLIFLOZIN. Label Image.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of DAPAGLIFLOZIN TABLETS in pediatric patients under 18 years of age have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. General. Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of or 10 mg per day in patients with type diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at Week 12. near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions (6.1)]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about days for the 10 mg dose.Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type Diabetes Mellitus (T2DM) (Semi-Log Plot). Figure1. Cardiac Electrophysiology. Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15-times the recommended maximum dose) in study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum dose) of dapagliflozin in healthy subjects.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption. Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of 10 mg dose is 78%. Administration of dapagliflozin with high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.. Distribution. Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.. Metabolism. The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.. Elimination. Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t 1/2 for dapagliflozin is approximately 12.9 hours following single oral dose of dapagliflozin 10 mg.. Specific Populations. Renal Impairment. At steady-state (20 mg once daily dapagliflozin for days), patients with type diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100%, and 200% higher, respectively, as compared to patients with type diabetes mellitus with normal renal function. There was no meaningful difference in exposure between patients with chronic kidney disease with and without type diabetes. Higher systemic exposure of dapagliflozin in patients with type diabetes mellitus with renal impairment did not result in correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type diabetes mellitus with normal renal function.The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.2) Warnings and Precautions (5.2) Use in Specific Populations (8.6), and Clinical Studies (14)].. Hepatic Impairment. In subjects with mild and moderate hepatic impairment (Child-Pugh classes and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [see Use in Specific Populations (8.7)].. Effects of Age, Gender, Race, and Body Weight on Pharmacokinetics. Based on population pharmacokinetic analysis, age, gender, race, and body weight do not have clinically meaningful effect on the pharmacokinetics of dapagliflozin and thus, no dose adjustment is recommended.. Pediatric. Pharmacokinetics in the pediatric population has not been studied.. Drug Interactions. In Vitro Assessment of Drug Interactions. In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.. Effects of Other Drugs on Dapagliflozin. Table shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. No dose adjustments are recommended for dapagliflozin.Table 6: Effects of Coadministered Drugs on Dapagliflozin Systemic ExposureCoadministered Drug(Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)Effect on Dapagliflozin Exposure(% Change [90% CI])Cmax AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.No dosing adjustments required for the following:Oral Antidiabetic Agents Metformin (1000 mg)20 mg<-><-> Pioglitazone (45 mg)50 mg<-><-> Sitagliptin (100 mg)20 mg<-><-> Glimepiride (4 mg)20 mg<-><-> Voglibose (0.2 mg three times daily)10 mg<-><->Other Medications Hydrochlorothiazide (25 mg)50 mg<-><-> Bumetanide (1 mg)10 mg once dailyfor days<-><-> Valsartan (320 mg)20 mg12%[3%, 20%]<-> Simvastatin (40 mg)20 mg<-><->Anti-infective Agent Rifampin (600 mg once daily for days)10 mg7%[22%, 11%]22%[27%, 17%]Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every hours)10 mg13%[3%, 24%]51%[44%, 58%]<-> no change (geometric mean ratio of test: reference within 0.80 to 1.25); or parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25). Effects of Dapagliflozin on Other Drugs. Table shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.Table 7: Effects of Dapagliflozin on the Systemic Exposures of Coadministered DrugsCoadministered Drug(Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)Effect on Coadministered Drug Exposure(% Change [90% CI])Cmax AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.No dosing adjustments required for the following:Oral Antidiabetic Agents Metformin (1000 mg)20 mg<-><-> Pioglitazone (45 mg)50 mg7%[25%, 15%]<-> Sitagliptin (100 mg)20 mg<-><-> Glimepiride (4 mg)20 mg<->13%[0%, 29%]Other Medications Hydrochlorothiazide (25 mg)50 mg<-><-> Bumetanide (1 mg)10 mg once dailyfor days13%[2%, 31%]13%[1%, 30%] Valsartan (320 mg)20 mg6%[24%, 16%]5%[15%, 29%] Simvastatin (40 mg)20 mg<->19% Digoxin (0.25 mg)20 mg loading dosethen 10 mg once dailyfor days<-><-> Warfarin (25 mg)20 mg loading dosethen 10 mg once dailyfor days<-><-><-> no change (geometric mean ratio of test: reference within 0.80 to 1.25); or parameter was lower or higher, respectively, with coadministration compared to the other medicine administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25).

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary. Based on animal data showing adverse renal effects, DAPAGLIFLOZIN TABLETS are not recommended during the second and third trimesters of pregnancy.Limited data with dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure 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 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 to 10% in women with pre-gestational diabetes with 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryofetal riskPoorly 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.DataAnimal DataDapagliflozin 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 1-month recovery period.In prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 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 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).

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1) 09/2023Dosage and Administration (2.3) 09/2023Warnings and Precautions (5.1) 09/2023.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEDAPAGLIFLOZIN [dap-a-gli-FLO-zin] TABLETSfor oral useWhat is the most important information should know about DAPAGLIFLOZIN TABLETSDAPAGLIFLOZIN TABLETS can cause serious side effects, including:oDiabetic ketoacidosis (increased ketones in your blood or urine) in people with type diabetes and other ketoacidosis. DAPAGLIFLOZIN TABLETS can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is serious condition which needs to be treated in hospital. People with type diabetes have high risk of getting ketoacidosis. People with type diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have loss of too much fluid from the body (volume depletion), or who have surgery. Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your healthcare provider may ask you to periodically check ketones in your urine or blood. Stop taking DAPAGLIFLOZIN TABLETS and call your healthcare provider or get medical help right away if you get any of the following. If possible, check for ketones in your urine or blood, even if your blood sugar is less than 250 mg/dL.onauseaovomitingostomach area (abdominal) painotiredness otrouble breathingoketones in your urine or bloodoDehydration. DAPAGLIFLOZIN TABLETS can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden kidney injury in people with Type diabetes who are taking DAPAGLIFLOZIN TABLETS. You may be at higher risk of dehydration if you:take medicines to lower your blood pressure, including water pills (diuretics)are on low salt diethave kidney problems are 65 years of age or older Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on daily basis. Call your healthcare provider right away if you reduce the amount of food or liquid you drink, for example if you cannot eat or you start to lose liquids from your body, for example from vomiting, diarrhea, or being in the sun too long. oVaginal yeast infection. Women who take DAPAGLIFLOZIN TABLETS may get vaginal yeast infections. Symptoms of vaginal yeast infection include:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itching oYeast infection of the penis (balanitis). Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:redness, itching, or swelling of the penisfoul smelling discharge from the penisrash of the penispain in the skin around the penis Talk to your healthcare provider about what to do if you get symptoms of yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away.What are DAPAGLIFLOZIN TABLETSoDAPAGLIFLOZIN TABLETS are prescription medicine used:to reduce the risk of further worsening of your kidney disease, end-stage kidney disease (ESKD), death due to cardiovascular disease, and hospitalization for heart failure in adults with chronic kidney diseaseto reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visit in adults with heart failure, when the heart cannot pump enough blood to the rest of your bodyto reduce the risk of hospitalization for heart failure in adults with type diabetes who also have known cardiovascular disease or multiple cardiovascular risk factorsalong with diet and exercise to improve blood sugar (glucose) control in adults with type diabetes.oDAPAGLIFLOZIN TABLETS are not for use to improve blood sugar (glucose) control in people with type diabetes.oDAPAGLIFLOZIN TABLETS are not for use to improve blood sugar (glucose) control in adults with type diabetes who have moderate to severe kidney problems, because it may not work.oDAPAGLIFLOZIN TABLETS are not for people with certain genetic forms of polycystic kidney disease, or who are taking or have recently received immunosuppressive therapy to treat kidney disease. DAPAGLIFLOZIN TABLETS are not expected to work if you have these conditions.oIt is not known if DAPAGLIFLOZIN TABLETS are safe and effective in children younger than 18 years of age.Who should not take DAPAGLIFLOZIN TABLETSDo not take DAPAGLIFLOZIN TABLETS if you:oare allergic to dapagliflozin or any of the ingredients in DAPAGLIFLOZIN TABLETS. See the end of this Medication Guide for list of ingredients in DAPAGLIFLOZIN TABLETS. Symptoms of serious allergic reaction to DAPAGLIFLOZIN TABLETS may include:rashraised red patches on your skin (hives)swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing. If you have any of these symptoms, stop taking DAPAGLIFLOZIN TABLETS and contact your healthcare provider or go to the nearest hospital emergency room right away.What should tell my healthcare provider before taking DAPAGLIFLOZIN TABLETSBefore you take DAPAGLIFLOZIN TABLETS, tell your healthcare provider if you:ohave type diabetes or have had diabetic ketoacidosis.ohave decrease in your insulin dose.ohave serious infection.ohave history of infection of the vagina or penis.ohave liver problems.ohave history of urinary tract infections or problems with urination.oare on low sodium (salt) diet. Your healthcare provider may ask you to change your diet.oare going to have surgery. Your healthcare provider may stop your DAPAGLIFLOZIN TABLETS before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking DAPAGLIFLOZIN TABLETS and when to start it again. oare eating less or there is change in your diet.oare dehydrated.ohave or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.odrink alcohol very often or drink lot of alcohol in the short term (binge drinking).oare pregnant or plan to become pregnant. DAPAGLIFLOZIN TABLETS may harm your unborn baby. If you become pregnant while taking DAPAGLIFLOZIN TABLETS, your healthcare provider may switch you to different medicine to control your blood sugar. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.oare breastfeeding or plan to breastfeed. It is not known if dapagliflozin passes into your breast milk. You should not breastfeed if you take DAPAGLIFLOZIN TABLETS.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.DAPAGLIFLOZIN TABLETS may affect the way other medicines work, and other medicines may affect how DAPAGLIFLOZIN TABLETS work. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take DAPAGLIFLOZIN TABLETSoTake DAPAGLIFLOZIN TABLETS exactly as your healthcare provider tells you to take it.oTake DAPAGLIFLOZIN TABLETS by mouth time each day, with or without food.oYour healthcare provider will tell you how much DAPAGLIFLOZIN TABLETS to take and when to take it. Your healthcare provider may change your dose if needed.oIf you miss dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take doses of DAPAGLIFLOZIN TABLETS at the same time. Talk with your healthcare provider if you have questions about missed dose.oIf you take too much DAPAGLIFLOZIN TABLETS, call your healthcare provider or go to the nearest emergency room right away.oIf you have diabetes:When your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare providers instructions.Your healthcare provider may tell you to take DAPAGLIFLOZIN TABLETS along with other diabetes medicines. Low blood sugar can happen more often when DAPAGLIFLOZIN TABLETS are taken with certain other diabetes medicines. See What are the possible side effects of DAPAGLIFLOZIN TABLETS.oDAPAGLIFLOZIN TABLETS will cause your urine to test positive for glucose.oYour healthcare provider may do certain blood tests before you start DAPAGLIFLOZIN TABLETS and during treatment as needed. Your healthcare provider may change your dose of DAPAGLIFLOZIN TABLETS based on the results of your blood tests.What are the possible side effects of DAPAGLIFLOZIN TABLETSDAPAGLIFLOZIN TABLETS may cause serious side effects, including:See What is the most important information should know about DAPAGLIFLOZIN TABLETS.oSerious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking DAPAGLIFLOZIN TABLETS. Tell your healthcare provider if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting.oLow blood sugar (hypoglycemia) in patients with diabetes mellitus. If you take DAPAGLIFLOZIN TABLETS with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take DAPAGLIFLOZIN TABLETS. Signs and symptoms of low blood sugar may include: headacheconfusionhungershaking or feeling jitterydrowsinessdizzinessfast heartbeatweaknesssweatingirritabilityoA rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men with diabetes mellitus who take DAPAGLIFLOZIN TABLETS. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention right away if you have fever or you are feeling very weak, tired, or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals: pain or tenderness swelling redness of skin (erythema) oSerious allergic reaction. If you have any symptoms of serious allergic reaction, stop taking DAPAGLIFLOZIN TABLETS and call your healthcare provider right away or go to the nearest hospital emergency room. See Who should not take DAPAGLIFLOZIN TABLETS. Your healthcare provider may give you medicine for your allergic reaction and prescribe different medicine for your diabetes.The most common side effects of DAPAGLIFLOZIN TABLETS include:ovaginal yeast infections and yeast infections of the penis ostuffy or runny nose and sore throatochanges in urination, including urgent need to urinate more often, in larger amounts, or at nightThese are not all the possible side effects of DAPAGLIFLOZIN TABLETS. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store DAPAGLIFLOZIN TABLETSStore DAPAGLIFLOZIN TABLETS at room temperature between 68F and 77F (20C and 25C).General information about the safe and effective use of DAPAGLIFLOZIN TABLETSMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use DAPAGLIFLOZIN TABLETS for condition for which it is not prescribed. Do not give DAPAGLIFLOZIN TABLETS to other people, even if they have the same symptoms you have. It may harm them.This Medication Guide summarizes the most important information about DAPAGLIFLOZIN TABLETS. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about DAPAGLIFLOZIN TABLETS that is written for healthcare professionals.For more information about DAPAGLIFLOZIN TABLETS, call 1-866-525-0688.What are the ingredients in DAPAGLIFLOZIN TABLETSActive ingredient: dapagliflozin.Inactive ingredients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate. The film coating contains: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide.Distributed by: Prasco Laboratories Mason, OH 45040 USAThis Medication Guide has been approved by the U.S. Food and Drug Administration. Revised 09/2023. oDiabetic ketoacidosis (increased ketones in your blood or urine) in people with type diabetes and other ketoacidosis. DAPAGLIFLOZIN TABLETS can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is serious condition which needs to be treated in hospital. People with type diabetes have high risk of getting ketoacidosis. People with type diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have loss of too much fluid from the body (volume depletion), or who have surgery. Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your healthcare provider may ask you to periodically check ketones in your urine or blood. Stop taking DAPAGLIFLOZIN TABLETS and call your healthcare provider or get medical help right away if you get any of the following. If possible, check for ketones in your urine or blood, even if your blood sugar is less than 250 mg/dL.. onausea. ovomiting. ostomach area (abdominal) pain. otiredness otrouble breathing. oketones in your urine or blood. oDehydration. DAPAGLIFLOZIN TABLETS can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden kidney injury in people with Type diabetes who are taking DAPAGLIFLOZIN TABLETS. You may be at higher risk of dehydration if you:take medicines to lower your blood pressure, including water pills (diuretics)are on low salt diethave kidney problems are 65 years of age or older take medicines to lower your blood pressure, including water pills (diuretics). are on low salt diet. have kidney problems are 65 years of age or older. Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on daily basis. Call your healthcare provider right away if you reduce the amount of food or liquid you drink, for example if you cannot eat or you start to lose liquids from your body, for example from vomiting, diarrhea, or being in the sun too long.. oVaginal yeast infection. Women who take DAPAGLIFLOZIN TABLETS may get vaginal yeast infections. Symptoms of vaginal yeast infection include:vaginal odorwhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)vaginal itching vaginal odor. white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese). vaginal itching. oYeast infection of the penis (balanitis). Swelling of an uncircumcised penis may develop that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:redness, itching, or swelling of the penisfoul smelling discharge from the penisrash of the penispain in the skin around the penis redness, itching, or swelling of the penis. foul smelling discharge from the penis. rash of the penis. pain in the skin around the penis. Talk to your healthcare provider about what to do if you get symptoms of yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away.. oDAPAGLIFLOZIN TABLETS are prescription medicine used:to reduce the risk of further worsening of your kidney disease, end-stage kidney disease (ESKD), death due to cardiovascular disease, and hospitalization for heart failure in adults with chronic kidney diseaseto reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visit in adults with heart failure, when the heart cannot pump enough blood to the rest of your bodyto reduce the risk of hospitalization for heart failure in adults with type diabetes who also have known cardiovascular disease or multiple cardiovascular risk factorsalong with diet and exercise to improve blood sugar (glucose) control in adults with type diabetes.. to reduce the risk of further worsening of your kidney disease, end-stage kidney disease (ESKD), death due to cardiovascular disease, and hospitalization for heart failure in adults with chronic kidney disease. to reduce the risk of cardiovascular death, hospitalization for heart failure and urgent heart failure visit in adults with heart failure, when the heart cannot pump enough blood to the rest of your body. to reduce the risk of hospitalization for heart failure in adults with type diabetes who also have known cardiovascular disease or multiple cardiovascular risk factors. along with diet and exercise to improve blood sugar (glucose) control in adults with type diabetes.. oDAPAGLIFLOZIN TABLETS are not for use to improve blood sugar (glucose) control in people with type diabetes.. oDAPAGLIFLOZIN TABLETS are not for use to improve blood sugar (glucose) control in adults with type diabetes who have moderate to severe kidney problems, because it may not work.. oDAPAGLIFLOZIN TABLETS are not for people with certain genetic forms of polycystic kidney disease, or who are taking or have recently received immunosuppressive therapy to treat kidney disease. DAPAGLIFLOZIN TABLETS are not expected to work if you have these conditions.. oIt is not known if DAPAGLIFLOZIN TABLETS are safe and effective in children younger than 18 years of age.. oare allergic to dapagliflozin or any of the ingredients in DAPAGLIFLOZIN TABLETS. See the end of this Medication Guide for list of ingredients in DAPAGLIFLOZIN TABLETS. Symptoms of serious allergic reaction to DAPAGLIFLOZIN TABLETS may include:rashraised red patches on your skin (hives)swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing. rash. raised red patches on your skin (hives). swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing.. If you have any of these symptoms, stop taking DAPAGLIFLOZIN TABLETS and contact your healthcare provider or go to the nearest hospital emergency room right away.. ohave type diabetes or have had diabetic ketoacidosis.. ohave decrease in your insulin dose.. ohave serious infection.. ohave history of infection of the vagina or penis.. ohave liver problems.. ohave history of urinary tract infections or problems with urination.. oare on low sodium (salt) diet. Your healthcare provider may ask you to change your diet.. oare going to have surgery. Your healthcare provider may stop your DAPAGLIFLOZIN TABLETS before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking DAPAGLIFLOZIN TABLETS and when to start it again. oare eating less or there is change in your diet.. oare dehydrated.. ohave or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.. odrink alcohol very often or drink lot of alcohol in the short term (binge drinking).. oare pregnant or plan to become pregnant. DAPAGLIFLOZIN TABLETS may harm your unborn baby. If you become pregnant while taking DAPAGLIFLOZIN TABLETS, your healthcare provider may switch you to different medicine to control your blood sugar. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.. oare breastfeeding or plan to breastfeed. It is not known if dapagliflozin passes into your breast milk. You should not breastfeed if you take DAPAGLIFLOZIN TABLETS.. oTake DAPAGLIFLOZIN TABLETS exactly as your healthcare provider tells you to take it.. oTake DAPAGLIFLOZIN TABLETS by mouth time each day, with or without food.. oYour healthcare provider will tell you how much DAPAGLIFLOZIN TABLETS to take and when to take it. Your healthcare provider may change your dose if needed.. oIf you miss dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take doses of DAPAGLIFLOZIN TABLETS at the same time. Talk with your healthcare provider if you have questions about missed dose.. oIf you take too much DAPAGLIFLOZIN TABLETS, call your healthcare provider or go to the nearest emergency room right away.. oIf you have diabetes:When your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare providers instructions.Your healthcare provider may tell you to take DAPAGLIFLOZIN TABLETS along with other diabetes medicines. Low blood sugar can happen more often when DAPAGLIFLOZIN TABLETS are taken with certain other diabetes medicines. See What are the possible side effects of DAPAGLIFLOZIN TABLETS.. When your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare providers instructions.. Your healthcare provider may tell you to take DAPAGLIFLOZIN TABLETS along with other diabetes medicines. Low blood sugar can happen more often when DAPAGLIFLOZIN TABLETS are taken with certain other diabetes medicines. See What are the possible side effects of DAPAGLIFLOZIN TABLETS.. oDAPAGLIFLOZIN TABLETS will cause your urine to test positive for glucose.. oYour healthcare provider may do certain blood tests before you start DAPAGLIFLOZIN TABLETS and during treatment as needed. Your healthcare provider may change your dose of DAPAGLIFLOZIN TABLETS based on the results of your blood tests.. oSerious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking DAPAGLIFLOZIN TABLETS. Tell your healthcare provider if you have any signs or symptoms of urinary tract infection such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting.. oLow blood sugar (hypoglycemia) in patients with diabetes mellitus. If you take DAPAGLIFLOZIN TABLETS with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take DAPAGLIFLOZIN TABLETS. Signs and symptoms of low blood sugar may include: . . headache. confusion. hunger. shaking or feeling jittery. drowsiness. dizziness. fast heartbeat. weakness. sweating. irritability. oA rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men with diabetes mellitus who take DAPAGLIFLOZIN TABLETS. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention right away if you have fever or you are feeling very weak, tired, or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals: pain or tenderness pain or tenderness. swelling swelling. redness of skin (erythema) redness of skin (erythema). oSerious allergic reaction. If you have any symptoms of serious allergic reaction, stop taking DAPAGLIFLOZIN TABLETS and call your healthcare provider right away or go to the nearest hospital emergency room. See Who should not take DAPAGLIFLOZIN TABLETS. Your healthcare provider may give you medicine for your allergic reaction and prescribe different medicine for your diabetes.. ovaginal yeast infections and yeast infections of the penis ostuffy or runny nose and sore throat. ochanges in urination, including urgent need to urinate more often, in larger amounts, or at night.

SPL UNCLASSIFIED SECTION.

2.1 Prior to Initiation of DAPAGLIFLOZIN TABLETS Assess renal function prior to initiation of DAPAGLIFLOZIN TABLETS therapy and then as clinically indicated [see Warnings and Precautions (5.2) ]. Assess volume status. In patients with volume depletion, correct this condition before initiating DAPAGLIFLOZIN TABLETS [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters. (8.1) oLactation: Not recommended when breastfeeding. (8.2) oGeriatrics: Higher incidence of adverse reactions related to hypotension. (8.5)oRenal Impairment: Higher incidence of adverse reactions related to volume depletion. (8.6). oPregnancy: Advise females of the potential risk to fetus especially during the second and third trimesters. (8.1) oLactation: Not recommended when breastfeeding. (8.2) oGeriatrics: Higher incidence of adverse reactions related to hypotension. (8.5). oRenal Impairment: Higher incidence of adverse reactions related to volume depletion. (8.6). 8.1 Pregnancy. Risk Summary. Based on animal data showing adverse renal effects, DAPAGLIFLOZIN TABLETS are not recommended during the second and third trimesters of pregnancy.Limited data with dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure 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 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 to 10% in women with pre-gestational diabetes with 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-associated maternal and/or embryofetal riskPoorly 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.DataAnimal DataDapagliflozin 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 1-month recovery period.In prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 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 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).. 8.2 Lactation Risk SummaryThere is no information regarding the presence of dapagliflozin in human milk, the effects on the breastfed infant, or the effects 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 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 DAPAGLIFLOZIN TABLETS is not recommended while breastfeeding.DataDapagliflozin was present in rat milk at milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at 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.. 8.4 Pediatric Use. Safety and effectiveness of DAPAGLIFLOZIN TABLETS in pediatric patients under 18 years of age have not been established.. 8.5 Geriatric Use. No DAPAGLIFLOZIN TABLETS dosage change is recommended based on age. 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 pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control in type diabetes mellitus. 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, higher proportion of patients treated with dapagliflozin for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].In the DAPA-CKD, DAPA-HF and DELIVER studies, safety and efficacy were similar for patients age 65 years and younger and those older than 65. In the DAPA-HF study, 2714 (57%) out of 4744 patients with HFrEF were older than 65 years. In the DELIVER study, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with CKD were older than 65 years.. 8.6 Renal Impairment. Dapagliflozin was evaluated in 4304 patients with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m2) in the DAPA-CKD study. Dapagliflozin 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 in these studies was consistent with the known safety profile [see Adverse Reactions (6.1) and Clinical Studies (14.3 and 14.4)]. Dapagliflozin was evaluated in two glycemic control studies that included patients with type diabetes mellitus with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2 [see Clinical Studies (14.1)], and an eGFR of 30 to less than 60 mL/min/1.73 m2, respectively). Patients with diabetes and renal impairment using dapagliflozin 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. Use of DAPAGLIFLOZIN TABLETS 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 (2.2)].Efficacy and safety studies with dapagliflozin did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis.. 8.7 Hepatic Impairment. No dose adjustment is recommended for patients with mild, moderate, or severe hepatic impairment. However, the benefit-risk for the use of dapagliflozin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of dapagliflozin have not been specifically studied in this population [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oDiabetic Ketoacidosis in Patients with Type Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients with type diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue DAPAGLIFLOZIN TABLETS if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.1) oVolume depletion: Before initiating DAPAGLIFLOZIN TABLETS, assess volume status and renal function in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.2)oUrosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.3) oHypoglycemia: Consider lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with DAPAGLIFLOZIN TABLETS. (5.4) oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in patients with diabetes, both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.5) oGenital Mycotic Infections: Monitor and treat if indicated. (5.6) oDiabetic Ketoacidosis in Patients with Type Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients with type diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue DAPAGLIFLOZIN TABLETS if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.1) oVolume depletion: Before initiating DAPAGLIFLOZIN TABLETS, assess volume status and renal function in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.2). oUrosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.3) oHypoglycemia: Consider lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with DAPAGLIFLOZIN TABLETS. (5.4) oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in patients with diabetes, both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.5) oGenital Mycotic Infections: Monitor and treat if indicated. (5.6) 5.1 Diabetic Ketoacidosis in Patients with Type Diabetes Mellitus and Other Ketoacidosis. In patients with type diabetes mellitus, dapagliflozin significantly increases the risk of diabetic ketoacidosis, life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium-glucose cotransporter (SGLT2) inhibitors compared to patients who received placebo. DAPAGLIFLOZIN TABLETS are not indicated for glycemic control in patients with type diabetes mellitus. Type diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type diabetes mellitus using SGLT2 inhibitors, including dapagliflozin.Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for days after discontinuing DAPAGLIFLOZIN TABLETS [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than days and some up to weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients with type diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue DAPAGLIFLOZIN TABLETS, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting DAPAGLIFLOZIN TABLETS.Withhold DAPAGLIFLOZIN TABLETS, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume DAPAGLIFLOZIN TABLETS when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.3)].Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue DAPAGLIFLOZIN TABLETS and seek medical attention immediately if signs and symptoms occur.. 5.2 Volume Depletion. Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating DAPAGLIFLOZIN TABLETS in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension, and renal function after initiating therapy.. 5.3 Urosepsis and Pyelonephritis Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6) ].. 5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues. Insulin and insulin secretagogues are known to cause hypoglycemia. DAPAGLIFLOZIN TABLETS may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with DAPAGLIFLOZIN TABLETS.. 5.5 Necrotizing Fasciitis of the Perineum (Fourniers Gangrene) Reports of necrotizing fasciitis of the perineum (Fourniers Gangrene), rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.Patients treated with DAPAGLIFLOZIN TABLETS presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue DAPAGLIFLOZIN TABLETS, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.. 5.6 Genital Mycotic Infections. Dapagliflozin increases the risk of genital mycotic infections. Patients with history of genital mycotic infections were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.