Saxagliptin Tablets: Package Insert / Prescribing Info

Absolute Lymphocyte Counts

There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin tablets. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin tablets 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical trials. Similar effects were observed when saxagliptin tablets 5 mg were given in initial combination with metformin HCl compared to metformin HCl alone. There was no difference observed for saxagliptin tablets 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count ≤ 750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin tablets 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to saxagliptin tablets although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin tablets. 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 tablets relative to placebo was observed. The proportion of patients who experienced a decrease in lymphocyte counts to a count of ≤ 750 cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on saxagliptin tablets 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 tablets on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Animal Data

In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.

In a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical dose, based on AUC.

Metabolism

The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP-4 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 a 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. A 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 a single oral dose of saxagliptin tablets 5 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.

Geriatric Patients

No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 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 a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.

Male and Female Patients

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 a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.

Racial or Ethnic Groups

No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 White subjects with 105 subjects of other races (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.

Patients with Renal Impairment

A single-dose, open-label trial 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/1.73 m2), 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.

Patients with 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 a 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 a significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis.

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 coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate but is not a significant inhibitor or inducer of P-gp.

In Vivo Assessment of Drug Interactions

Add-On Combination Therapy with Metformin HCl

A total of 743 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin tablets in combination with metformin HCl in patients with inadequate glycemic control (A1C ≥ 7% and ≤ 10%) on metformin HCl alone. To qualify for enrollment, patients were required to be on a stable dose of metformin HCl (1,500-2,550 mg daily) for at least 8 weeks.

Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin HCl at their pre-trial dose, up to 2,500 mg daily. Following the lead-in period, eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of saxagliptin tablets or placebo in addition to their current dose of open-label metformin HCl. The 10 mg dosage of saxagliptin tablets is not an approved dosage. Patients who failed to meet specific glycemic goals during the trial were treated with pioglitazone rescue therapy, added on to existing trial medications. Dose titrations of saxagliptin tablets and metformin HCl were not permitted.

Saxagliptin tablets 2.5 mg and 5 mg add-on to metformin HCl provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin HCl (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 tablets 2.5 mg add-on to metformin HCl group, 13% in the saxagliptin tablets 5 mg add-on to metformin HCl group, and 27% in the placebo add-on to metformin HCl group.

Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled Trial of Saxagliptin Tablets as Add-On Combination Therapy with Metformin HCl*

Week 24 (LOCF) includes intent-to-treat population using last observation on trial prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value.

Add-On Combination Therapy with a Thiazolidinedione

A total of 565 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin tablets in combination with a 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 a stable dose of pioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once daily or 8 mg either once daily or in two divided doses of 4 mg) for at least 12 weeks.

Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received TZD at their pre-trial dose. Following the lead-in period, eligible patients were randomized to 2.5 mg or 5 mg of saxagliptin tablets or placebo in addition to their current dose of TZD. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCl rescue, added on to existing trial medications. Dose titration of saxagliptin tablets or TZD was not permitted during the trial. A change in TZD regimen from rosiglitazone to pioglitazone at specified, equivalent therapeutic doses was permitted at the investigator’s discretion if believed to be medically appropriate.

Saxagliptin tablets 2.5 mg and 5 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 tablets 2.5 mg add-on to TZD group, 6% for the saxagliptin tablets 5 mg add-on to TZD group, and 10% in the placebo add-on to TZD group.

Add-On Combination Therapy with Glyburide

A total of 768 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin tablets in combination with a sulfonylurea (SU) in patients with inadequate glycemic control at enrollment (A1C ≥ 7.5% to ≤ 10%) on a submaximal dose of SU alone. To qualify for enrollment, patients were required to be on a submaximal dose of SU for 2 months or greater. In this trial, saxagliptin tablets in combination with a fixed, intermediate dose of SU was compared to titration to a higher dose of SU.

Patients who met eligibility criteria were enrolled in a 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 5 mg of saxagliptin tablets add-on to 7.5 mg glyburide or to placebo plus a 10 mg total daily dose of glyburide. Patients who received placebo were eligible to have glyburide up-titrated to a total daily dose of 15 mg. Up-titration of glyburide was not permitted in patients who received saxagliptin tablets 2.5 mg or 5 mg. Glyburide could be down-titrated in any treatment group once during the 24-week trial period due to hypoglycemia as deemed necessary by the investigator. Approximately 92% of patients in the placebo plus glyburide group were up-titrated to a final total daily dose of 15 mg during the first 4 weeks of the trial period. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCl rescue, added on to existing trial medication. Dose titration of saxagliptin tablets was not permitted during the trial.

In combination with glyburide, saxagliptin tablets 2.5 mg and 5 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 tablets 2.5 mg add-on to glyburide group, 17% in the saxagliptin tablets 5 mg add-on to glyburide group, and 30% in the placebo plus up-titrated glyburide group.

Coadministration with Metformin HCl in Treatment-Naive Patients

A total of 1306 treatment-naive patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, active-controlled trial to evaluate the efficacy and safety of saxagliptin tablets coadministered with metformin HCl 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 trial.

Patients who met eligibility criteria were enrolled in a single-blind, 1-week, dietary and exercise placebo lead-in period. Patients were randomized to one of four treatment arms: saxagliptin tablets 5 mg + metformin HCl 500 mg, saxagliptin 10 mg + metformin HCl 500 mg, saxagliptin 10 mg + placebo, or metformin HCl 500 mg + placebo. The 10 mg saxagliptin dosage is not an approved dosage. Saxagliptin tablets were dosed once daily. In the 3 treatment groups using metformin HCl, the metformin HCl dose was up-titrated weekly in 500 mg per day increments, as tolerated, to a maximum of 2,000 mg per day based on FPG. Patients who failed to meet specific glycemic goals during the trials were treated with pioglitazone rescue as add-on therapy.

Coadministration of saxagliptin tablets 5 mg plus metformin HCl provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin HCl (Table 8).

Add-On Combination Therapy with Metformin HCl versus Glipizide Add-On Combination Therapy with Metformin HCl

In this 52-week, active-controlled trial, a total of 858 patients with type 2 diabetes mellitus and inadequate glycemic control (A1C > 6.5% and ≤ 10%) on metformin HCl alone were randomized to double-blind add-on therapy with saxagliptin tablets or glipizide. Patients were required to be on a stable dose of metformin HCl (at least 1,500 mg daily) for at least 8 weeks prior to enrollment.

Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin HCl (1,500-3,000 mg based on their pre-trial dose). Following the lead-in period, eligible patients were randomized to 5 mg of saxagliptin tablets or 5 mg of glipizide in addition to their current dose of open-label metformin HCl. Patients in the glipizide plus metformin HCl group underwent blinded titration of the glipizide dose during the first 18 weeks of the trial up to a maximum glipizide dose of 20 mg per day. Titration was based on a 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 a final daily glipizide dose of 5 mg or less. The mean final daily dose of glipizide was 15 mg.

After 52 weeks of treatment, saxagliptin tablets and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin HCl 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 a baseline mean body weight of 89 kg, there was a statistically significant mean reduction of 1.1 kg in patients treated with saxagliptin tablets compared to a mean weight gain of 1.1 kg in patients treated with glipizide (p < 0.0001).

Add-On Combination Therapy with Insulin (with or without metformin HCl)

A total of 455 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin tablets 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 a stable dose of metformin HCl (N = 314). Patients were required to be on a stable dose of insulin (≥ 30 units to ≤ 150 units daily) with ≤ 20% variation in total daily dose for ≥ 8 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 a premixed insulin.

Patients who met eligibility criteria were enrolled in a single-blind, four-week, dietary and exercise placebo lead-in period during which patients received insulin (and metformin HCl if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either saxagliptin tablets 5 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 tablets 5 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 tablets 5 mg add-on to insulin alone and saxagliptin tablets 5 mg add-on to insulin in combination with metformin HCl (-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 tablets group and 32% in the placebo group.

The mean daily insulin dose at baseline was 53 units in patients treated with saxagliptin tablets 5 mg and 55 units in patients treated with placebo. The mean change from baseline in daily dose of insulin was 2 units for the saxagliptin tablets 5 mg group and 5 units for the placebo group.

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 tablets in combination with insulin compared to 7% (10/149) with placebo. Significance was not tested.

Add-On Combination Therapy with Metformin HCl plus Sulfonylurea

A total of 257 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin tablets in combination with metformin HCl plus a sulfonylurea in patients with inadequate glycemic control (A1C ≥ 7% and ≤ 10%). Patients were to be on a stable combined dose of metformin HCl extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1,500 mg) and a sulfonylurea (at maximum tolerated dose, with minimum dose for enrollment being ≥ 50% of the maximum recommended dose) for ≥ 8 weeks prior to enrollment.

Patients who met eligibility criteria were entered in a 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 tablets (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 HCl and a sulfonylurea at the same constant dose ascertained during enrollment. Sulfonylurea dose could be down titrated once in the case of a major hypoglycemic event or recurring minor hypoglycemic events. In the absence of hypoglycemia, titration (up or down) of trial medication during the treatment period was prohibited.

Saxagliptin tablets in combination with metformin HCl plus a sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin HCl plus a sulfonylurea (Table 11). The percentage of patients who discontinued for lack of glycemic control was 6% in the saxagliptin tablets group and 5% in the placebo group.

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 tablets in combination with metformin HCl plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.

Add-on Combination Therapy with Metformin HCl plus an SGLT2 Inhibitor

A total of 315 patients with type 2 diabetes mellitus participated in this 24-week randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin tablets added to dapagliflozin (an SGLT2 inhibitor) and metformin HCl in patients with a baseline of HbA1c ≥ 7% to ≤ 10.5%. The mean age of these patients 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 races. At baseline the population had diabetes mellitus for an average of 7.7 years and a mean HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m2. Patients were required to be on a stable dose of metformin HCl (≥ 1,500 mg per day) for at least 8 weeks prior to enrollment. Eligible patients who completed the screening period entered the lead in treatment period, which included open-label metformin HCl and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to saxagliptin tablets 5 mg (N = 153) or placebo (N = 162).

The group treated with add-on saxagliptin tablets had statistically significant greater reductions in HbA1c from baseline versus the group treated with placebo (see Table 12).

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.