DailyMed Label: Saxagliptin and Metformin Hydrochloride

DailyMed Label: Saxagliptin and Metformin

2023

DailyMed Prescription

Saxagliptin and Metformin

saxagliptin and metformin

Mylan Pharmaceuticals Inc.

NDC: 0378-8175

NDC: 0378-8175

NDC: 0378-8177

NDC: 0378-8177

NDC: 0378-8176

NDC: 0378-8176

Saxagliptin and metformin hydrochloride extended-release tablets contain two oral antihyperglycemic medications used in the management of type 2 diabetes: saxagliptin and metformin hydrochloride. Saxagliptin:   Saxagliptin is an orally active inhibitor of the dipeptidyl-peptidase-4 (DPP4) enzyme. Saxagliptin hydrochloride dihydrate is described chemically as (1S,3S,5S)-2-[(2S)-Amino-(3-hydroxytricyclo[3.3.1.1 3,7 ]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride dihydrate or (1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride dihydrate. The molecular formula is C 18 H 25 N 3 O 2 •HCl•2 H 2 O and the molecular weight is 387.92. The structural formula is: Saxagliptin hydrochloride dihydrate is a white to off white, non-hygroscopic, crystalline powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400). Metformin Hydrochloride:   Metformin hydrochloride, USP (1,1-Dimethylbiguanide monohydrochloride) is a white, crystalline powder with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.36. The structural formula is: Saxagliptin and Metformin Hydrochloride Extended-Release Tablets:   Saxagliptin and metformin hydrochloride extended-release tablets are available for oral administration as tablets containing either 6.149 mg saxagliptin hydrochloride dihydrate equivalent to 5 mg saxagliptin and 500 mg metformin hydrochloride (saxagliptin and metformin hydrochloride extended-release tablets 5 mg/500 mg), or 6.149 mg saxagliptin hydrochloride dihydrate equivalent to 5 mg saxagliptin and 1000 mg metformin hydrochloride (saxagliptin and metformin hydrochloride extended-release tablets 5 mg/1000 mg), or 3.075 mg saxagliptin hydrochloride dihydrate equivalent to 2.5 mg saxagliptin and 1000 mg metformin hydrochloride (saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1000 mg). Each film-coated tablet of saxagliptin and metformin hydrochloride extended-release contains the following inactive ingredients: carbomer homopolymer type A, colloidal silicon dioxide, hypromellose, magnesium stearate, polyethylene glycol, polyvinyl alcohol, povidone, red iron oxide, stearic acid, talc and titanium dioxide. The 2.5 mg/1000 mg tablets also contain yellow iron oxide. In addition, the black imprinting ink contains ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze. The biologically inert components of the tablet may occasionally remain intact during gastrointestinal transit and will be eliminated in the feces as a soft, hydrated mass. Saxagliptin Hydrochloride Structural Formula Metformin Hydrochloride Structural Formula

Saxagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate [ see Clinical Studies (14) ]. Saxagliptin and metformin hydrochloride extended-release tablets are a combination of saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and metformin, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate. ( 1 , 14 ) Limitations of Use: • Not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ( 1.1 ) Saxagliptin and metformin hydrochloride extended-release tablets are not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

• Administer once daily with the evening meal. ( 2.1 ) • Individualize the starting dose based on the patient’s current regimen then adjust the dosage based on effectiveness and tolerability. ( 2.1 ) • Do not exceed a daily dosage of 5 mg saxagliptin/2000 mg metformin HCl extended-release. ( 2.1 ) • Swallow whole. Never crush, cut, or chew. ( 2.1 ) • Limit the saxagliptin dosage to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole). ( 2.2 , 7.1 ) • Assess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and periodically thereafter. ( 2.3 ) o Do not use in patients with eGFR below 30 mL/min/1.73 m 2 . o Initiation is not recommended in patients with eGFR between 30-45 mL/min/1.73 m 2 . o Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m 2 . o Limit the saxagliptin component to 2.5 mg daily if eGFR is less than 45 mL/min/1.73 m 2 . o Discontinue if eGFR falls below 30 mL/min/1.73 m 2 . • Saxagliptin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.4 ) The dosage of saxagliptin and metformin hydrochloride extended-release tablets should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability. Saxagliptin and metformin hydrochloride extended-release tablets should generally be administered once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin. The following dosage forms are available: • Saxagliptin and metformin hydrochloride extended-release tablets 5 mg/500 mg • Saxagliptin and metformin hydrochloride extended-release tablets 5 mg/1000 mg • Saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1000 mg The recommended starting dose of saxagliptin and metformin hydrochloride extended-release tablets in patients who need 5 mg of saxagliptin and who are not currently treated with metformin is 5 mg saxagliptin/500 mg metformin extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin. In patients treated with metformin, the dosage of saxagliptin and metformin hydrochloride extended-release tablets should provide metformin at the dose already being taken, or the nearest therapeutically appropriate dose. Following a switch from metformin immediate-release to metformin extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly. Patients who need 2.5 mg saxagliptin in combination with metformin extended-release may be treated with saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1000 mg. Patients who need 2.5 mg saxagliptin who are either metformin naive or who require a dose of metformin higher than 1000 mg should use the individual components. The maximum daily recommended dosage is 5 mg for saxagliptin and 2000 mg for metformin extended-release. No studies have been performed specifically examining the safety and efficacy of saxagliptin and metformin hydrochloride extended-release tablets in patients previously treated with other antihyperglycemic medications and switched to saxagliptin and metformin hydrochloride extended-release tablets. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur. Inform patients that saxagliptin and metformin hydrochloride extended-release tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of saxagliptin and metformin hydrochloride extended-release tablets will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet. The maximum recommended dosage of saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). For these patients, limit the saxagliptin and metformin hydrochloride extended-release tablet dosage to 2.5 mg/1000 mg once daily [ see Dosage and Administration (2.1) , Drug Interactions (7.1) , and Clinical Pharmacology (12.3) ]. Assess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and periodically thereafter. Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . Initiation of saxagliptin and metformin hydrochloride extended-release tablets in patients with an eGFR between 30-45 mL/minute/1.73 m 2 is not recommended. In patients taking saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit risk of continuing therapy and limit dose of the saxagliptin component to 2.5 mg once daily. Discontinue saxagliptin and metformin hydrochloride extended-release tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m 2 [ see Contraindications (4) and Warnings and Precautions (5.1) ]. Discontinue saxagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; a history of liver disease, alcoholism or heart failure; or in any patient who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart saxagliptin and metformin hydrochloride extended-release tablets if renal function is stable [ see Warnings and Precautions (5.1) ].

• Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 5 mg/500 mg, are pink, film-coated, round, unscored tablets imprinted with SM3 over M in black ink on one side of the tablet and blank on the other side. • Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 5 mg/1000 mg, are pink, film-coated, capsule shaped, unscored tablets imprinted with SM6 over M in black ink on one side of the tablet and blank on the other side. • Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 2.5 mg/1000 mg, are light peach, film-coated, capsule shaped, unscored tablets imprinted with SM4 over M in black ink on one side of the tablet and blank on the other side. Tablets: • 5 mg saxagliptin/500 mg metformin HCl extended-release ( 3 ) • 5 mg saxagliptin/1000 mg metformin HCl extended-release ( 3 ) • 2.5 mg saxagliptin/1000 mg metformin HCl extended-release ( 3 )

Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with: • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). • Hypersensitivity to metformin hydrochloride. • Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin. • History of a serious hypersensitivity reaction to saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions [ see Warnings and Precautions (5.7) and Adverse Reactions (6.2) ]. • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ). ( 4 ) • Hypersensitivity to metformin hydrochloride. ( 4 ) • Metabolic acidosis, including diabetic ketoacidosis. ( 4 , 5.1 ) • History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin. ( 4 )

• Lactic Acidosis: See boxed warning. ( 5.1 ) • Pancreatitis: If pancreatitis is suspected, promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets. ( 5.2 ) • Heart Failure: Consider the risks and benefits of saxagliptin and metformin hydrochloride extended-release tablets in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. ( 5.3 ) • Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. ( 5.4 , 6.1 ) • Hypoglycemia: In the saxagliptin add-on to sulfonylurea, add-on to insulin, and add-on to metformin plus sulfonylurea trials, confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin compared to placebo. When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. ( 5.6 , 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 in patients treated with saxagliptin. Promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. ( 5.7 , 6.1 , 6.2 ) • Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.8 ) • Bullous Pemphigoid: There have been post-marketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue saxagliptin and metformin hydrochloride extended-release tablets ( 5.9 ). • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with saxagliptin and metformin hydrochloride extended-release tablets. ( 5.10 ) There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally > 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of saxagliptin and metformin hydrochloride extended-release tablets. In saxagliptin and metformin hydrochloride extended-release tablet-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue saxagliptin and metformin hydrochloride extended-release tablets and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: The post-marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [ see Clinical Pharmacology (12.3) ]. • Before initiating saxagliptin and metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR). • Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m 2 [ see Contraindications (4) ]. • Initiation of saxagliptin and metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m 2 . • Obtain an eGFR at least annually in all patients taking saxagliptin and metformin hydrochloride extended-release tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. • In patients taking saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m 2 , assess the benefit and risk of continuing therapy. The concomitant use of saxagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [ see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients. The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [ see Use in Specific Populations (8.5) ]. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop saxagliptin and metformin hydrochloride extended-release tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart saxagliptin and metformin hydrochloride extended-release tablets if renal function is stable. Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Saxagliptin and metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. Several of the post-marketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue saxagliptin and metformin hydrochloride extended-release tablets. Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving saxagliptin and metformin hydrochloride extended-release tablets. Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of saxagliptin and metformin hydrochloride extended-release tablets in patients with clinical or laboratory evidence of hepatic disease. There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin. 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 compared to 9 of 8173 (0.1%) receiving placebo. Pre-existing 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 and metformin hydrochloride extended-release tablets, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin and metformin hydrochloride extended-release 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 and metformin hydrochloride extended-release tablets. In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin (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 group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with a prior history of heart failure and subjects with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment. Consider the risks and benefits of saxagliptin and metformin hydrochloride extended-release 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 and metformin hydrochloride extended-release tablets. In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on saxagliptin and metformin hydrochloride extended-release tablets and any apparent abnormalities should be appropriately investigated and managed [ see Adverse Reactions (6.1) ]. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. In these patients, routine serum vitamin B 12 measurements at 2- to 3-year intervals may be useful. A patient with type 2 diabetes previously well-controlled on saxagliptin and metformin hydrochloride extended-release tablets who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, saxagliptin and metformin hydrochloride extended-release tablets must be stopped immediately and other appropriate corrective measures initiated. When saxagliptin was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin [ see Adverse Reactions (6.1) ]. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with saxagliptin and metformin hydrochloride extended-release tablets [ see Dosage and Administration (2.3) ]. Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. 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 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue saxagliptin and metformin hydrochloride extended-release 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 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with saxagliptin and metformin hydrochloride extended-release tablets. 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. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP4 inhibitor. Consider DPP4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate. Post-marketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP4 inhibitor. Tell patients to report development of blisters or erosions while receiving saxagliptin and metformin hydrochloride extended-release tablets. If bullous pemphigoid is suspected, saxagliptin and metformin hydrochloride extended-release tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with saxagliptin and metformin hydrochloride extended-release tablets.

The following serious adverse reactions are described below or elsewhere in the prescribing information:

The concomitant use of saxagliptin and metformin hydrochloride extended-release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [ see Drug Interactions (7) ]. Therefore, consider more frequent monitoring of patients.

• Geriatric Use: Assess renal function more frequently. ( 8.5 ) • Hepatic Impairment: Avoid use in patients with hepatic impairment. ( 8.7 ) Limited available data with saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [ see Data ]. No adverse developmental effects independent of maternal toxicity were observed when saxagliptin and metformin were administered separately or in combination to pregnant rats and rabbits during the period of organogenesis [ see Data ]. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an HbA1c greater than 7 and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. 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. In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats. In a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical dose, based on AUC. Metformin hydrochloride did not cause adverse developmental effect when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively. Saxagliptin and metformin coadministered to pregnant rats and rabbits during the period of organogenesis did not result in adverse developmental effects considered clinically relevant in either species. Doses tested in rats provided exposure up to 100- and 10-times clinical exposure, and doses tested in rabbits provided exposure up to 249- and 1-times clinical exposure relative to the clinical dose of 5 mg saxagliptin and 2000 mg metformin. Minor skeletal abnormalities associated with maternal toxicity were observed in rats. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29, associated with fetal body weight decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid bone. There is no information regarding the presence of saxagliptin and metformin or saxagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [ see Data ]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Saxagliptin is present in the milk of lactating rats [ see Data ]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for saxagliptin and metformin hydrochloride extended-release tablets and any potential adverse effects on the breastfed child from saxagliptin and metformin hydrochloride extended-release tablets or from the underlying maternal condition. Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants. No studies in lactating animals have been conducted with the combined components of saxagliptin and metformin hydrochloride extended-release tablets. In studies performed with the individual components, both saxagliptin and metformin are secreted in the milk of lactating rats. Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. Safety and effectiveness of saxagliptin and metformin hydrochloride extended-release tablets in pediatric patients under 18 years of age have not been established. Additionally, studies characterizing the pharmacokinetics of saxagliptin and metformin hydrochloride extended-release tablets in pediatric patients have not been performed. Elderly patients are more likely to have decreased renal function. Assess renal function more frequently in the elderly [ see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. In the seven, double-blind, controlled clinical safety and efficacy trials of saxagliptin, a total of 4751 (42.0%) of the 11301 patients randomized to saxagliptin were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between subjects ≥ 65 years old and younger subjects. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [ see Contraindications (4) , Warnings and Precautions (5.1) , and Clinical Pharmacology (12.3) ]. In a 12-week randomized placebo-controlled trial, saxagliptin 2.5 mg was administered to 85 subjects with moderate (n = 48) or severe (n = 18) renal impairment or end-stage renal disease (ESRD) (n = 19) [ see Clinical Studies (14) ]. The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo. The overall incidence of reported hypoglycemia was 20% among subjects treated with saxagliptin 2.5 mg and 22% among subjects treated with placebo. Four saxagliptin-treated subjects (4.7%) and three placebo-treated subjects (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤ 50 mg/dL). Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [ see Dosage and Administration (2.3) , Contraindications (4) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Saxagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with hepatic impairment [ see Warnings and Precautions (5.1) ].

Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 5 mg/500 mg, are pink, film-coated, round, unscored tablets imprinted with SM3 over M in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-8175-93 bottles of 30 tablets NDC 0378-8175-77 bottles of 90 tablets Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 5 mg/1000 mg, are pink, film-coated, capsule shaped, unscored tablets imprinted with SM6 over M in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-8177-93 bottles of 30 tablets NDC 0378-8177-77 bottles of 90 tablets Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, 2.5 mg/1000 mg, are light peach, film-coated, capsule shaped, unscored tablets imprinted with SM4 over M in black ink on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-8176-93 bottles of 30 tablets NDC 0378-8176-91 bottles of 60 tablets Storage and Handling: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.

Saxagliptin and metformin hydrochloride extended-release tablets combine two antihyperglycemic medications with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin hydrochloride, a biguanide. 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 DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 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. Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in unusual circumstances [ see Warnings and Precautions (5.6) ] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. In patients with type 2 diabetes mellitus, administration of saxagliptin inhibits DPP4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 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. In a 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). Bioequivalence and food effect of saxagliptin and metformin hydrochloride extended-release tablets were characterized under low calorie diet. The low calorie diet consisted of 324 kcal with meal composition that contained 11.1% protein, 10.5% fat, and 78.4% carbohydrate. The results of bioequivalence studies in healthy subjects demonstrated that saxagliptin and metformin hydrochloride extended-release combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin (ONGLYZA ® ) and metformin hydrochloride extended-release (GLUCOPHAGE ® XR) as individual tablets under fed conditions. 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. Metformin extended-release C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and C max are less than dose proportional for metformin extended-release within the range of 500 to 2000 mg. After repeated administration of metformin extended-release, metformin did not accumulate in plasma. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. Peak plasma levels of metformin extended-release tablets are approximately 20% lower compared to the same dose of metformin immediate-release tablets, however, the extent of absorption (as measured by AUC) is similar between extended-release tablets and immediate-release tablets. 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. 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. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as saxagliptin and metformin hydrochloride extended-release combination tablets. Following a single oral dose of metformin extended-release, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release. Food has no significant effect on the pharmacokinetics of metformin when administered as saxagliptin and metformin hydrochloride extended-release combination tablets. 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. Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins. The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a 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) ]. Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted. 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 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. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. A 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 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. In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [ see Contraindications (4) and Warnings and Precautions (5.1) ]. No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. 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. 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. Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females. 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. Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. 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. No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n = 249), Blacks (n = 51), and Hispanics (n = 24). Specific pharmacokinetic drug interaction studies with saxagliptin and metformin hydrochloride extended-release tablets have not been performed, although such studies have been conducted with the individual saxagliptin and metformin components. 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. Table 3: Effect of Coadministered Drug 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 1000 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 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 Dapagliflozin 10 mg single dose 5 mg single dose saxagliptin ↓ 1% ↓ 7% 5-hydroxy saxagliptin ↑ 9% ↑ 6% 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 dipeptidyl peptidase-4 (DPP4) 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 and metformin hydrochloride extended-release tablet dose to 2.5 mg/1000 mg once daily when coadministered with strong CYP3A4/5 inhibitors [ see Drug Interactions (7.1) and Dosage and Administration (2.2) ]: 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 4: 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 saxagliptin dose is not an approved dosage. 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 1000 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   Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses. Dose of Metformin Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC AUC = AUC(INF). C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 Ratio of arithmetic means. 0.93 Furosemide 40 mg 850 mg metformin 1.09 1.22 Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 1.07 Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [ see Drug Interactions (7.3) ]. Cimetidine 400 mg 850 mg metformin 1.40 1.61   Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin and coadministered drugs were given as single doses. Dose of Metformin Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC AUC = AUC(INF) unless otherwise noted. C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 Ratio of arithmetic means, p-value of difference < 0.05. 0.63 Furosemide 40 mg 850 mg furosemide 0.87 0.69 Nifedipine 10 mg 850 mg nifedipine 1.10 AUC(0-24 hr) reported. 1.08 Propranolol 40 mg 850 mg propranolol 1.01 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 Ratio of arithmetic means. 1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01

No animal studies have been conducted with the combined products in saxagliptin and metformin hydrochloride extended-release tablets to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on studies with saxagliptin and metformin administered individually. 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 1165-times (females) the 5 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 2217-times (females) the 5 mg/day clinical dose, based on AUC. Saxagliptin was not mutagenic or clastogenic in a 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. Saxagliptin administered to rats had no effect on fertility or the ability to maintain a litter at exposures up to 603-times and 776-times the 5 mg clinical dose in males and females, based on AUC. Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test ( S. typhimurium ), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons. 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 5 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 5 mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

There have been no clinical efficacy or safety studies conducted with saxagliptin and metformin hydrochloride extended-release tablets to characterize their effect on A1C reduction. Bioequivalence of saxagliptin and metformin hydrochloride extended-release tablets with coadministered saxagliptin and metformin hydrochloride extended-release tablets has been demonstrated; however, relative bioavailability studies between saxagliptin and metformin hydrochloride extended-release tablets and coadministered saxagliptin and metformin hydrochloride immediate-release tablets have not been conducted. The metformin hydrochloride extended-release tablets and metformin hydrochloride immediate-release tablets have a similar extent of absorption (as measured by AUC) while peak plasma levels of extended-release tablets are approximately 20% lower than those of immediate-release tablets at the same dose. The coadministration of saxagliptin and metformin immediate-release tablets has been studied in adults with type 2 diabetes inadequately controlled on metformin alone and in treatment-naive patients inadequately controlled on diet and exercise alone. In these two trials, treatment with saxagliptin dosed in the morning plus metformin immediate-release tablets at all doses produced clinically relevant and statistically significant improvements in A1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following a standard oral glucose tolerance test (OGTT), compared to control. Reductions in A1C were seen across subgroups including gender, age, race, and baseline BMI. In these two trials, decrease in body weight in the treatment groups given saxagliptin in combination with metformin immediate-release was similar to that in the groups given metformin immediate-release alone. Saxagliptin plus metformin immediate-release was not associated with significant changes from baseline in fasting serum lipids compared to metformin alone. The coadministration of saxagliptin and metformin immediate-release tablets has also been evaluated in an active-controlled trial comparing add-on therapy with saxagliptin to glipizide in 858 patients inadequately controlled on metformin alone, in a placebo-controlled trial where a subgroup of 314 patients inadequately controlled on insulin plus metformin received add-on therapy with saxagliptin or placebo, a trial comparing saxagliptin to placebo in 257 patients inadequately controlled on metformin plus a sulfonylurea, and a trial comparing saxagliptin to placebo in 315 patients inadequately controlled on dapagliflozin and metformin. In a 24-week, double-blind, randomized trial, patients treated with metformin immediate-release 500 mg twice daily for at least 8 weeks were randomized to continued treatment with metformin immediate-release 500 mg twice daily or to metformin extended-release either 1000 mg once daily or 1500 mg once daily. The mean change in A1C from baseline to Week 24 was 0.1% (95% confidence interval 0%, 0.3%) for the metformin immediate-release treatment arm, 0.3% (95% confidence interval 0.1%, 0.4%) for the 1000 mg metformin extended-release treatment arm, and 0.1% (95% confidence interval 0%, 0.3%) for the 1500 mg metformin extended-release treatment arm. Results of this trial suggest that patients receiving metformin immediate-release treatment may be safely switched to metformin extended-release once daily at the same total daily dose, up to 2000 mg once daily. Following a switch from metformin immediate-release to metformin extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly. A 24-week monotherapy trial was conducted to assess a range of dosing regimens for saxagliptin. Treatment-naive patients with inadequately controlled diabetes (A1C ≥ 7% to ≤ 10%) underwent a 2-week, single-blind diet, exercise, and placebo lead-in period. A total of 365 patients were randomized to 2.5 mg every morning, 5 mg every morning, 2.5 mg with possible titration to 5 mg every morning, or 5 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 5 mg every morning or 5 mg every evening provided significant improvements in A1C versus placebo (mean placebo-corrected reductions of -0.4% and -0.3%, respectively). 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 coadministered with metformin immediate-release 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 a single-blind, 1-week, dietary and exercise placebo lead-in period. Patients were randomized to one of four treatment arms: saxagliptin 5 mg + metformin immediate-release 500 mg, saxagliptin 10 mg + metformin immediate-release 500 mg, saxagliptin 10 mg + placebo, or metformin immediate-release 500 mg + placebo (the maximum recommended approved saxagliptin dose is 5 mg daily; the 10 mg daily dose of saxagliptin does not provide greater efficacy than the 5 mg daily dose and the 10 mg saxagliptin dosage is not an approved dosage). Saxagliptin was dosed once daily. In the 3 treatment groups using metformin immediate-release, the metformin dose was up-titrated weekly in 500 mg per day increments, as tolerated, to a maximum of 2000 mg per day based on FPG. Patients who failed to meet specific glycemic goals during this study were treated with pioglitazone rescue as add-on therapy. Coadministration of saxagliptin 5 mg plus metformin immediate-release provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin immediate-release (Table 7). Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of Saxagliptin Coadministration with Metformin Immediate-Release in Treatment-Naive Patients Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue. Efficacy Parameter Saxagliptin 5 mg + Metformin N = 320 Placebo + Metformin N = 328 Hemoglobin A1C (%) N = 306 N = 313     Baseline (mean) 9.4 9.4     Change from baseline (adjusted mean Least squares mean adjusted for baseline value. ) -2.5 -2.0     Difference from placebo + metformin (adjusted mean ) -0.5 p-value < 0.0001 compared to placebo + metformin        95% Confidence Interval (-0.7, -0.4)     Percent of patients achieving A1C < 7% 60% p-value < 0.05 compared to placebo + metformin (185/307) 41% (129/314) Fasting Plasma Glucose (mg/dL) N = 315 N = 320     Baseline (mean) 199 199     Change from baseline (adjusted mean ) -60 -47     Difference from placebo + metformin (adjusted mean ) -13        95% Confidence Interval (-19, -6) 2-hour Postprandial Glucose (mg/dL) N = 146 N = 141     Baseline (mean) 340 355     Change from baseline (adjusted mean ) -138 -97     Difference from placebo + metformin (adjusted mean ) -41        95% Confidence Interval (-57, -25) A total of 743 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with metformin immediate-release in patients with inadequate glycemic control (A1C ≥ 7% and ≤ 10%) on metformin alone. To qualify for enrollment, patients were required to be on a stable dose of metformin (1500-2550 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 immediate-release at their pre-study dose, up to 2500 mg daily, for the duration of the study. Following the lead-in period, eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of saxagliptin or placebo in addition to their current dose of open-label metformin immediate-release (the maximum recommended approved saxagliptin dose is 5 mg daily; the 10 mg daily dose of saxagliptin does not provide greater efficacy than the 5 mg daily dose and 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 immediate-release were not permitted. Saxagliptin 2.5 mg and 5 mg add-on to metformin immediate-release provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin immediate-release (Table 8). 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 immediate-release group, 13% in the saxagliptin 5 mg add-on to metformin immediate-release group, and 27% in the placebo add-on to metformin immediate-release group. Table 8: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of Saxagliptin as Add-On Combination Therapy with Metformin Immediate-Release Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue. Efficacy Parameter Saxagliptin 2.5 mg + Metformin N = 192 Saxagliptin 5 mg + Metformin N = 191 Placebo + Metformin N = 179 Hemoglobin A1C (%) N = 186 N = 186 N = 175      Baseline (mean) 8.1 8.1 8.1      Change from baseline (adjusted mean Least squares mean adjusted for baseline value. ) -0.6 -0.7 +0.1      Difference from placebo (adjusted mean ) -0.7 p-value < 0.0001 compared to placebo + metformin. -0.8         95% Confidence Interval (-0.9, -0.5) (-1.0, -0.6)      Percent of patients achieving A1C < 7% 37% p-value < 0.05 compared to placebo + metformin. (69/186) 44% (81/186) 17% (29/175) Fasting Plasma Glucose (mg/dL) N = 188 N = 187 N = 176      Baseline (mean) 174 179 175      Change from baseline (adjusted mean ) -14 -22 +1      Difference from placebo (adjusted mean ) -16 -23         95% Confidence Interval (-23, -9) (-30, -16) 2-hour Postprandial Glucose (mg/dL) N = 155 N = 155 N = 135      Baseline (mean) 294 296 295      Change from baseline (adjusted mean ) -62 -58 -18      Difference from placebo (adjusted mean ) -44 -40         95% Confidence Interval (-60, -27) (-56, -24)    Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin Immediate-Release 5 5 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. Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin Immediate-Release* In this 52-week, active-controlled trial, a total of 858 patients with type 2 diabetes and inadequate glycemic control (A1C > 6.5% and ≤ 10%) on metformin immediate-release alone were randomized to double-blind add-on therapy with saxagliptin or glipizide. Patients were required to be on a stable dose of metformin immediate-release (at least 1500 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 immediate-release (1500-3000 mg based on their prestudy dose). Following the lead-in period, eligible patients were randomized to 5 mg of saxagliptin or 5 mg of glipizide in addition to their current dose of open-label metformin immediate-release. Patients in the glipizide plus metformin immediate-release 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 and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin immediate-release 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 compared to a 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 Metformin Immediate-Release Intent-to-treat population using last observation on study. Efficacy Parameter Saxagliptin 5 mg + Metformin N = 428 Titrated Glipizide + Metformin N = 430 Hemoglobin A1C (%) N = 423 N = 423      Baseline (mean) 7.7 7.6      Change from baseline (adjusted mean Least squares mean adjusted for baseline value. ) -0.6 -0.7      Difference from glipizide + metformin (adjusted mean ) 0.1         95% Confidence Interval (-0.02, 0.2) 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%. Fasting Plasma Glucose (mg/dL) N = 420 N = 420      Baseline (mean) 162 161      Change from baseline (adjusted mean ) -9 -16      Difference from glipizide + metformin (adjusted mean ) 6         95% Confidence Interval (2, 11) Significance not tested. A total of 455 patients with type 2 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 a stable dose of metformin immediate-release (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, 4-week, dietary and exercise placebo lead-in period during which patients received insulin (and metformin immediate-release if applicable) at their pretrial dose(s). Following the lead-in period, eligible patients were randomized to add-on therapy with either saxagliptin 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 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 5 mg add-on to insulin alone and saxagliptin 5 mg add-on to insulin in combination with metformin immediate-release (-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 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 5 mg group and 5 units for the placebo group. Table 10: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Insulin Intent-to-treat population using last observation on study or last observation prior to insulin rescue therapy for patients needing rescue. Efficacy Parameter Saxagliptin 5 mg + Insulin (+/- Metformin) N = 304 Placebo + Insulin (+/- Metformin) N = 151 Hemoglobin A1C (%) N = 300 N = 149      Baseline (mean) 8.7 8.7      Change from baseline (adjusted mean Least squares mean adjusted for baseline value and metformin use at baseline. ) -0.7 -0.3      Difference from placebo (adjusted mean ) -0.4 p-value < 0.0001 compared to placebo + insulin.         95% Confidence Interval (-0.6, -0.2) 2-hour Postprandial Glucose (mg/dL) N = 262 N = 129      Baseline (mean) 251 255      Change from baseline (adjusted mean ) -27 -4      Difference from placebo (adjusted mean ) -23 p-value < 0.05 compared to placebo + insulin.         95% Confidence Interval (-37, -9) 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. A total of 257 subjects with type 2 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 a sulfonylurea in patients with inadequate glycemic control (A1C ≥ 7% and ≤ 10%). Patients were to be on a stable combined dose of metformin extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1500 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 (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 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 study medication during the treatment period was prohibited. Saxagliptin in combination with metformin plus a sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin plus a 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 a Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin Plus Sulfonylurea Intent-to-treat population using last observation prior to discontinuation. Efficacy Parameter Saxagliptin 5 mg + Metformin Plus Sulfonylurea N = 129 Placebo + Metformin Plus Sulfonylurea N = 128 Hemoglobin A1C (%) N = 127 N = 127      Baseline (mean) 8.4 8.2      Change from baseline (adjusted mean Least squares mean adjusted for baseline value. ) -0.7 -0.1      Difference from placebo (adjusted mean ) -0.7 p-value < 0.0001 compared to placebo + metformin plus sulfonylurea.         95% Confidence Interval (-0.9, -0.5) 2-hour Postprandial Glucose (mg/dL) N = 115 N = 113      Baseline (mean) 268 262      Change from baseline (adjusted mean ) -12 5      Difference from placebo (adjusted mean ) -17 p-value < 0.05 compared to placebo + metformin plus sulfonylurea.         95% Confidence Interval (-32, -2) 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 a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested. A total of 315 patients with type 2 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 a 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 a mean HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m 2 . Patients were required to be on a stable dose of metformin (≥ 1500 mg per day) for at least 8 weeks prior to enrollment. Eligible subjects who completed the screening period entered the lead-in treatment period, which included 16 weeks of open-label metformin and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to saxagliptin 5 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 a Placebo-Controlled Trial of Saxagliptin as Add-On to Dapagliflozin and Metformin 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. Saxagliptin 5 mg (N = 153) Number of randomized and treated patients. Placebo (N = 162) In combination with Dapagliflozin and Metformin Hemoglobin A1C (%) 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. Baseline (mean) 8.0 7.9 Change from baseline (adjusted mean Least squares mean adjusted for baseline value. )      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 p-value < 0.0001 (-0.5, -0.2) 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. The cardiovascular risk of saxagliptin was evaluated in SAVOR, a multicenter, multinational, randomized, double-blind study comparing saxagliptin (N = 8280) to placebo (N = 8212), both administered in combination with standard of care, in adult patients with type 2 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 2 years. The trial was event-driven, and patients were followed until a 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 a history of ischemic heart disease, peripheral vascular disease, or ischemic stroke. The majority of subjects were male (67%) and Caucasian (75%) with a mean age of 65 years. Approximately 16% of the population had moderate (estimated glomerular filtration rate [eGFR] ≥ 30 to ≤ 50 mL/min) to severe (eGFR < 30 mL/min) renal impairment, and 13% had a prior history of heart failure. Subjects had a median duration of type 2 diabetes mellitus of approximately 10 years, and a 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 (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 primary analysis in SAVOR was time to first occurrence of a Major Adverse Cardiac Event (MACE). A major adverse cardiac event in SAVOR was defined as a cardiovascular death, or a nonfatal myocardial infarction (MI) or a nonfatal ischemic stroke. The study was designed as a non-inferiority trial with a pre-specified risk margin of 1.3 for the hazard ratio of MACE, and was also powered for a 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 13. 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 a 95.1% confidence interval of (0.89, 1.12). The upper bound of this confidence interval, 1.12, excluded a risk margin larger than 1.3. Table 13: Major Adverse Cardiovascular Events (MACE) by Treatment Group in the SAVOR Trial Saxagliptin Placebo Hazard Ratio Number of Subjects (%) Rate per 100 PY Number 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 = 8280 Total PY = 16308.8 N = 8212 Total PY = 16156.0 613 (7.4) 3.8 609 (7.4) 3.8 1.00 (0.89, 1.12)     CV death 245 (3.0) 1.5 234 (2.8) 1.4     Non-fatal MI 233 (2.8) 1.4 260 (3.2) 1.6     Non-fatal ischemic stroke 135 (1.6) 0.8 115 (1.4) 0.7 The Kaplan-Meier-based cumulative event probability is presented in Figure 2 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 MACE Vital 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 14) was not statistically different between the treatment groups (HR: 1.11; 95.1% CI: 0.96, 1.27). Table 14: All-Cause Mortality by Treatment Group in the SAVOR Study Saxagliptin Placebo Hazard Ratio Number of Subjects (%) Rate per 100 PY Number of Subjects (%) Rate per 100 PY (95.1% CI) N = 8280 PY = 16645.3 N = 8212 PY = 16531.5 All-cause mortality 420 (5.1) 2.5 378 (4.6) 2.3 1.11 (0.96, 1.27)     CV death 269 (3.2) 1.6 260 (3.2) 1.6     Non-CV death 151 (1.8) 0.9 118 (1.4) 0.7 Figure 2: Cumulative Percent of Time to First MACE

NDC 0378-8175-93 Saxagliptin and Metformin HCl Extended-Release Tablets 5 mg/500 mg PHARMACIST: Dispense the accompanying Medication Guide to each patient.   Do not crush, cut, or chew tablets. Tablets must be swallowed whole.   Rx only     30 Tablets Each film-coated extended-release tablet contains 6.149 mg saxagliptin hydrochloride dihydrate equivalent to 5 mg saxagliptin and 500 mg metformin hydrochloride, USP. Usual Dosage: See accompanying prescribing information. Keep this and all medication out of the reach of children. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in India Mylan.com RMXA8175H1 Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Keep container tightly closed. Code No.: MH/DRUGS/AD/089 Saxagliptin and Metformin HCl Extended-Release Tablets 5 mg/500 mg Bottle Label