Saxagliptin

5 WARNINGS AND PRECAUTIONS

• Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin tablets. ( 5.1 )
• Heart Failure: Consider the risks and benefits of saxagliptin tablets in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.2 )
• Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues: Consider a lower dosage of insulin or insulin secretagogue when used in combination with saxagliptin tablets. ( 5.3 )
• Hypersensitivity-Related Events: There have been postmarketing reports of serious hypersensitivity reactions such as anaphylaxis, angioedema, and exfoliative skin conditions. If hypersensitivity reactions occur, discontinue saxagliptin tablets, treat promptly, and monitor until signs and symptoms resolve. ( 5.4 )
• Arthralgia : Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.5 )
• Bullous Pemphigoid: There have been postmarketing 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 tablets. ( 5.6 )

5.1 Pancreatitis There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin tablets. In a 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 8240 (0.2%) patients receiving saxagliptin tablets compared to 9 of 8173 (0.1%) receiving placebo. Preexisting risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin tablets and in 100% (9/9) of those patients receiving placebo. After initiation of saxagliptin tablets, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin tablets and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using saxagliptin tablets.

5.2 Heart Failure In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin tablets (289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event analysis the risk of hospitalization for heart failure was higher in the saxagliptin tablets group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Patients with a prior history of heart failure and patients with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment. Consider the risks and benefits of saxagliptin tablets prior to initiating treatment in patients at a 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 tablets.

5.3 Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues When saxagliptin tablets were used in combination with insulin or an insulin secretagogue, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with insulin or an insulin secretagogue [ see Adverse Reactions (6.1) ]. Therefore, a lower dosage of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with saxagliptin tablets [ see Drug Interactions (7.2) ]. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.4 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin tablets. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin tablets, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue saxagliptin tablets, assess for other potential causes for the event, and institute alternative treatment for diabetes [ see Adverse Reactions (6.2) ]. Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with saxagliptin tablets.

5.5 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 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. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.6 Bullous Pemphigoid Postmarketing 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 tablets. If bullous pemphigoid is suspected, saxagliptin tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

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 Insulin or Insulin Secretagogues [ 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) ]
• Most common adverse reactions (incidence ≥ 5% and more often than 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 tablets and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 Placebo-Controlled Trials in Adults with Type 2 Diabetes Mellitus The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [ see Clinical Studies (14) ]. These data shown in the table reflect exposure of 882 patients to saxagliptin tablets and a mean duration of exposure to saxagliptin tablets of 21 weeks. The mean age of these patients was 55 years, 1.4% were 75 years of age or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, 10.5% other races and 9.8% were of Hispanic or Latino ethnicity. At baseline, the population had type 2 diabetes mellitus for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR ≥ 60 mL/min/1.73 m 2 ) in 91% of these patients. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin tablets. These adverse reactions occurred more commonly on saxagliptin tablets than on placebo and occurred in at least 5% of patients treated with saxagliptin tablets. Table 1: Adverse Reactions in Placebo-Controlled Trials The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin hydrochloride (HCl), thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue. Reported in ≥ 5% of Patients Treated with Saxagliptin Tablets 5 mg and More Commonly than in Patients Treated with Placebo % of Patients Saxagliptin Tablets 5 mg N = 882 Placebo N = 799 Upper respiratory tract infection 7.7 7.6 Urinary tract infection 6.8 6.1 Headache 6.5 5.9 In patients treated with saxagliptin tablets 2.5 mg, headache (6.5%) was the only adverse reaction reported at a 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 tablets 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin tablets 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in trial drug discontinuation. Rates of peripheral edema for saxagliptin tablets 2.5 mg and saxagliptin tablets 5 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 HCl, 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 tablets (pooled analysis of 2.5 mg, 5 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 tablets did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin tablets on bone. An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin tablets is not known. Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin tablets 2.5 mg, saxagliptin tablets 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 patients treated with saxagliptin tablets 2.5 mg or at least 2 patients treated with saxagliptin tablets 5 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 reactions, including serious adverse reactions and discontinuations due to adverse reactions, was similar between saxagliptin tablets and placebo, except for confirmed hypoglycemia [ see Adverse Reactions (6.1) ]. Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A 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 trial, the overall incidence of reported hypoglycemia was higher for saxagliptin tablets 2.5 mg and saxagliptin tablets 5 mg (13.3% and 14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this trial, defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤ 50 mg/dL, was 2.4% and 0.8% for saxagliptin tablets 2.5 mg and saxagliptin tablets 5 mg and 0.7% for placebo [ see Warnings and Precautions (5.3) ]. The incidence of reported hypoglycemia for saxagliptin tablets 2.5 mg and saxagliptin tablets 5 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 HCl, 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 tablets 5 mg plus metformin HCl and 4% in patients given metformin HCl alone. In the active-controlled trial comparing add-on therapy with saxagliptin tablets 5 mg to glipizide in patients inadequately controlled on metformin HCl alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with saxagliptin tablets 5 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 tablet-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 tablets 5 mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤ 50 mg/dL) was higher with saxagliptin tablets 5 mg (5.3%) versus placebo (3.3%). In the add-on to metformin HCl plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for saxagliptin tablets 5 mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the saxagliptin tablet-treated patients and in none of the placebo-treated patients [ see Warnings and Precautions (5.3) ]. Hypersensitivity Reactions Hypersensitivity reactions, such as urticaria and facial edema in the 5-trial pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received saxagliptin tablets 2.5 mg, saxagliptin tablets 5 mg, and placebo, respectively. None of these events in patients who received saxagliptin tablets required hospitalization or were reported as life-threatening by the investigators. One saxagliptin tablet-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% (483/8280) of saxagliptin tablet-treated patients and 5.1% (422/8212) of placebo-treated patients. 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 tablets versus placebo groups, respectively. From baseline to the end of treatment, there was a mean decrease in eGFR of 2.5 mL/min/1.73 m 2 for saxagliptin tablet-treated patients and a mean decrease of 2.4 mL/min/1.73 m 2 for placebo-treated patients. More patients randomized to saxagliptin tablets (421/5227, 8.1%) compared to patients randomized to placebo (344/5073, 6.8%) had downward shifts in eGFR from > 50 mL/min/1.73 m 2 (i.e., normal or mild renal impairment) to ≤ 50 mL/min/1.73 m 2 (i.e., moderate or severe renal impairment). The proportions of patients 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 tablets to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 saxagliptin tablet-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 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 a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin tablets 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 tablets that remained stable throughout saxagliptin tablet 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 tablet use. Causality has not been estimated and there are too few cases to date to determine whether tuberculosis is related to saxagliptin tablet use. There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in a saxagliptin tablet-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin tablet therapy. There have been no spontaneous reports of opportunistic infections associated with saxagliptin tablet use. Vital Signs No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin tablets. Laboratory Tests 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.

6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of saxagliptin tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Gastrointestinal Disorders: Pancreatitis
• Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
• Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, Severe and disabling arthralgia
• Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid

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 a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.

12.2 Pharmacodynamics In patients with type 2 diabetes mellitus, administration of saxagliptin tablets inhibits DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 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 a meal. Cardiac Electrophysiology In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator trial using moxifloxacin in 40 healthy subjects, saxagliptin tablets were 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 2 diabetes mellitus. The C max and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng

• h/mL and 214 ng
• h/mL, respectively. The corresponding plasma C max values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and C max 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 to 400 mg. Absorption The median time to maximum concentration (T max ) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Effect of Food Administration with a high-fat meal resulted in an increase in T max of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Saxagliptin tablets 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. Elimination 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 14 C-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 (t 1/2 ) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively. Specific Populations Geriatric Patients No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean C max 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 C max of saxagliptin or its metabolite. In subjects with moderate renal impairment with (eGFR 30 to less than 45 mL/min/1.73 m 2 ), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m 2 ) 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 C max 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 C max 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. 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 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 Table 2: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin ND = not determined; QD = once daily; q6h = every 6 hours; q12h = every 12 hours; BID = twice daily; LA = long acting. Coadministered Drug Dosage of Coadministered Drug Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. Dosage of Saxagliptin Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. C max No dosing adjustments required for the following: Metformin 1,000 mg 100 mg saxagliptin 0.98 0.79 5-hydroxy saxagliptin 0.99 0.88 Glyburide 5 mg 10 mg saxagliptin 0.98 1.08 5-hydroxy saxagliptin ND ND Dapagliflozin 10 mg single dose 5 mg single dose saxagliptin ↓ 1% ↓ 7% 5-hydroxy saxagliptin ↑ 9% ↑ 6% Pioglitazone Results exclude one subject. 45 mg QD for 10 days 10 mg QD for 5 days saxagliptin 1.11 1.11 5-hydroxy saxagliptin ND ND Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days saxagliptin 1.05 0.99 5-hydroxy saxagliptin 1.06 1.02 Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days saxagliptin 1.12 1.21 5-hydroxy saxagliptin 1.02 1.08 Diltiazem 360 mg LA QD for 9 days 10 mg saxagliptin 2.09 1.63 5-hydroxy saxagliptin 0.66 0.57 Rifampin The plasma DPP-4 activity inhibition over a 24-hour dose interval was not affected by rifampin. 600 mg QD for 6 days 5 mg saxagliptin 0.24 0.47 5-hydroxy saxagliptin 1.03 1.39 Omeprazole 40 mg QD for 5 days 10 mg saxagliptin 1.13 0.98 5-hydroxy saxagliptin ND ND Aluminum hydroxide + magnesium hydroxide + simethicone aluminum hydroxide: 2400 mg magnesium hydroxide: 2400 mg simethicone: 240 mg 10 mg saxagliptin 0.97 0.74 5-hydroxy saxagliptin ND ND Famotidine 40 mg 10 mg saxagliptin 1.03 1.14 5-hydroxy saxagliptin ND ND Limit saxagliptin tablet dose to 2.5 mg once daily when coadministered with strong CYP3A4/5 inhibitors [ see Drug Interactions (7.1) and Dosage and Administration (2.3) ]: Ketoconazole 200 mg BID for 9 days 100 mg saxagliptin 2.45 1.62 5-hydroxy saxagliptin 0.12 0.05 Ketoconazole 200 mg BID for 7 days 20 mg saxagliptin 3.67 2.44 5-hydroxy saxagliptin ND ND Table 3: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs ND = not determined; QD = once daily; q6h = every 6 hours; q12h = every 12 hours; BID = twice daily; LA = long acting. Coadministered Drug Dosage of Coadministered Drug Single dose unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not approved dosages. Dosage of Saxagliptin Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00 AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. C max No dosing adjustments required for the following: Metformin 1,000 mg 100 mg metformin 1.20 1.09 Glyburide 5 mg 10 mg glyburide 1.06 1.16 Pioglitazone Results include all subjects. 45 mg QD for 10 days 10 mg QD for 5 days pioglitazone 1.08 1.14 hydroxy-pioglitazone ND ND Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days digoxin 1.06 1.09 Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days simvastatin 1.04 0.88 simvastatin acid 1.16 1.00 Diltiazem 360 mg LA QD for 9 days 10 mg diltiazem 1.10 1.16 Ketoconazole 200 mg BID for 9 days 100 mg ketoconazole 0.87 0.84 Ethinyl estradiol and Norgestimate ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days 5 mg QD for 21 days ethinyl estradiol 1.07 0.98 norelgestromin 1.10 1.09 norgestrel 1.13 1.17

The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The C max and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng

• h/mL and 214 ng
• h/mL, respectively. The corresponding plasma C max values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and C max 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 to 400 mg. Absorption The median time to maximum concentration (T max ) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Effect of Food Administration with a high-fat meal resulted in an increase in T max of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Saxagliptin tablets 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. Elimination 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 14 C-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 (t 1/2 ) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively. Specific Populations Geriatric Patients No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean C max 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 C max of saxagliptin or its metabolite. In subjects with moderate renal impairment with (eGFR 30 to less than 45 mL/min/1.73 m 2 ), severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m 2 ) 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 C max 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 C max 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. 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 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 Table 2: Effect of Coadministered Drugs on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy Saxagliptin ND = not determined; QD = once daily; q6h = every 6 hours; q12h = every 12 hours; BID = twice daily; LA = long acting. Coadministered Drug Dosage of Coadministered Drug Single dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage. Dosage of Saxagliptin Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. C max No dosing adjustments required for the following: Metformin 1,000 mg 100 mg saxagliptin 0.98 0.79 5-hydroxy saxagliptin 0.99 0.88 Glyburide 5 mg 10 mg saxagliptin 0.98 1.08 5-hydroxy saxagliptin ND ND Dapagliflozin 10 mg single dose 5 mg single dose saxagliptin ↓ 1% ↓ 7% 5-hydroxy saxagliptin ↑ 9% ↑ 6% Pioglitazone Results exclude one subject. 45 mg QD for 10 days 10 mg QD for 5 days saxagliptin 1.11 1.11 5-hydroxy saxagliptin ND ND Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days saxagliptin 1.05 0.99 5-hydroxy saxagliptin 1.06 1.02 Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days saxagliptin 1.12 1.21 5-hydroxy saxagliptin 1.02 1.08 Diltiazem 360 mg LA QD for 9 days 10 mg saxagliptin 2.09 1.63 5-hydroxy saxagliptin 0.66 0.57 Rifampin The plasma DPP-4 activity inhibition over a 24-hour dose interval was not affected by rifampin. 600 mg QD for 6 days 5 mg saxagliptin 0.24 0.47 5-hydroxy saxagliptin 1.03 1.39 Omeprazole 40 mg QD for 5 days 10 mg saxagliptin 1.13 0.98 5-hydroxy saxagliptin ND ND Aluminum hydroxide + magnesium hydroxide + simethicone aluminum hydroxide: 2400 mg magnesium hydroxide: 2400 mg simethicone: 240 mg 10 mg saxagliptin 0.97 0.74 5-hydroxy saxagliptin ND ND Famotidine 40 mg 10 mg saxagliptin 1.03 1.14 5-hydroxy saxagliptin ND ND Limit saxagliptin tablet dose to 2.5 mg once daily when coadministered with strong CYP3A4/5 inhibitors [ see Drug Interactions (7.1) and Dosage and Administration (2.3) ]: Ketoconazole 200 mg BID for 9 days 100 mg saxagliptin 2.45 1.62 5-hydroxy saxagliptin 0.12 0.05 Ketoconazole 200 mg BID for 7 days 20 mg saxagliptin 3.67 2.44 5-hydroxy saxagliptin ND ND Table 3: Effect of Saxagliptin on Systemic Exposures of Coadministered Drugs ND = not determined; QD = once daily; q6h = every 6 hours; q12h = every 12 hours; BID = twice daily; LA = long acting. Coadministered Drug Dosage of Coadministered Drug Single dose unless otherwise noted. The 10 mg and 100 mg saxagliptin doses are not approved dosages. Dosage of Saxagliptin Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00 AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. C max No dosing adjustments required for the following: Metformin 1,000 mg 100 mg metformin 1.20 1.09 Glyburide 5 mg 10 mg glyburide 1.06 1.16 Pioglitazone Results include all subjects. 45 mg QD for 10 days 10 mg QD for 5 days pioglitazone 1.08 1.14 hydroxy-pioglitazone ND ND Digoxin 0.25 mg q6h first day followed by q12h second day followed by QD for 5 days 10 mg QD for 7 days digoxin 1.06 1.09 Simvastatin 40 mg QD for 8 days 10 mg QD for 4 days simvastatin 1.04 0.88 simvastatin acid 1.16 1.00 Diltiazem 360 mg LA QD for 9 days 10 mg diltiazem 1.10 1.16 Ketoconazole 200 mg BID for 9 days 100 mg ketoconazole 0.87 0.84 Ethinyl estradiol and Norgestimate ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days 5 mg QD for 21 days ethinyl estradiol 1.07 0.98 norelgestromin 1.10 1.09 norgestrel 1.13 1.17