CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Glycemic Efficacy Trials. Saxagliptin has been studied as monotherapy and in combination with metformin, glyburide, and thiazolidinedione (pioglitazone and rosiglitazone) therapy.A total of 4,148 patients with type diabetes mellitus were randomized in six, double-blind, controlled clinical trials conducted to evaluate the safety and glycemic efficacy of saxagliptin. total of 3,021 patients in these trials were treated with saxagliptin. In these trials, the mean age was 54 years, and 71% of patients were Caucasian, 16% were Asian, 4% were black, and 9% were of other racial groups. An additional 423 patients, including 315 who received saxagliptin, participated in placebo-controlled, dose-ranging study of to 12 weeks in duration.In these six, double-blind trials, saxagliptin was evaluated at doses of 2.5 mg and mg once daily. Three of these trials also evaluated an saxagliptin dose of 10 mg daily. The 10 mg daily dose of saxagliptin did not provide greater efficacy than the mg daily dose. The 10 mg dosage is not an approved dosage. Treatment with saxagliptin mg and 2.5 mg doses produced clinically relevant and statistically significant improvements in A1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following standard oral glucose tolerance test (OGTT), compared to control. Reductions in A1C were seen across subgroups including gender, age, race, and baseline BMI.Saxagliptin was not associated with significant changes from baseline in body weight or fasting serum lipids compared to placebo.Saxagliptin has also been evaluated in five additional trials in patients with type diabetes: an active-controlled trial comparing add-on therapy with saxagliptin to glipizide in 858 patients inadequately controlled on metformin alone, trial comparing saxagliptin to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin, trial comparing saxagliptin to placebo in 257 patients inadequately controlled on metformin plus sulfonylurea, trial comparing saxagliptin to placebo in 315 patients inadequately controlled on dapagliflozin and metformin, and trial comparing saxagliptin to placebo in 170 patients with type diabetes and moderate or severe renal impairment or ESRD.MonotherapyA total of 766 patients with type diabetes inadequately controlled on diet and exercise (A1C >= 7% to <= 10%) participated in two 24-week, double-blind, placebo-controlled trials evaluating the efficacy and safety of saxagliptin monotherapy.In the first trial, following 2-week single-blind diet, exercise, and placebo lead-in period, 401 patients were randomized to 2.5 mg, mg, or 10 mg of saxagliptin or placebo. The 10 mg dosage is not an approved dosage. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy, added on to placebo or saxagliptin. Efficacy was evaluated at the last measurement prior to rescue therapy for patients needing rescue. Dose titration of saxagliptin was not permitted.Treatment with saxagliptin 2.5 mg and mg daily provided significant improvements in A1C, FPG, and PPG compared to placebo (Table 4). The percentage of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 16% in the saxagliptin 2.5 mg treatment group, 20% in the saxagliptin mg treatment group, and 26% in the placebo group).Table 4: Glycemic Parameters at Week 24 in Placebo-Controlled Study of Saxagliptin Monotherapy in Patients with Type Diabetes Efficacy ParameterSaxagliptin2.5 mgN=102Saxagliptin5 mgN=106PlaceboN=95Hemoglobin A1C (%)N=100N=103N=92Baseline (mean)7.98.07.9Change from baseline (adjusted mean+)-0.4-0.5+0.2Difference from placebo (adjusted mean+)-0.6 -0.6 95% Confidence Interval(-0.9, -0.3)(-0.9, -0.4)Percent of patients achieving A1C 7%35% (35/100)38%(39/103)24% (22/92)Fasting Plasma Glucose (mg/dL)N=101N=105N=92Baseline (mean)178171172Change from baseline (adjusted mean+)-15-9+6Difference from placebo (adjusted mean+)-21 -15 95% Confidence Interval(-31, -10)(-25, -4)2-hour Postprandial Glucose (mg/dL)N=78N=84N=71Baseline (mean)279278283Change from baseline (adjusted mean+)-45-43-6Difference from placebo (adjusted mean+)-39 -37 95% Confidence Interval(-61, -16)(-59, -15) Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue.+ Least squares mean adjusted for baseline value. p-value 0.0001 compared to placebo. p-value 0.05 compared to placebo.Significance was not tested for the 2-hour PPG for the 2.5 mg dose of saxagliptin.A second 24-week monotherapy trial was conducted to assess range of dosing regimens for saxagliptin. Treatment-naive patients with inadequately controlled diabetes (A1C >= 7% to <= 10%) underwent 2-week, single-blind diet, exercise, and placebo lead-in period. total of 365 patients were randomized to 2.5 mg every morning, mg every morning, 2.5 mg with possible titration to mg every morning, or mg every evening of saxagliptin, or placebo. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy added on to placebo or saxagliptin; the number of patients randomized per treatment group ranged from 71 to 74.Treatment with either saxagliptin mg every morning or mg every evening provided significant improvements in A1C versus placebo (mean placebo-corrected reductions of -0.4% and -0.3%, respectively). Treatment with saxagliptin 2.5 mg every morning also provided significant improvement in A1C versus placebo (mean placebo-corrected reduction of -0.4%).Combination TherapyAdd-On Combination Therapy with MetforminA total of 743 patients with type diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with metformin in patients with inadequate glycemic control (A1C >= 7% and <= 10%) on metformin alone. To qualify for enrollment, patients were required to be on stable dose of metformin (1,500 to 2,550 mg daily) for at least weeks.Patients who met eligibility criteria were enrolled in single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin at their pre-study dose, up to 2500 mg daily. Following the lead-in period, eligible patients were randomized to 2.5 mg, mg, or 10 mg of saxagliptin or placebo in addition to their current dose of open-label metformin. The 10 mg dosage is not an approved dosage. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue therapy, added on to existing study medications. Dose titrations of saxagliptin and metformin were not permitted.Saxagliptin 2.5 mg and mg add-on to metformin provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin (Table 5). Mean changes from baseline for A1C over time and at endpoint are shown in Figure 1. The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 15% in the saxagliptin 2.5 mg add-on to metformin group, 13% in the saxagliptin mg add-on to metformin group, and 27% in the placebo add-on to metformin group.Table 5: Glycemic Parameters at Week 24 in Placebo-Controlled Study of Saxagliptin as Add-On Combination Therapy with Metformin Efficacy ParameterSaxagliptin 2.5 mg Metformin N=192Saxagliptin mg Metformin N=191Placebo Metformin N=179Hemoglobin A1C (%)N=186N=186N=175Baseline (mean)8.18.18.1Change from baseline (adjusted mean+)-0.6-0.7+0.1Difference from placebo (adjusted mean+)-0.7 -0.8 95% Confidence Interval(-0.9, -0.5)(-1.0, -0.6)Percent of patients achieving A1C 7%37%(69/186)44%(81/186)17% (29/175)Fasting Plasma Glucose (mg/dL)N=188N=187N=176Baseline (mean)174179175Change from baseline (adjusted mean+)-14-22+1Difference from placebo (adjusted mean+)-16 -23 95% Confidence Interval(-23, -9)(-30, -16)2-hour Postprandial Glucose (mg/dL)N=155N=155N=135Baseline (mean)294296295Change from baseline (adjusted mean+)-62-58-18Difference from placebo (adjusted mean+)-44 -40 95% Confidence Interval(-60, -27)(-56, -24)Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue.+Least squares mean adjusted for baseline value.p-value 0.0001 compared to placebo metformin.p-value 0.05 compared to placebo metformin.Figure 1: Mean Change from Baseline in A1C in Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin Includes patients with baseline and week 24 value.Week 24 (LOCF) includes intent-to-treat population using last observation on study prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value.Add-On Combination Therapy with ThiazolidinedioneA total of 565 patients with type diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with thiazolidinedione (TZD) in patients with inadequate glycemic control (A1C >= 7% to <= 10.5%) on TZD alone. To qualify for enrollment, patients were required to be on stable dose of pioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once daily or mg either once daily or in two divided doses of mg) for at least 12 weeks.Patients who met eligibility criteria were enrolled in single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received TZD at their pre-study dose. Following the lead-in period, eligible patients were randomized to 2.5 mg or mg of saxagliptin or placebo in addition to their current dose of TZD. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue, added on to existing study medications. Dose titration of saxagliptin or TZD was not permitted during the study. change in TZD regimen from rosiglitazone to pioglitazone at specified, equivalent therapeutic doses was permitted at the investigators discretion if believed to be medically appropriate.Saxagliptin 2.5 mg and mg add-on to TZD provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to TZD (Table 6). The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 10% in the saxagliptin 2.5 mg add-on to TZD group, 6% for the saxagliptin mg add-on to TZD group, and 10% in the placebo add-on to TZD group.Table 6: Glycemic Parameters at Week 24 in Placebo-Controlled Study of Saxagliptin as Add-On Combination Therapy with Thiazolidinedione Efficacy ParameterSaxagliptin 2.5 mg TZD N=195Saxagliptin mg TZD N=186Placebo TZD N=184Hemoglobin A1C (%)N=192N=183N=180Baseline (mean)8.38.48.2Change from baseline (adjusted mean+)-0.7-0.9-0.3Difference from placebo (adjusted mean+)-0.4 -0.6 95% Confidence Interval(-0.6, -0.2)(-0.8, -0.4)Percent of patients achieving A1C 7%42%(81/192)42%(77/184)26% (46/180)Fasting Plasma Glucose (mg/dL)N=193N=185N=181Baseline (mean)163160162Change from baseline (adjusted mean+)-14-17-3Difference from placebo (adjusted mean+)-12 -15 95% Confidence Interval(-20, -3)(-23, -6)2-hour Postprandial Glucose (mg/dL)N=156N=134N=127Baseline (mean)296303291Change from baseline (adjusted mean+)-55-65-15Difference from placebo (adjusted mean+)-40 -50 95% Confidence Interval(-56, -24)(-66, -34)Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue.+Least squares mean adjusted for baseline value.p-value 0.0001 compared to placebo TZD.p-value 0.05 compared to placebo TZD.Add-On Combination Therapy with GlyburideA total of 768 patients with type diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with sulfonylurea (SU) in patients with inadequate glycemic control at enrollment (A1C >= 7.5% to <= 10%) on submaximal dose of SU alone. To qualify for enrollment, patients were required to be on submaximal dose of SU for months or greater. In this study, saxagliptin in combination with fixed, intermediate dose of SU was compared to titration to higher dose of SU.Patients who met eligibility criteria were enrolled in single-blind, 4-week, dietary and exercise lead-in period, and placed on glyburide 7.5 mg once daily. Following the lead-in period, eligible patients with A1C >= 7% to <= 10% were randomized to either 2.5 mg or mg of saxagliptin add-on to 7.5 mg glyburide or to placebo plus 10 mg total daily dose of glyburide. Patients who received placebo were eligible to have glyburide up-titrated to total daily dose of 15 mg. Up-titration of glyburide was not permitted in patients who received saxagliptin 2.5 mg or mg. Glyburide could be down-titrated in any treatment group once during the 24-week study period due to hypoglycemia as deemed necessary by the investigator. Approximately 92% of patients in the placebo plus glyburide group were up-titrated to final total daily dose of 15 mg during the first weeks of the study period. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue, added on to existing study medication. Dose titration of saxagliptin was not permitted during the study.In combination with glyburide, saxagliptin 2.5 mg and mg provided significant improvements in A1C, FPG, and PPG compared with the placebo plus up-titrated glyburide group (Table 7). The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 18% in the saxagliptin 2.5 mg add-on to glyburide group, 17% in the saxagliptin mg add-on to glyburide group, and 30% in the placebo plus up-titrated glyburide group.Table 7: Glycemic Parameters at Week 24 in Placebo-Controlled Study of Saxagliptin as Add-On Combination Therapy with Glyburide Efficacy ParameterSaxagliptin2.5 mg+Glyburide7.5 mgN=248Saxagliptin5 mg+Glyburide7.5 mgN=253Placebo+Up-Titrated Glyburide N=267Hemoglobin A1C (%)N=246N=250N=264Baseline (mean)8.48.58.4Change from baseline (adjusted mean+)-0.5-0.6+0.1Difference from up-titrated glyburide (adjusted mean+)-0.6 -0.7 95% Confidence Interval(-0.8, -0.5)(-0.9, -0.6)Percent of patients achieving A1C 7%22%(55/246)23%(57/250)9% (24/264)Fasting Plasma Glucose (mg/dL)N=247N=252N=265Baseline (mean)170175174Change from baseline (adjusted mean+)-7-10+1Difference from up-titrated glyburide (adjusted mean+)-8 -10 95% Confidence Interval(-14, -1)(-17, -4)2-hour Postprandial Glucose (mg/dL)N=195N=202N=206Baseline (mean)309315323Change from baseline (adjusted mean+)-31-34+8Difference from up-titrated glyburide (adjusted mean+)-38 -42 95% Confidence Interval(-50, -27)(-53, -31)Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue.+Least squares mean adjusted for baseline value. p-value 0.0001 compared to placebo up-titrated glyburide.p-value 0.05 compared to placebo up-titrated glyburide.Co-administration with Metformin in Treatment-Naive PatientsA total of 1306 treatment-naive patients with type diabetes mellitus participated in this 24-week, randomized, double-blind, active-controlled trial to evaluate the efficacy and safety of saxagliptin co-administered with metformin in patients with inadequate glycemic control (A1C >= 8% to <= 12%) on diet and exercise alone. Patients were required to be treatment-naive to be enrolled in this study.Patients who met eligibility criteria were enrolled in single-blind, 1-week, dietary and exercise placebo lead-in period. Patients were randomized to one of four treatment arms: saxagliptin mg metformin 500 mg, saxagliptin 10 mg metformin 500 mg, saxagliptin 10 mg placebo, or metformin 500 mg placebo. The 10 mg saxagliptin dosage is not an approved dosage. saxagliptin was dosed once daily. In the treatment groups using metformin, the metformin dose was up-titrated weekly in 500 mg per day increments, as tolerated, to maximum of 2000 mg per day based on FPG. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue as add-on therapy.Co-administration of saxagliptin mg plus metformin provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin (Table 8).Table 8: Glycemic Parameters at Week 24 in Placebo-Controlled Trial of Saxagliptin Co-administration with Metformin in Treatment-Naive Patients Efficacy ParameterSaxagliptin mg+ Metformin N=320Placebo+ Metformin N=328Hemoglobin A1C (%)N=306N=313Baseline (mean)9.49.4Change from baseline (adjusted mean+)-2.5-2.0Difference from placebo metformin (adjusted mean+)-0.5 95% Confidence Interval(-0.7, -0.4)Percent of patients achieving A1C 7%60%(185/307)41% (129/314)Fasting Plasma Glucose (mg/dL)N=315N=320Baseline (mean)199199Change from baseline (adjusted mean+)-60-47Difference from placebo metformin (adjusted mean+)-13 95% Confidence Interval(-19, -6)2-hour Postprandial Glucose (mg/dL)N=146N=141Baseline (mean)340355Change from baseline (adjusted mean+)-138-97Difference from placebo metformin (adjusted mean+)-41 95% Confidence Interval(-57, -25)Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue.+Least squares mean adjusted for baseline value.p-value 0.0001 compared to placebo metformin.p-value 0.05 compared to placebo metformin.Add-On Combination Therapy with Metformin versus Glipizide Add-On Combination Therapy with MetforminIn this 52-week, active-controlled trial, total of 858 patients with type diabetes and inadequate glycemic control (A1C 6.5% and <= 10%) on metformin alone were randomized to double-blind add-on therapy with saxagliptin or glipizide. Patients were required to be on stable dose of metformin (at least 1500 mg daily) for at least weeks prior to enrollment.Patients who met eligibility criteria were enrolled in single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin (1,500 mg to 3,000 mg based on their pre-study dose). Following the lead-in period, eligible patients were randomized to mg of saxagliptin or mg of glipizide in addition to their current dose of open-label metformin. Patients in the glipizide plus metformin group underwent blinded titration of the glipizide dose during the first 18 weeks of the trial up to maximum glipizide dose of 20 mg per day. Titration was based on goal FPG <= 110 mg/dL or the highest tolerable glipizide dose. Fifty percent (50%) of the glipizide-treated patients were titrated to the 20-mg daily dose; 21% of the glipizide-treated patients had final daily glipizide dose of mg or less. The mean final daily dose of glipizide was 15 mg.After 52 weeks of treatment, saxagliptin and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin therapy (Table 9). This conclusion may be limited to patients with baseline A1C comparable to those in the trial (91% of patients had baseline A1C 9%).From baseline mean body weight of 89 kg, there was statistically significant mean reduction of 1.1 kg in patients treated with saxagliptin compared to mean weight gain of 1.1 kg in patients treated with glipizide (p 0.0001).Table 9: Glycemic Parameters at Week 52 in an Active-Controlled Trial of Saxagliptin versus Glipizide in Combination with MetforminEfficacy ParameterSaxagliptin mg+MetforminN=428Titrated Glipizide+MetforminN=430Hemoglobin A1C (%)N=423N=423Baseline (mean)7.77.6Change from baseline (adjusted mean+)-0.6-0.7Difference from glipizide metformin (adjusted mean+)0.195% Confidence Interval(-0.02, 0.2) Fasting Plasma Glucose (mg/dL)N=420N=420Baseline (mean)162161Change from baseline (adjusted mean+)-9-16Difference from glipizide metformin (adjusted mean+)695% Confidence Interval(2, 11) Intent-to-treat population using last observation on study.+Least squares mean adjusted for baseline value.Saxagliptin metformin is considered non-inferior to glipizide metformin because the upper limit of this confidence interval is less than the prespecified non-inferiority margin of 0.35%.Significance not tested.Add-On Combination Therapy with Insulin (with or without metformin)A total of 455 patients with type diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with insulin in patients with inadequate glycemic control (A1C >= 7.5% and <= 11%) on insulin alone (N=141) or on insulin in combination with stable dose of metformin (N=314). Patients were required to be on stable dose of insulin (>= 30 units to <= 150 units daily) with <= 20% variation in total daily dose for >= weeks prior to screening. Patients entered the trial on intermediate- or long-acting (basal) insulin or premixed insulin. Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of premixed insulin.Patients who met eligibility criteria were enrolled in single-blind, four-week, dietary and exercise placebo lead-in period during which patients received insulin (and metformin if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either saxagliptin mg or placebo. Doses of the antidiabetic therapies were to remain stable but patients were rescued and allowed to adjust the insulin regimen if specific glycemic goals were not met or if the investigator learned that the patient had self-increased the insulin dose by 20%. Data after rescue were excluded from the primary efficacy analyses.Add-on therapy with saxagliptin mg provided significant improvements from baseline to Week 24 in A1C and PPG compared with add-on placebo (Table 10). Similar mean reductions in A1C versus placebo were observed for patients using saxagliptin mg add-on to insulin alone and saxagliptin mg add-on to insulin in combination with metformin (-0.4% and -0.4%, respectively). The percentage of patients who discontinued for lack of glycemic control or who were rescued was 23% in the saxagliptin group and 32% in the placebo group.The mean daily insulin dose at baseline was 53 units in patients treated with saxagliptin mg and 55 units in patients treated with placebo. The mean change from baseline in daily dose of insulin was units for the saxagliptin mg group and units for the placebo group.Table 10: Glycemic Parameters at Week 24 in Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with InsulinEfficacy ParameterSaxagliptin mg+Insulin(+/- Metformin)N=304Placebo+Insulin(+/- Metformin)N=151Hemoglobin A1C (%)N=300N=149Baseline (mean)8.78.7Change from baseline (adjusted mean+)-0.7-0.3Difference from placebo (adjusted mean+)-0.4 95% Confidence Interval(-0.6, -0.2)2-hour Postprandial Glucose (mg/dL)N=262N=129Baseline (mean)251255Change from baseline (adjusted mean+)-27-4Difference from placebo (adjusted mean+)-23 95% Confidence Interval(-37, -9)Intent-to-treat population using last observation on study or last observation prior to insulin rescue therapy for patients needing rescue.+Least squares mean adjusted for baseline value and metformin use at baseline.p-value 0.0001 compared to placebo insulin.p-value 0.05 compared to placebo insulin.The change in fasting plasma glucose from baseline to Week 24 was also tested, but was not statistically significant. The percent of patients achieving an A1C 7% was 17% (52/300) with saxagliptin in combination with insulin compared to 7% (10/149) with placebo. Significance was not tested.Add-On Combination Therapy with Metformin plus SulfonylureaA total of 257 patients with type diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with metformin plus sulfonylurea in patients with inadequate glycemic control (A1C >= 7% and <= 10%). Patients were to be on stable combined dose of metformin extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1,500 mg) and sulfonylurea (at maximum tolerated dose, with minimum dose for enrollment being >= 50% of the maximum recommended dose) for >= weeks prior to enrollment.Patients who met eligibility criteria were entered in 2-week enrollment period to allow assessment of inclusion/exclusion criteria. Following the 2-week enrollment period, eligible patients were randomized to either double-blind saxagliptin (5 mg once daily) or double-blind matching placebo for 24 weeks. During the 24-week double-blind treatment period, patients were to receive metformin and sulfonylurea at the same constant dose ascertained during enrollment. Sulfonylurea dose could be down titrated once in the case of major hypoglycemic event or recurring minor hypoglycemic events. In the absence of hypoglycemia, titration (up or down) of study medication during the treatment period was prohibited.Saxagliptin in combination with metformin plus sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin plus sulfonylurea (Table 11). The percentage of patients who discontinued for lack of glycemic control was 6% in the saxagliptin group and 5% in the placebo group.Table 11: Glycemic Parameters at Week 24 in Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin plus SulfonylureaEfficacy ParameterSaxagliptin mg+Metformin plusSulfonylureaN=129Placebo+Metformin plusSulfonylureaN=128Hemoglobin A1C (%)N=127N=127Baseline (mean)8.48.2Change from baseline (adjusted mean+)-0.7-0.1Difference from placebo (adjusted mean+)-0.7 95% Confidence Interval(-0.9, -0.5)2-hour Postprandial Glucose (mg/dL)N=115N=113Baseline (mean)268262Change from baseline (adjusted mean+)-125Difference from placebo (adjusted mean+)-17 95% Confidence Interval(-32, -2)Intent-to-treat population using last observation prior to discontinuation.+Least squares mean adjusted for baseline value.p-value 0.0001 compared to placebo metformin plus sulfonylurea.p-value 0.05 compared to placebo metformin plus sulfonylurea.The change in fasting plasma glucose from baseline to Week 24 was also tested, but was not statistically significant. The percent of patients achieving an A1C 7% was 31% (39/127) with saxagliptin in combination with metformin plus sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.Add-on Combination Therapy with Metformin plus an SGLT2 InhibitorA total of 315 patients with type diabetes participated in this 24-week randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin added to dapagliflozin (an SGLT2 inhibitor) and metformin in patients with baseline of HbA1c >= 7% to <= 10.5%. The mean age of these subjects was 54.6 years, 1.6% were 75 years or older and 52.7% were female. The population was 87.9% White, 6.3% Black or African American, 4.1% Asian, and 1.6% Other race. At baseline the population had diabetes for an average of 7.7 years and mean HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m2. Patients were required to be on stable dose of metformin (>= 1,500 mg per day) for at least weeks prior to enrollment. Eligible subjects who completed the screening period entered the lead in treatment period, which included open-label metformin and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to saxagliptin mg (N=153) or placebo (N =162).The group treated with add-on saxagliptin had statistically significant greater reductions in HbA1c from baseline versus the group treated with placebo (see Table 12).Table 12: HbA1c Change from Baseline at Week 24 in Placebo-Controlled Trial of Saxagliptin as Add-on to Dapagliflozin and Metformin Saxagliptin mg(N=153)+Placebo(N=162)+In combination with Dapagliflozin and MetforminHemoglobin A1C (%)Baseline (mean)8.07.9Change from baseline (adjusted mean)95% Confidence Interval-0.5(-0.6, -0.4)-0.2(-0.3, -0.1)Difference from placebo (adjusted mean)95% Confidence Interval-0.4 (-0.5, -0.2)Analysis of Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using placebo data for all subjects having missing week 24 data.+Number of randomized and treated patients.Least squares mean adjusted for baseline value.There were 6.5% (n=10) of randomized subjects in the saxagliptin arm and 3.1% (n=5) in the placebo arm for whom change from baseline HbA1c data was missing at week 24. Of the subjects who discontinued study medication early, 9.1% (1 of 11) in the saxagliptin arm and 16.7% (1 of 6) in the placebo arm had HbA1c measured at week 24.p-value 0.0001.The known proportion of patients achieving HbA1c 7% at Week 24 was 35.3% in the saxagliptin treated group compared to 23.1% in the placebo treated group.. 14.2 Renal Impairment. total of 170 patients participated in 12-week, randomized, double-blind, placebo-controlled trial conducted to evaluate the efficacy and safety of saxagliptin 2.5 mg once daily compared with placebo in patients with type diabetes and moderate (n=90) or severe (n=41) renal impairment or ESRD (n=39). In this trial, 98% of the patients were using background antidiabetic medications (75% were using insulin and 31% were using oral antidiabetic medications, mostly sulfonylureas). After 12 weeks of treatment, saxagliptin 2.5 mg provided significant improvement in A1C compared to placebo (Table 13). In the subgroup of patients with ESRD, saxagliptin and placebo resulted in comparable reductions in A1C from baseline to Week 12. This finding is inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment. After 12 weeks of treatment, the mean change in FPG was -12 mg/dL with saxagliptin 2.5 mg and -13 mg/dL with placebo. Compared to placebo, the mean change in FPG with saxagliptin was -12 mg/dL in the subgroup of patients with moderate renal impairment, -4 mg/dL in the subgroup of patients with severe renal impairment, and +44 mg/dL in the subgroup of patients with ESRD. These findings are inconclusive because the trial was not adequately powered to show efficacy within specific subgroups of renal impairment. Table 13: A1C at Week 12 in Placebo-Controlled Trial of Saxagliptin in Patients with Renal ImpairmentEfficacy Parameter Saxagliptin 2.5 mgN=85PlaceboN=85Hemoglobin A1C (%) N=81N=83Baseline (mean) 8.48.1Change from baseline (adjusted mean+) -0.9-0.4Difference from placebo (adjusted mean+) 95% Confidence Interval -0.4 (-0.7, -0.1) Intent-to-treat population using last observation on study.+ Least squares mean adjusted for baseline value. p-value 0.01 compared to placebo.. 14.3 Cardiovascular Safety Trial. The cardiovascular risk of saxagliptin was evaluated in SAVOR, multicenter, multinational, randomized, double-blind study comparing saxagliptin (N=8,280) to placebo (N=8,212), both administered in combination with standard of care, in adult patients with type diabetes at high risk for atherosclerotic cardiovascular disease. Of the randomized study subjects, 97.5% completed the trial, and the median duration of follow-up was approximately years. The trial was event-driven, and patients were followed until sufficient number of events were accrued. Subjects were at least 40 years of age, had A1C >= 6.5%, and multiple risk factors (21% of randomized subjects) for cardiovascular disease (age >= 55 years for men and >= 60 years for women plus at least one additional risk factor of dyslipidemia, hypertension, or current cigarette smoking) or established (79% of the randomized subjects) cardiovascular disease defined as history of ischemic heart disease, peripheral vascular disease, or ischemic stroke. Overall, the use of diabetes medications was balanced across treatment groups (metformin 69%, insulin 41%, sulfonylureas 40%, and TZDs 6%). The use of cardiovascular disease medications was also balanced (angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs] 79%, statins 78%, aspirin 75%, beta-blockers 62%, and non-aspirin antiplatelet medications 24%). The majority of subjects were male (67%) and Caucasian (75%) with mean age of 65 years. Approximately 16% of the population had moderate (estimated glomerular filtration rate [eGFR] >= 30 to <= 50 mL/min/1.73 m2) to severe (eGFR 30 mL/min/1.73 m2) renal impairment, and 13% had prior history of heart failure. Subjects had median duration of type diabetes mellitus of approximately 10 years, and mean baseline A1C level of 8.0%. Approximately 5% of subjects were treated with diet and exercise only at baseline. Overall, the use of diabetes medications was balanced across treatment groups (metformin 69%, insulin 41%, sulfonylureas 40%, and TZDs 6%). The use of cardiovascular disease medications was also balanced (ACE inhibitors or ARBs 79%, statins 78%, aspirin 75%, beta-blockers 62%, and non-aspirin antiplatelet medications 24%). The primary analysis in SAVOR was time to first occurrence of Major Adverse Cardiac Event (MACE). major adverse cardiac event in SAVOR was defined as cardiovascular death or nonfatal myocardial infarction (MI) or nonfatal ischemic stroke. The study was designed as non-inferiority trial with pre-specified risk margin of 1.3 for the hazard ratio of MACE and was also powered for superiority comparison if non-inferiority was demonstrated. The results of SAVOR, including the contribution of each component to the primary composite endpoint, are shown in Table 14. The incidence rate of MACE was similar in both treatment arms: 3.8 MACE per 100 patient-years on placebo vs. 3.8 MACE per 100 patient-years on saxagliptin. The estimated hazard ratio of MACE associated with saxagliptin relative to placebo was 1.00 with 95.1% confidence interval of (0.89, 1.12). The upper bound of this confidence interval, 1.12, excluded risk margin larger than 1.3. Table 14: Major Adverse Cardiovascular Events (MACE) by Treatment Group in the SAVOR TrialSaxagliptinPlaceboHazard RatioNumber of Subjects (%)Rate per 100 PYNumber of Subjects (%)Rate per 100 PY(95.1% CI)Composite of first event of CV death, non-fatal MI or non-fatal ischemic stroke (MACE) N=8,280Total PY 16,308.8N=8,212Total PY 16,156.0613 (7.4)3.8609 (7.4)3.81.00 (0.89, 1.12)CV death 245 (3.0)1.5234 (2.8)1.4Non-fatal MI 233 (2.8)1.4260 (3.2)1.6Non-fatal ischemic stroke 135 (1.6)0.8115 (1.4)0.7The Kaplan-Meier-based cumulative event probability is presented in Figure for time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for both saxagliptin and placebo arms are close together throughout the duration of the trial. The estimated cumulative event probability is approximately linear for both arms, indicating that the incidence of MACE for both arms was constant over the trial duration.Figure 2: Cumulative Percent of Time to First MACEVital status was obtained for 99% of subjects in the trial. There were 798 deaths in the SAVOR trial. Numerically more patients (5.1%) died in the saxagliptin group than in the placebo group (4.6%). The risk of deaths from all cause (Table 15) was not statistically different between the treatment groups (HR: 1.11; 95.1% CI: 0.96, 1.27).Table 15: All-cause mortality by Treatment Group in the SAVOR StudySaxagliptinPlaceboHazard RatioNumber of Subjects (%)Rate per 100 PYNumber of Subjects (%)Rate per 100 PY(95.1% CI)N=8,280PY=16,645.3N=8,212PY=16,531.5All-cause mortality 420 (5.1)2.5378 (4.6)2.31.11 (0.96, 1.27)CV death 269 (3.2)1.6260 (3.2)1.6Non-CV death 151 (1.8)0.9118 (1.4)0.7. 1.

SPL UNCLASSIFIED SECTION.

1.1 Monotherapy and Combination Therapy. Saxagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus [see Clinical Studies (14) ].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk Summary Limited data with saxagliptin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriages. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the pre- and postnatal period [see Data]. The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with an HbA1c greater than and has been reported to be as high as 20% to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal DataIn embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats. In prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day through lactation day 21 at exposures up to 470-times the mg clinical dose, based on AUC. 8.2 Lactation. Risk Summary There is no information regarding the presence of saxagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Saxagliptin is present in the milk of lactating rats [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for saxagliptin and any potential adverse effects on the breastfed infant from saxagliptin or from the underlying maternal condition. Data Saxagliptin is secreted in the milk of lactating rats at approximately 1:1 ratio with plasma drug concentrations. 8.4 Pediatric Use. Safety and effectiveness of saxagliptin in pediatric patients under 18 years of age have not been established. Additionally, studies characterizing the pharmacokinetics of saxagliptin in pediatric patients have not been performed.. 8.5 Geriatric Use. In the seven, double-blind, controlled clinical safety and efficacy trials of saxagliptin, total of 4,751 (42.0%) of the 11,301 patients randomized to saxagliptin were 65 years and over, and 1,210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between subjects >= 65 years old and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. 8.6 Renal Impairment. In 12-week randomized placebo-controlled trial, saxagliptin 2.5 mg was administered to 85 subjects with moderate (n=48) or severe (n=18) renal impairment or end-stage renal disease (ESRD) (n=19) [see Clinical Studies (14) ]. The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo. The overall incidence of reported hypoglycemia was 20% among subjects treated with saxagliptin 2.5 mg and 22% among subjects treated with placebo. Four saxagliptin-treated subjects (4.7%) and three placebo-treated subjects (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose <= 50 mg/dL).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Pancreatitis: If pancreatitis is suspected, promptly discontinue saxagliptin. (5.1)Heart Failure: Consider the risks and benefits of saxagliptin in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. (5.2)Hypoglycemia: In add-on to sulfonylurea, add-on to insulin, and add-on to metformin plus sulfonylurea trials, confirmed hypoglycemia was more common in patients treated with saxagliptin compared to placebo. When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, lower dose of insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. (5.3, 6.1)Hypersensitivity-Related Events (e.g., urticaria, facial edema): More common in patients treated with saxagliptin than in patients treated with placebo; and post-marketing reports of serious hypersensitivity reactions such as anaphylaxis, angioedema, and exfoliative skin conditions. Promptly discontinue saxagliptin, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.4, 6.1, 6.2)Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.5)Bullous Pemphigoid: There have been post-marketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue saxagliptin. (5.6)Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with saxagliptin. (5.7). Pancreatitis: If pancreatitis is suspected, promptly discontinue saxagliptin. (5.1). Heart Failure: Consider the risks and benefits of saxagliptin in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. (5.2). Hypoglycemia: In add-on to sulfonylurea, add-on to insulin, and add-on to metformin plus sulfonylurea trials, confirmed hypoglycemia was more common in patients treated with saxagliptin compared to placebo. When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, lower dose of insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. (5.3, 6.1). Hypersensitivity-Related Events (e.g., urticaria, facial edema): More common in patients treated with saxagliptin than in patients treated with placebo; and post-marketing reports of serious hypersensitivity reactions such as anaphylaxis, angioedema, and exfoliative skin conditions. Promptly discontinue saxagliptin, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.4, 6.1, 6.2). Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.5). Bullous Pemphigoid: There have been post-marketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue saxagliptin. (5.6). Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with saxagliptin. (5.7). 5.1 Pancreatitis. There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin. In cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8,240 (0.2%) patients receiving saxagliptin compared to of 8,173 (0.1%) receiving placebo. Preexisting risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin and in 100% (9/9) of those patients receiving placebo. After initiation of saxagliptin, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin and initiate appropriate management. It is unknown whether patients with history of pancreatitis are at increased risk for the development of pancreatitis while using saxagliptin. 5.2 Heart Failure. In cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin (289/8,280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8,212, 2.8%). In time-to-first-event analysis the risk of hospitalization for heart failure was higher in the saxagliptin group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with prior history of heart failure and subjects with renal impairment had higher risk for hospitalization for heart failure, irrespective of treatment assignment. Consider the risks and benefits of saxagliptin prior to initiating treatment in patients at higher risk for heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of saxagliptin. 5.3 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin. When saxagliptin was used in combination with sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with sulfonylurea or with insulin [see Adverse Reactions (6.1) ]. Therefore, lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with saxagliptin [see Dosage and Administration (2.4) ]. 5.4Hypersensitivity Reactions. There have been post-marketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If serious hypersensitivity reaction is suspected, discontinue saxagliptin, assess for other potential causes for the event, and institute alternative treatment for diabetes [see Adverse Reactions (6.2) ].Use caution in patient with history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with saxagliptin.. 5.5 Severe and Disabling Arthralgia. There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. subset of patients experienced recurrence of symptoms when restarting the same drug or different DPP4 inhibitor. Consider DPP4 inhibitors as possible cause for severe joint pain and discontinue drug if appropriate. 5.6 Bullous Pemphigoid. Post-marketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving saxagliptin. If bullous pemphigoid is suspected, saxagliptin should be discontinued and referral to dermatologist should be considered for diagnosis and appropriate treatment.. 5.7 Macrovascular Outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with saxagliptin.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described below or elsewhere in the prescribing information: Pancreatitis [see Warnings and Precautions (5.1) Heart Failure [see Warnings and Precautions (5.2) Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.3) Hypersensitivity Reactions [see Warnings and Precautions (5.4) Severe and disabling arthralgia [see Warnings and Precautions (5.5) Bullous pemphigoid [see Warnings and Precautions (5.6) . Pancreatitis [see Warnings and Precautions (5.1) . Heart Failure [see Warnings and Precautions (5.2) . Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.3) . Hypersensitivity Reactions [see Warnings and Precautions (5.4) . Severe and disabling arthralgia [see Warnings and Precautions (5.5) . Bullous pemphigoid [see Warnings and Precautions (5.6) . Adverse reactions reported in >= 5% of patients treated with saxagliptin and more commonly than in patients treated with placebo are upper respiratory tract infection, urinary tract infection, and headache. (6.1)Peripheral edema was reported more commonly in patients treated with the combination of saxagliptin and thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Adverse reactions reported in >= 5% of patients treated with saxagliptin and more commonly than in patients treated with placebo are upper respiratory tract infection, urinary tract infection, and headache. (6.1). Peripheral edema was reported more commonly in patients treated with the combination of saxagliptin and thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD. (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 practice. Adverse Reactions in Efficacy Trials The data in Table are derived from pool of placebo-controlled clinical trials [see Clinical Studies (14) ]. These data shown in the table reflect exposure of 882 patients to saxagliptin and mean duration of exposure to saxagliptin of 21 weeks. The mean age of these patients was 55 years, 1.4 were 75 years or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, Other 10.5% and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 5.2 years and mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR >= 60 mL/min/1.73 m2) in 91% of these patients.Table shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin. These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least 5% of patients treated with saxagliptin.Table 1: Adverse Reactions in Placebo-Controlled Trials Reported in >= 5% of Patients Treated with Saxagliptin mg and More Commonly than in Patients Treated with Placebo% of PatientsSaxagliptin mgN=882PlaceboN=799Upper respiratory tract infection 7.77.6Urinary tract infection 6.86.1Headache 6.55.9 The placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue.In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction reported at rate >= 5% and more commonly than in patients treated with placebo. In the add-on to TZD trial, the incidence of peripheral edema was higher for saxagliptin mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in study drug discontinuation. Rates of peripheral edema for saxagliptin 2.5 mg and saxagliptin mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide. The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled analysis of 2.5 mg, mg, and 10 mg) and placebo. The 10 mg dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone. An event of thrombocytopenia, consistent with diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not known. Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of subjects receiving saxagliptin 2.5 mg, saxagliptin mg, and placebo, respectively. The most common adverse reactions (reported in at least subjects treated with saxagliptin 2.5 mg or at least subjects treated with saxagliptin mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). Adverse Reactions with Concomitant Use with Insulin In the add-on to insulin trial [see Clinical Studies (14.1) ], the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo, except for confirmed hypoglycemia [see Adverse Reactions (6.1) ].Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. In the add-on to glyburide study, the overall incidence of reported hypoglycemia was higher for saxagliptin 2.5 mg and saxagliptin mg (13.3% and 14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this study, defined as symptoms of hypoglycemia accompanied by fingerstick glucose value of <= 50 mg/dL, was 2.4% and 0.8% for saxagliptin 2.5 mg and saxagliptin mg and 0.7% for placebo [see Warnings and Precautions (5.3) ]. The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively, 7.8% and 5.8% versus 5% given as add-on therapy to metformin, and 4.1% and 2.7% versus 3.8% given as add-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in treatment-naive patients given saxagliptin mg plus metformin and 4% in patients given metformin alone. In the active-controlled trial comparing add-on therapy with saxagliptin mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with saxagliptin mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose <= 50 mg/dL) was reported in none of the saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%) (p 0.0001). In the add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for saxagliptin mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose <= 50 mg/dL) was higher with saxagliptin mg (5.3%) versus placebo (3.3%).In the add-on to metformin plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for saxagliptin mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in none of the placebo-treated patients [see Warnings and Precautions (5.3) ]. Hypersensitivity Reactions Hypersensitivity-related events, such as urticaria and facial edema in the 5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received saxagliptin 2.5 mg, saxagliptin mg, and placebo, respectively. None of these events in patients who received saxagliptin required hospitalization or were reported as life-threatening by the investigators. One saxagliptin-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema. Renal Impairment In the SAVOR trial, adverse reactions related to renal impairment, including laboratory changes (i.e. doubling of serum creatinine compared with baseline and serum creatinine 6 mg/dL), were reported in 5.8% (483/8,280) of saxagliptin-treated subjects and 5.1% (422/8,212) of placebo-treated subjects. The most frequently reported adverse reactions included renal impairment (2.1% vs. 1.9%), acute renal failure (1.4% vs. 1.2%), and renal failure (0.8% vs. 0.9%), in the saxagliptin versus placebo groups, respectively. From baseline to the end of treatment, there was mean decrease in eGFR of 2.5 mL/min/1.73 m2 for saxagliptin-treated patients and mean decrease of 2.4 mL/min/1.73 m2 for placebo-treated patients. More subjects randomized to saxagliptin (421/5,227, 8.1%) compared to subjects randomized to placebo (344/5,073, 6.8%) had downward shifts in eGFR from 50 mL/min/1.73 m2 (i.e. normal or mild renal impairment) to <= 50 mL/min/1.73 m2 (i.e. moderate or severe renal impairment). The proportions of subjects with renal adverse reactions increased with worsening baseline renal function and increased age, regardless of treatment assignment.Infections In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been (0.12%) reports of tuberculosis among the 4,959 saxagliptin-treated patients (1.1 per 1,000 patient-years) compared to no reports of tuberculosis among the 2,868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of saxagliptin that remained stable throughout saxagliptin treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with saxagliptin use. Causality has not been estimated and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use. There has been one case of potential opportunistic infection in the unblinded, controlled clinical trial database to date in an saxagliptin-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin therapy. There have been no spontaneous reports of opportunistic infections associated with saxagliptin use. Vital Signs No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin. Laboratory Tests Absolute Lymphocyte Counts There was dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. From baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in pooled analysis of five placebo-controlled clinical studies. Similar effects were observed when saxagliptin mg was given in initial combination with metformin compared to metformin alone. There was no difference observed for saxagliptin 2.5 mg relative to placebo. The proportion of patients who were reported to have lymphocyte count <= 750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg dosage is not an approved dosage. In the SAVOR trial mean decreases of approximately 84 cells/microL with saxagliptin relative to placebo was observed. The proportion of patients who experienced decrease in lymphocyte counts to count of <= 750 cells/microL was 1.6% (136/8,280) and 1.0% (78/8,212) on saxagliptin and placebo respectively. The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown. 6.2 Post-marketing Experience. Additional adverse reactions have been identified during post-approval use of saxagliptin. 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.Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions Pancreatitis Severe and disabling arthralgia Bullous pemphigoid Rhabdomyolysis Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions Pancreatitis Severe and disabling arthralgia Bullous pemphigoid Rhabdomyolysis.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposure approximately 20-times the mg clinical dose, but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Carcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Saxagliptin did not increase the incidence of tumors in mice dosed orally at 50, 250, and 600 mg/kg up to 870-times (males) and 1,165-times (females) the mg/day clinical dose, based on AUC. Saxagliptin did not increase the incidence of tumors in rats dosed orally at 25, 75, 150, and 300 mg/kg up to 355-times (males) and 2,217-times (females) the mg/day clinical dose, based on AUC. Mutagenesis Saxagliptin was not mutagenic or clastogenic in battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNA repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay. Impairment of Fertility Saxagliptin administered to rats had no effect on fertility or the ability to maintain litter at exposures up to 603-times and 776-times the mg clinical dose in males and females, based on AUC.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in glucose-dependent manner in patients with type diabetes mellitus.. 12.2 Pharmacodynamics. In patients with type diabetes mellitus, administration of saxagliptin inhibits DPP4 enzyme activity for 24-hour period. After an oral glucose load or meal, this DPP4 inhibition resulted in 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or meal. Cardiac Electrophysiology In randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the MRHD). 12.3 Pharmacokinetics. The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 mg to 400 mg dose range. Following 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ngoh/mL and 214 ngoh/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%. No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg. Absorption The median time to maximum concentration (Tmax) following the mg once daily dose was hours for saxagliptin and hours for its active metabolite. Administration with high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was 27% increase in the AUC of saxagliptin when given with meal as compared to fasted conditions. Saxagliptin may be administered with or without food. Distribution The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. Metabolism The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions (7.1) ]. Excretion Saxagliptin is eliminated by both renal and hepatic pathways. Following single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following single oral dose of saxagliptin mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively. Specific Populations Renal Impairment single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment with (eGFR 30 to less than 45 mL/min/1.73m2), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were 2 fold higher than AUC values in subjects with normal renal function. Hepatic Impairment In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful. Body Mass Index No dosage adjustment is recommended based on body mass index (BMI) which was not identified as significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis. Gender No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis. Geriatric No dosage adjustment is recommended based on age alone. Elderly subjects (65 to 80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18 to 40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis. Race and Ethnicity No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 Caucasian subjects with 105 non-Caucasian subjects (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.Drug Interaction Studies In Vitro Assessment of Drug Interactions The metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Saxagliptin is P-glycoprotein (P-gp) substrate but is not significant inhibitor or inducer of P-gp. In Vivo Assessment of Drug Interactions Table 2: Effect of Co-administered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinCo-administered Drug Dosage of Co-administered DrugDosage of SaxagliptinGeometric Mean Ratio(ratio with/without co-administered drug) No Effect 1.00AUC+CmaxNo dosing adjustments required for the following: Metformin 1,000 mg100 mgsaxagliptin5-hydroxy saxagliptin0.980.990.790.88Glyburide mg10 mgsaxagliptin5-hydroxy saxagliptin0.98 ND1.08NDDapagliflozin 10 mg single-dose5 mg single-dosesaxagliptin5-hydroxy saxagliptin1%9%7%6%Pioglitazone 45 mg QD for 10 days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin1.11ND1.11NDDigoxin 0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin1.051.060.991.02Simvastatin 40 mg QD for days10 mg QD for dayssaxagliptin 5-hydroxy saxagliptin1.121.021.211.08Diltiazem 360 mg LA QD for days10 mgsaxagliptin5-hydroxy saxagliptin2.090.661.630.57Rifampin 600 mg QD for days5 mgsaxagliptin5-hydroxy saxagliptin0.241.030.471.39Omeprazole 40 mg QD for days10 mgsaxagliptin5-hydroxy saxagliptin1.13ND0.98NDAluminum hydroxide magnesium hydroxide simethicone aluminum hydroxide:2,400 mgmagnesium hydroxide:2,400 mgsimethicone: 240 mg10 mgsaxagliptin5-hydroxy saxagliptin0.97ND0.74NDFamotidine 40 mg10 mgsaxagliptin5-hydroxy saxagliptin1.03ND1.14NDLimit saxagliptin dose to 2.5 mg once daily when co-administered with strong CYP3A4/5 inhibitors [see Drug Interactions (7.1) and Dosage and Administration (2.3)]: Ketoconazole 200 mg BID for days100 mgsaxagliptin 5-hydroxy saxagliptin 2.45 0.121.62 0.05Ketoconazole 200 mg BID for days20 mgsaxagliptin 5-hydroxy saxagliptin 3.67 ND2.44 ND Single-dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. AUC AUC (INF) for drugs given as single-dose and AUC AUC (TAU) for drugs given in multiple-doses. Results exclude one subject. The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over 24-hour dose interval was not affected by rifampin ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.Table 3: Effect of Saxagliptin on Systemic Exposures of Co-administered DrugsCo-administered Drug Dosage of Co-administered DrugDosage of SaxagliptinGeometric Mean Ratio(ratio with/without saxagliptin) No Effect 1.00AUC+CmaxNo dosing adjustments required for the following: Metformin 1,000 mg100 mgmetformin1.201.09Glyburide mg10 mgglyburide1.061.16Pioglitazone 45 mg QD for 10 days10 mg QDfor dayspioglitazone hydroxy-pioglitazone1.08ND1.14NDDigoxin 0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QDfor daysdigoxin1.061.09Simvastatin 40 mg QD for days10 mg QDfor dayssimvastatin simvastatin acid1.041.160.88 1.00Diltiazem 360 mg LA QD for days10 mgdiltiazem1.101.16Ketoconazole 200 mg BID for days100 mgketoconazole0.870.84Ethinyl estradiol and Norgestimate ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days5 mg QDfor 21 daysethinyl estradiol norelgestromin norgestrel1.071.101.130.981.091.17 Single-dose unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not approved dosages. AUC AUC (INF) for drugs given as single-dose and AUC AUC (TAU) for drugs given in multiple-doses. Results include all subjects. ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Saxagliptin tablets are contraindicated in patients with history of serious hypersensitivity reaction to saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)].. History of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin. (4) History of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Saxagliptin hydrochloride dihydrate is an orally-active inhibitor of the DPP4 enzyme.Saxagliptin hydrochloride dihydrate is described chemically as (1S,3S,5S)-2-[2(S)-Amino-2-(3- hydroxadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride, dihydrate or (1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxytricyclo-[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride, dihydrate. The molecular formula is C18H30ClN3O4 and the molecular weight is 387.90 g/mol. The structural formula is: Saxagliptin hydrochloride dihydrate is white to off-white solid. It is soluble in methanol.Each film-coated tablet of saxagliptin hydrochloride for oral use contains either 2.79 mg saxagliptin hydrochloride equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptin hydrochloride equivalent to mg saxagliptin and the following inactive ingredients: croscarmellose sodium, hydrochloric acid, magnesium stearate, mannitol, microcrystalline cellulose and povidone. In addition, the film coating contains the following inactive ingredients: hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol, talc and titanium dioxide. The imprinting ink contains the following inactive ingredients: ammonium hydroxide, iron oxide black, isopropyl alcohol, propylene glycol and shellac.. 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage is 2.5 mg or mg once daily taken regardless of meals. (2.1)Patients eGFR 45 mL/min/1.73 m2 (with moderate or severe renal impairment, or end-stage renal disease): Recommended dosage is 2.5 mg once daily regardless of meals. (2.2)Assess renal function before starting saxagliptin tablets and periodically thereafter. (2.2)2.5 mg daily is recommended for patients also taking strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.1). Recommended dosage is 2.5 mg or mg once daily taken regardless of meals. (2.1). Patients eGFR 45 mL/min/1.73 m2 (with moderate or severe renal impairment, or end-stage renal disease): Recommended dosage is 2.5 mg once daily regardless of meals. (2.2). Assess renal function before starting saxagliptin tablets and periodically thereafter. (2.2). 2.5 mg daily is recommended for patients also taking strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.1). 2.1 Recommended Dosage. The recommended dosage of saxagliptin tablet is 2.5 mg or mg once daily taken regardless of meals. Saxagliptin tablets must not be split or cut.. 2.2 Dosage in Patients with Renal Impairment. No dosage adjustment for saxagliptin tablets are recommended for patients with eGFR >= 45 mL/min/1.73 m2.The dosage of saxagliptin tablet is 2.5 mg once daily (regardless of meals) for patients with eGFR 45 mL/min/1.73 m2 (which includes subset of moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. Saxagliptin tablets should be administered following hemodialysis. Saxagliptin tablets have not been studied in patients undergoing peritoneal dialysis.Because the dosage of saxagliptin tablets should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of saxagliptin tablets and periodically thereafter.. 2.3 Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors. The dosage of saxagliptin tablet is 2.5 mg once daily when co-administered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].. 2.4 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin. When saxagliptin tablets are used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia [see Warnings and Precautions (5.3) ].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Saxagliptin tablets, mg are available as brown colored, round shaped, biconvex, film-coated tablets imprinted 60 with black ink on one side and plain on other side.Saxagliptin tablets, 2.5 mg are available as light yellow to yellow colored, round shaped, biconvex, film-coated tablets imprinted 59 with black ink on one side and plain on other side.. Tablets: mg and 2.5 mg. (3). Tablets: mg and 2.5 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Co-administration with saxagliptin significantly increases saxagliptin concentrations. Recommend limiting saxagliptin dosage to 2.5 mg once daily. (2.3, 7.1). Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Co-administration with saxagliptin significantly increases saxagliptin concentrations. Recommend limiting saxagliptin dosage to 2.5 mg once daily. (2.3, 7.1). 7.1 Strong Inhibitors of CYP3A4/5 Enzymes. Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of saxagliptin should be limited to 2.5 mg when coadministered with strong CYP3A4/5 inhibitor [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedSaxagliptin tablets, mg, are supplied as brown colored, round shaped, biconvex, film-coated tablets imprinted 60 with black ink on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-060-03Bottles of 90: NDC 65162-060-09Bottles of 500: NDC 65162-060-50Saxagliptin tablets, 2.5 mg, are supplied as light yellow to yellow colored, round shaped, biconvex, film-coated tablets imprinted 59 with black ink on one side and plain on the other side. They are available as follows: Bottles of 30: NDC 65162-059-03Bottles of 90: NDC 65162-059-09Bottles of 500: NDC 65162-059-50Storage and Handling Store at 20 to 25C (68 to 77F); excursions permitted between 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Saxagliptin tablets are dipeptidyl peptidase-4 (DPP4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. (1.1, 14)Limitation of use:Not used for the treatment of type diabetes mellitus or diabetic ketoacidosis. (1.2). Not used for the treatment of type diabetes mellitus or diabetic ketoacidosis. (1.2). 1.1 Monotherapy and Combination Therapy. Saxagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus [see Clinical Studies (14) ].. 1.2 Limitation of Use. Saxagliptin tablets are not indicated for the treatment of type diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read FDA-approved patient labeling (Medication Guide). Medication Guide Healthcare providers should instruct their patients to read the Medication Guide before starting saxagliptin therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptom or if any existing symptom persists or worsens. Patients should be informed of the potential risks and benefits of saxagliptin and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly. Pancreatitis Patients should be informed that acute pancreatitis has been reported during post-marketing use of saxagliptin. Before initiating saxagliptin, patients should be questioned about other risk factors for pancreatitis, such as history of pancreatitis, alcoholism, gallstones, or hypertriglyceridemia. Patients should also be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue saxagliptin and contact their healthcare provider if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1) ]. Heart Failure Patients should be informed of the signs and symptoms of heart failure. Before initiating saxagliptin, patients should be asked about history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Patients should be instructed to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.2) ]. Hypersensitivity ReactionsPatients should be informed that serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions, have been reported during post-marketing use of saxagliptin. If symptoms of these allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking saxagliptin and seek medical advice promptly. Severe and Disabling Arthralgia Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.5) ]. Bullous Pemphigoid Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.6) ]. Missed Dose Patients should be informed that if they miss dose of saxagliptin they should take the next dose as prescribed, unless otherwise instructed by their healthcare provider. Patients should be instructed not to take an extra dose the next day. Administration Instructions Patients should be informed that saxagliptin tablets must not be split or cut. Laboratory Tests Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C, with goal of decreasing these levels toward the normal range. A1C is especially useful for evaluating long-term glycemic control. Patients should be informed of the potential need to adjust their dose based on changes in renal function tests over time. Manufactured by:Amneal Pharmaceuticals Pvt. Ltd.Ahmedabad 382220, INDIADistributed by: Amneal Pharmaceuticals LLCBridgewater, NJ 08807Rev. 04-2022-00Dispense with Medication Guide available at: documents.amneal.com/mg/saxagliptin.pdf.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in glucose-dependent manner in patients with type diabetes mellitus.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis Carcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Saxagliptin did not increase the incidence of tumors in mice dosed orally at 50, 250, and 600 mg/kg up to 870-times (males) and 1,165-times (females) the mg/day clinical dose, based on AUC. Saxagliptin did not increase the incidence of tumors in rats dosed orally at 25, 75, 150, and 300 mg/kg up to 355-times (males) and 2,217-times (females) the mg/day clinical dose, based on AUC. Mutagenesis Saxagliptin was not mutagenic or clastogenic in battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNA repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay. Impairment of Fertility Saxagliptin administered to rats had no effect on fertility or the ability to maintain litter at exposures up to 603-times and 776-times the mg clinical dose in males and females, based on AUC. 13.2 Animal Toxicology and/or Pharmacology. Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposure approximately 20-times the mg clinical dose, but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

OVERDOSAGE SECTION.

10 OVERDOSAGE. In controlled clinical trial, once-daily, orally-administered saxagliptin in healthy subjects at doses up to 400 mg daily for weeks (80 times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate. In the event of an overdose, appropriate supportive treatment should be initiated as dictated by the patients clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over hours).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. NDC 65162-060-03Saxagliptin Tablets mgRx only30 TabletsAmneal Pharmaceuticals LLCNDC 65162-059-03Saxagliptin Tablets 2.5 mg Rx only30 TabletsAmneal Pharmaceuticals LLC. 1. 1.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In patients with type diabetes mellitus, administration of saxagliptin inhibits DPP4 enzyme activity for 24-hour period. After an oral glucose load or meal, this DPP4 inhibition resulted in 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or meal. Cardiac Electrophysiology In randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the MRHD).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 mg to 400 mg dose range. Following 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ngoh/mL and 214 ngoh/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%. No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 mg to 400 mg. Absorption The median time to maximum concentration (Tmax) following the mg once daily dose was hours for saxagliptin and hours for its active metabolite. Administration with high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was 27% increase in the AUC of saxagliptin when given with meal as compared to fasted conditions. Saxagliptin may be administered with or without food. Distribution The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin. Metabolism The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions (7.1) ]. Excretion Saxagliptin is eliminated by both renal and hepatic pathways. Following single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following single oral dose of saxagliptin mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively. Specific Populations Renal Impairment single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment with (eGFR 30 to less than 45 mL/min/1.73m2), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were 2 fold higher than AUC values in subjects with normal renal function. Hepatic Impairment In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of single 10 mg dose of saxagliptin. The 10 mg dosage is not an approved dosage. The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. These differences are not considered to be clinically meaningful. Body Mass Index No dosage adjustment is recommended based on body mass index (BMI) which was not identified as significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis. Gender No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis. Geriatric No dosage adjustment is recommended based on age alone. Elderly subjects (65 to 80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18 to 40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis. Race and Ethnicity No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 Caucasian subjects with 105 non-Caucasian subjects (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.Drug Interaction Studies In Vitro Assessment of Drug Interactions The metabolism of saxagliptin is primarily mediated by CYP3A4/5. In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of co-administered drugs that are metabolized by these enzymes. Saxagliptin is P-glycoprotein (P-gp) substrate but is not significant inhibitor or inducer of P-gp. In Vivo Assessment of Drug Interactions Table 2: Effect of Co-administered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinCo-administered Drug Dosage of Co-administered DrugDosage of SaxagliptinGeometric Mean Ratio(ratio with/without co-administered drug) No Effect 1.00AUC+CmaxNo dosing adjustments required for the following: Metformin 1,000 mg100 mgsaxagliptin5-hydroxy saxagliptin0.980.990.790.88Glyburide mg10 mgsaxagliptin5-hydroxy saxagliptin0.98 ND1.08NDDapagliflozin 10 mg single-dose5 mg single-dosesaxagliptin5-hydroxy saxagliptin1%9%7%6%Pioglitazone 45 mg QD for 10 days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin1.11ND1.11NDDigoxin 0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QDfor dayssaxagliptin5-hydroxy saxagliptin1.051.060.991.02Simvastatin 40 mg QD for days10 mg QD for dayssaxagliptin 5-hydroxy saxagliptin1.121.021.211.08Diltiazem 360 mg LA QD for days10 mgsaxagliptin5-hydroxy saxagliptin2.090.661.630.57Rifampin 600 mg QD for days5 mgsaxagliptin5-hydroxy saxagliptin0.241.030.471.39Omeprazole 40 mg QD for days10 mgsaxagliptin5-hydroxy saxagliptin1.13ND0.98NDAluminum hydroxide magnesium hydroxide simethicone aluminum hydroxide:2,400 mgmagnesium hydroxide:2,400 mgsimethicone: 240 mg10 mgsaxagliptin5-hydroxy saxagliptin0.97ND0.74NDFamotidine 40 mg10 mgsaxagliptin5-hydroxy saxagliptin1.03ND1.14NDLimit saxagliptin dose to 2.5 mg once daily when co-administered with strong CYP3A4/5 inhibitors [see Drug Interactions (7.1) and Dosage and Administration (2.3)]: Ketoconazole 200 mg BID for days100 mgsaxagliptin 5-hydroxy saxagliptin 2.45 0.121.62 0.05Ketoconazole 200 mg BID for days20 mgsaxagliptin 5-hydroxy saxagliptin 3.67 ND2.44 ND Single-dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. AUC AUC (INF) for drugs given as single-dose and AUC AUC (TAU) for drugs given in multiple-doses. Results exclude one subject. The plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over 24-hour dose interval was not affected by rifampin ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.Table 3: Effect of Saxagliptin on Systemic Exposures of Co-administered DrugsCo-administered Drug Dosage of Co-administered DrugDosage of SaxagliptinGeometric Mean Ratio(ratio with/without saxagliptin) No Effect 1.00AUC+CmaxNo dosing adjustments required for the following: Metformin 1,000 mg100 mgmetformin1.201.09Glyburide mg10 mgglyburide1.061.16Pioglitazone 45 mg QD for 10 days10 mg QDfor dayspioglitazone hydroxy-pioglitazone1.08ND1.14NDDigoxin 0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QDfor daysdigoxin1.061.09Simvastatin 40 mg QD for days10 mg QDfor dayssimvastatin simvastatin acid1.041.160.88 1.00Diltiazem 360 mg LA QD for days10 mgdiltiazem1.101.16Ketoconazole 200 mg BID for days100 mgketoconazole0.870.84Ethinyl estradiol and Norgestimate ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days5 mg QDfor 21 daysethinyl estradiol norelgestromin norgestrel1.071.101.130.981.091.17 Single-dose unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not approved dosages. AUC AUC (INF) for drugs given as single-dose and AUC AUC (TAU) for drugs given in multiple-doses. Results include all subjects. ND=not determined; QD=once daily; q6h=every hours; q12h=every 12 hours; BID=twice daily; LA=long acting.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. Saxagliptin (sax glip tin) tablets, for oral use What is the most important information should know about saxagliptin tabletsSerious side effects can happen to people taking saxagliptin tablets, including: 1) Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking saxagliptin tablets:Tell your healthcare provider if you have ever had inflammation of your pancreas (pancreatitis) stones in your gallbladder (gallstones) history of alcoholism high blood triglyceride levels It is not known if having these medical problems will make you more likely to get pancreatitis with saxagliptin tablets.Stop taking saxagliptin tablets and contact your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis. 2) Heart failure. Heart failure means your heart does not pump blood well enough. Before you start taking saxagliptin tablets: Tell your healthcare provider if you have ever had heart failure or have problems with your kidneys.Contact your healthcare provider right away if you have any of the following symptoms:increasing shortness of breath or trouble breathing, especially when you lie down an unusually fast increase in weight swelling or fluid retention, especially in the feet, ankles or legs unusual tiredness These may be symptoms of heart failure. What is saxagliptin tablets Saxagliptin tablets are prescription medicine used with diet and exercise to control high blood sugar (hyperglycemia) in adults with type diabetes.Saxagliptin tablets lowers blood sugar by helping the body increase the level of insulin after meals. Saxagliptin tablets are unlikely by itself to cause your blood sugar to be lowered to dangerous level (hypoglycemia) because it does not work well when your blood sugar is low. However, hypoglycemia may still occur with saxagliptin tablets. Your risk for getting hypoglycemia is higher if you take saxagliptin tablets with some other diabetes medicines, such as sulfonylurea or insulin. Saxagliptin tablets is not for people with type diabetes. Saxagliptin tablets is not for people with diabetic ketoacidosis (increased ketones in your blood or urine). It is not known if saxagliptin tablets is safe and effective in children younger than 18 years old.Who should not take saxagliptin tablets Do not take saxagliptin tablets if you:are allergic to any ingredients in saxagliptin tablets. See the end of this Medication Guide for complete list of ingredients in saxagliptin tablets. Symptoms of serious allergic reaction to saxagliptin tablets may include:swelling of your face, lips, throat, and other areas on your skin difficulty with swallowing or breathing raised, red areas on your skin (hives) skin rash, itching, flaking, or peeling If you have these symptoms, stop taking saxagliptin tablets and contact your healthcare provider right away. Before taking saxagliptin tablets, tell your healthcare provider about all of your medical conditions, including if you:have kidney problems. are pregnant or plan to become pregnant. It is not known if saxagliptin tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant. are breast-feeding or plan to breast-feed. Saxagliptin may be passed in your milk to your baby. Talk with your healthcare provider about the best way to feed your baby while you take saxagliptin tablets. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. Saxagliptin tablets may affect the way other medicines work, and other medicines may affect how saxagliptin tablets works. Contact your healthcare provider if you will be starting or stopping certain other types of medications, such as antibiotics, or medicines that treat fungus or HIV/AIDS, because your dose of saxagliptin tablets might need to be changed. How should take saxagliptin tabletsTake saxagliptin tablets by mouth one time each day exactly as directed by your healthcare provider. Do not change your dose without talking to your healthcare provider. saxagliptin tablets can be taken with or without food. Do not split or cut saxagliptin tablets.During periods of stress on the body, such as fever, trauma, infection, or surgery. Contact your healthcare provider right away as your medication needs may change. Your healthcare provider should test your blood to measure how well your kidneys are working before and during your treatment with saxagliptin tablets. You may need lower dose of saxagliptin tablets if your kidneys are not working well. Follow your healthcare providers instructions for treating blood sugar that is too low (hypoglycemia). Talk to your healthcare provider if low blood sugar is problem for you. If you miss dose of saxagliptin tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take two doses at the same time unless your healthcare provider tells you to do so. Talk to your healthcare provider if you have questions about missed dose.If you take too much saxagliptin tablets, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of saxagliptin tabletsSaxagliptin tablets can cause serious side effects, including: See What is the most important information should know about saxagliptin tabletsAllergic (hypersensitivity) reactions, such as:swelling of your face, lips, throat, and other areas on your skin difficulty with swallowing or breathing raised, red areas on your skin (hives) skin rash, itching, flaking, or peeling If you have these symptoms, stop taking saxagliptin tablets and contact your healthcare provider right away. Joint pain. Some people who take medicines called DPP-4 inhibitors like saxagliptin tablets, may develop joint pain that can be severe. Call your healthcare provider if you have severe joint pain. Skin reaction. Some people who take medicines called DPP-4 inhibitors, like saxagliptin tablets, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your healthcare provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to stop taking saxagliptin tablets. Common side effects of saxagliptin tablets include: upper respiratory tract infection urinary tract infection headache Low blood sugar (hypoglycemia) may become worse in people who also take another medication to treat diabetes, such as sulfonylureas or insulin. Tell your healthcare provider if you take other diabetes medicines. If you have symptoms of low blood sugar, you should check your blood sugar and treat if low, then call your healthcare provider. Symptoms of low blood sugar include:shaking sweating rapid heartbeat change in vision hunger headache change in mood Swelling or fluid retention in your hands, feet, or ankles (peripheral edema) may become worse in people who also take thiazolidinedione to treat diabetes. If you do not know whether you are already on this type of medication, ask your healthcare provider. These are not all of the possible side effects of saxagliptin tablets. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. How should store saxagliptin tabletsStore saxagliptin tablets between 68 to 77F (20 to 25C). Keep saxagliptin tablets and all medicines out of the reach of children. General information about the use of saxagliptin tablets Medicines are sometimes prescribed for conditions that are not mentioned in Medication Guides. Do not use saxagliptin tablets for condition for which it was not prescribed. Do not give saxagliptin tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider for additional information about saxagliptin tablets that is written for health professionals. What are the ingredients of saxagliptin tablets Active ingredient: saxagliptin Inactive ingredients: croscarmellose sodium, hydrochloric acid, magnesium stearate, mannitol, microcrystalline cellulose and povidone. In addition, the film coating contains the following inactive ingredients: hypromellose, iron oxide red, iron oxide yellow, polyethylene glycol, talc and titanium dioxide. The imprinting ink contains the following inactive ingredients: ammonium hydroxide, iron oxide black, isopropyl alcohol, propylene glycol and shellac. What is type diabetes Type diabetes is condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems. The main goal of treating diabetes is to lower your blood sugar so that it is as close to normal as possible. High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary. All trademarks are the property of their respective owners. Manufactured by:Amneal Pharmaceuticals Pvt. Ltd.Ahmedabad 382220, INDIA Distributed by:Amneal Pharmaceuticals LLCBridgewater, NJ 08807Rev. 04-2022-00 This Medication Guide has been approved by the U.S. Food and Drug Administration.Dispense with Medication Guide available at: documents.amneal.com/mg/saxagliptin.pdf. inflammation of your pancreas (pancreatitis) stones in your gallbladder (gallstones) a history of alcoholism high blood triglyceride levels have ever had heart failure or have problems with your kidneys.. increasing shortness of breath or trouble breathing, especially when you lie down an unusually fast increase in weight swelling or fluid retention, especially in the feet, ankles or legs unusual tiredness Saxagliptin tablets are prescription medicine used with diet and exercise to control high blood sugar (hyperglycemia) in adults with type diabetes.. Saxagliptin tablets lowers blood sugar by helping the body increase the level of insulin after meals. Saxagliptin tablets are unlikely by itself to cause your blood sugar to be lowered to dangerous level (hypoglycemia) because it does not work well when your blood sugar is low. However, hypoglycemia may still occur with saxagliptin tablets. Your risk for getting hypoglycemia is higher if you take saxagliptin tablets with some other diabetes medicines, such as sulfonylurea or insulin. Saxagliptin tablets is not for people with type diabetes. Saxagliptin tablets is not for people with diabetic ketoacidosis (increased ketones in your blood or urine). are allergic to any ingredients in saxagliptin tablets. See the end of this Medication Guide for complete list of ingredients in saxagliptin tablets. swelling of your face, lips, throat, and other areas on your skin difficulty with swallowing or breathing raised, red areas on your skin (hives) skin rash, itching, flaking, or peeling have kidney problems. are pregnant or plan to become pregnant. It is not known if saxagliptin tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant. are breast-feeding or plan to breast-feed. Saxagliptin may be passed in your milk to your baby. Talk with your healthcare provider about the best way to feed your baby while you take saxagliptin tablets. Take saxagliptin tablets by mouth one time each day exactly as directed by your healthcare provider. Do not change your dose without talking to your healthcare provider. saxagliptin tablets can be taken with or without food. Do not split or cut saxagliptin tablets.. During periods of stress on the body, such as fever, trauma, infection, or surgery. Contact your healthcare provider right away as your medication needs may change. Your healthcare provider should test your blood to measure how well your kidneys are working before and during your treatment with saxagliptin tablets. You may need lower dose of saxagliptin tablets if your kidneys are not working well. Follow your healthcare providers instructions for treating blood sugar that is too low (hypoglycemia). Talk to your healthcare provider if low blood sugar is problem for you. If you miss dose of saxagliptin tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take two doses at the same time unless your healthcare provider tells you to do so. Talk to your healthcare provider if you have questions about missed dose.. If you take too much saxagliptin tablets, call your healthcare provider or go to the nearest hospital emergency room right away.. See What is the most important information should know about saxagliptin tablets. Allergic (hypersensitivity) reactions, such as:. swelling of your face, lips, throat, and other areas on your skin difficulty with swallowing or breathing raised, red areas on your skin (hives) skin rash, itching, flaking, or peeling Joint pain. Some people who take medicines called DPP-4 inhibitors like saxagliptin tablets, may develop joint pain that can be severe. Call your healthcare provider if you have severe joint pain. Skin reaction. Some people who take medicines called DPP-4 inhibitors, like saxagliptin tablets, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your healthcare provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to stop taking saxagliptin tablets. upper respiratory tract infection urinary tract infection headache shaking sweating rapid heartbeat change in vision hunger headache change in mood.