ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information:oLactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) oPancreatitis [see Warnings and Precautions (5.2) ]oHeart Failure [see Warnings and Precautions (5.3) oVitamin B12 Concentrations [see Warnings and Precautions (5.4) ]oHypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5) ]oHypersensitivity Reactions [see Warnings and Precautions (5.6) ]oSevere and disabling arthralgia [see Warnings and Precautions (5.7) ]oBullous pemphigoid [see Warnings and Precautions (5.8) ]. oLactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) . oPancreatitis [see Warnings and Precautions (5.2) ]. oHeart Failure [see Warnings and Precautions (5.3) . oVitamin B12 Concentrations [see Warnings and Precautions (5.4) ]. oHypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5) ]. oHypersensitivity Reactions [see Warnings and Precautions (5.6) ]. oSevere and disabling arthralgia [see Warnings and Precautions (5.7) ]. oBullous pemphigoid [see Warnings and Precautions (5.8) ]. oMost common adverse reactions with metformin HCl extended release (incidence 5% and more often than placebo) are: diarrhea and nausea/vomiting. (6.1)oMost common adverse reactions with saxagliptin (incidence >= 5% and more often than placebo) are: upper respiratory tract infection, urinary tract infection, and headache. (6.1)oAdverse reactions with coadministered saxagliptin and metformin HCl (incidence >= 5% and more often than placebo) are: headache and nasopharyngitis. (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. oMost common adverse reactions with metformin HCl extended release (incidence 5% and more often than placebo) are: diarrhea and nausea/vomiting. (6.1). oMost common adverse reactions with saxagliptin (incidence >= 5% and more often than placebo) are: upper respiratory tract infection, urinary tract infection, and headache. (6.1). oAdverse reactions with coadministered saxagliptin and metformin HCl (incidence >= 5% and more often than placebo) are: headache and nasopharyngitis. (6.1). 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions in Placebo-Controlled Trials in Adults with Type Diabetes Mellitus. Metformin HCl In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and nausea/vomiting were reported in 5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of trial medication in 0.6% of the patients treated with metformin HCl extended-release.. Saxagliptin The data in Table are derived from pool of placebo-controlled clinical trials [see Clinical Studies (14) ]. These data shown in the table reflect exposure of 882 patients to saxagliptin and mean duration of exposure to saxagliptin of 21 weeks. The mean age of these patients was 55 years, 1.4% were 75 years or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, 10.5% other races and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 5.2 years and mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR >= 60 mL/min/1.73 m2) in 91% of these patients.Table shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin. These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least 5% of patients treated with saxagliptin.Table 1: Adverse Reactions in Placebo-Controlled TrialsThe placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin HCl, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue. Reported in >= 5% of Patients Treated with Saxagliptin mg and More Commonly than in Patients Treated with Placebo% of PatientsSaxagliptin mgN 882PlaceboN 799Upper respiratory tract infection7.77.6Urinary tract infection6.86.1Headache6.55.9In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction reported at rate >= 5% and more commonly than in patients treated with placebo. In the add-on to TZD trial, the incidence of peripheral edema was higher for saxagliptin mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in trial drug discontinuation. Rates of peripheral edema for saxagliptin 2.5 mg and saxagliptin mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin 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 (pooled analysis of 2.5 mg, mg, and 10 mg) and placebo. The 10 mg saxagliptin dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin on bone.An event of thrombocytopenia, consistent with diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to saxagliptin is not known.Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of patients receiving saxagliptin 2.5 mg, saxagliptin mg, and placebo, respectively. The most common adverse reactions (reported in at least patients treated with saxagliptin 2.5 mg or at least patients treated with saxagliptin mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%).. Adverse Reactions with Concomitant Use with Insulin. In the add-on to insulin trial [see Clinical Studies (14.1) ], the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo, except for confirmed hypoglycemia [see Adverse Reactions (6.1) ].. Adverse Reactions Associated with Saxagliptin Coadministered with Metformin HCl Immediate-Release in Treatment-Naive Patients with Type Diabetes Mellitus. Table shows the adverse reactions reported (regardless of investigator assessment of causality) in >= 5% of patients participating in an additional 24-week, active-controlled trial of coadministered saxagliptin and metformin HCl in treatment-naive patients.Table 2: Coadministration of Saxagliptin and Metformin HCl Immediate-Release in Treatment-Naive Patients: Adverse Reactions Reported in >= 5% of Patients Treated with Combination Therapy of Saxagliptin mg Plus Metformin HCl Immediate-Release (and More Commonly than in Patients Treated with Metformin HCl Immediate-Release Alone)Number (%) of PatientsSaxagliptin mg Metformin HClMetformin HCl immediate-release was initiated at starting dose of 500 mg daily and titrated up to maximum of 2,000 mg daily.N 320Placebo Metformin HClN 328Headache24 (7.5)17 (5.2)Nasopharyngitis22 (6.9)13 (4.0)In patients treated with the combination of saxagliptin and metformin HCl immediate-release, either as saxagliptin add-on to metformin HCl immediate-release therapy or as coadministration in treatment-naive patients, diarrhea was the only gastrointestinal-related event that occurred with an incidence >= 5% in any treatment group in both trials. In the saxagliptin add-on to metformin HCl immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the saxagliptin 2.5 mg, mg, and placebo groups, respectively. When saxagliptin and metformin HCl immediate-release were coadministered in treatment-naive patients, the incidence of diarrhea was 6.9% in the saxagliptin mg metformin HCl immediate-release group and 7.3% in the placebo metformin HCl immediate-release group.. Hypoglycemia. In the saxagliptin clinical trials, adverse reactions of hypoglycemia were based on all reports of hypoglycemia. concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia.The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively. In the add-on to metformin HCl immediate-release trial, the incidence of reported hypoglycemia was 7.8% with saxagliptin 2.5 mg, 5.8% with saxagliptin mg, and 5% with placebo. When saxagliptin and metformin HCl immediate-release were coadministered in treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in patients given saxagliptin mg metformin HCl immediate-release and 4% in patients given placebo metformin HCl immediate-release.In the active-controlled trial comparing add-on therapy with saxagliptin 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 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose <= 50 mg/dL) was reported in none of the saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%) (p 0.0001).In the saxagliptin add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for saxagliptin mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose <= 50 mg/dL) was higher with saxagliptin mg (5.3%) versus placebo (3.3%). Among the patients using insulin in combination with metformin HCl, the incidence of confirmed symptomatic hypoglycemia was 4.8% with saxagliptin versus 1.9% with placebo.In the saxagliptin add-on to metformin HCl plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for saxagliptin mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in none of the placebo-treated patients [see Warnings and Precautions (5.5) ].. Hypersensitivity Reactions. Saxagliptin 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 2.5 mg, saxagliptin mg, and placebo, respectively. None of these events in patients who received saxagliptin required hospitalization or were reported as life-threatening by the investigators. One saxagliptin-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema.. Renal Impairment. In the SAVOR trial, adverse reactions related to renal impairment, including laboratory changes (i.e., doubling of serum creatinine compared with baseline and serum creatinine 6 mg/dL), were reported in 5.8% (483/8280) of saxagliptin-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 versus placebo groups, respectively. From baseline to the end of treatment, there was mean decrease in eGFR of 2.5 mL/min/1.73 m2 for saxagliptin-treated patients and mean decrease of 2.4 mL/min/1.73 m2 for placebo-treated patients. More patients randomized to saxagliptin (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 m2 (i.e., normal or mild renal impairment) to <= 50 mL/min/1.73 m2 (i.e., moderate or severe renal impairment). The proportions of patients with renal adverse reactions increased with worsening baseline renal function and increased age, regardless of treatment assignment.. Infections. Saxagliptin In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been (0.12%) reports of tuberculosis among the 4959 saxagliptin-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 patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with saxagliptin until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of saxagliptin that remained stable throughout saxagliptin treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with saxagliptin use. Causality has not been established and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use.There has been one case of potential opportunistic infection in the unblinded, controlled clinical trial database to date in saxagliptin-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of saxagliptin therapy. There have been no spontaneous reports of opportunistic infections associated with saxagliptin use.. Vital Signs. Saxagliptin No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin alone or in combination with metformin HCl.. Laboratory Tests. Absolute Lymphocyte CountsSaxagliptinThere was dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. From baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in pooled analysis of five placebo-controlled clinical trials. Similar effects were observed when saxagliptin mg and metformin HCl were coadministered in treatment-naive patients compared to placebo and metformin HCl. There was no difference observed for saxagliptin 2.5 mg relative to placebo. The proportion of patients who were reported to have lymphocyte count <= 750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg saxagliptin dosage is not an approved dosage.In the SAVOR trial mean decreases of approximately 84 cells/microL with saxagliptin relative to placebo was observed. The proportion of patients who experienced decrease in lymphocyte counts to count of <= 750 cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on saxagliptin and placebo, respectively.The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.Vitamin B12 ConcentrationsMetformin HClIn metformin clinical trials of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.. 6.2Postmarketing Experience Additional adverse reactions have been identified during post-approval use of saxagliptin and metformin hydrochloride extended-release tablets, saxagliptin, or metformin HCl. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.SaxagliptinoGastrointestinal Disorders: Pancreatitis oImmune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions oMusculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgiaoSkin and Subcutaneous Tissue Disorders: Bullous pemphigoidMetformin HCloHepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury. oGastrointestinal Disorders: Pancreatitis oImmune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions oMusculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgia. oSkin and Subcutaneous Tissue Disorders: Bullous pemphigoid. oHepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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

BOXED WARNING SECTION.

WARNING: LACTIC ACIDOSIS oPost-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally 5 mcg/mL [see Warnings and Precautions (5.1) ].oRisk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, hepatic impairment, and mitochondrial diseases [see Warnings and Precautions (5.1) ].oSteps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7) ].oIf metformin-associated lactic acidosis is suspected, immediately discontinue saxagliptin and metformin hydrochloride extended-release tablets and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ].. oPost-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally 5 mcg/mL [see Warnings and Precautions (5.1) ].. oRisk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, hepatic impairment, and mitochondrial diseases [see Warnings and Precautions (5.1) ].. oSteps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7) ].. oIf metformin-associated lactic acidosis is suspected, immediately discontinue saxagliptin and metformin hydrochloride extended-release tablets and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ].. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.oPost-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally 5 mcg/mL. (5.1)oRisk factors include renal impairment, concomitant use of certain drugs, age 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, hepatic impairment, and mitochondrial diseases. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1)oIf lactic acidosis is suspected, discontinue saxagliptin and metformin hydrochloride extended-release tablets and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.1). oPost-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally 5 mcg/mL. (5.1). oRisk factors include renal impairment, concomitant use of certain drugs, age 65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, hepatic impairment, and mitochondrial diseases. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.1). oIf lactic acidosis is suspected, discontinue saxagliptin and metformin hydrochloride extended-release tablets and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Saxagliptin and Metformin Hydrochloride Extended-Release Tablets. 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.. Saxagliptin. CarcinogenesisCarcinogenicity 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 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 mg/day clinical dose, based on AUC.MutagenesisSaxagliptin was not mutagenic or clastogenic in battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNA repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.Impairment of FertilitySaxagliptin administered to rats had no effect on fertility or the ability to maintain litter at exposures up to 603-times and 776-times the mg clinical dose in males and females, based on AUC.. Metformin HCl. CarcinogenesisLong-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 1,500 mg/kg/day, respectively. These doses are both approximately times the maximum recommended human daily dose of 2,000 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.MutagenesisThere was no evidence of 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.Impairment of FertilityFertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately times the maximum recommended human daily dose based on body surface area comparisons.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Saxagliptin and Metformin Hydrochloride Extended-Release Tablets. Saxagliptin and metformin hydrochloride extended-release tablets contain two antihyperglycemic medications: saxagliptin, dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin HCl, biguanide.. Saxagliptin. Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in glucose-dependent manner in patients with type diabetes mellitus.. Metformin HCl. Metformin improves glucose tolerance in patients with type diabetes mellitus, 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 diabetes mellitus or in healthy subjects except in unusual circumstances [see Warnings and Precautions (5.5)] 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.. 12.2 Pharmacodynamics Saxagliptin. In patients with type diabetes mellitus, administration of saxagliptin inhibits DPP4 enzyme activity for 24-hour period. After an oral glucose load or meal, this DPP4 inhibition resulted in 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or meal.. Cardiac Electrophysiology. Saxagliptin In randomized, double-blind, placebo-controlled, 4-way crossover, active comparator trial using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8-times the MRHD).. 12.3 Pharmacokinetics Saxagliptin and Metformin Hydrochloride Extended-Release Tablets. 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(R)) and metformin HCl extended-release as individual tablets under fed conditions.. Saxagliptin. The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ngoh/mL and 214 ngoh/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.. Metformin HCl. Metformin extended-release Cmax is achieved with median value of hours and range of to hours. At steady state, the AUC and Cmax are less than dose proportional for metformin extended-release within the range of 500 to 2,000 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.. Absorption. Saxagliptin The median time to maximum concentration (Tmax) following the mg once daily dose was hours for saxagliptin and hours for its active metabolite. Metformin HCl Following single oral dose of metformin extended-release, Cmax is achieved with median value of hours and range of to hours.. Effect of Food. Saxagliptin Administration with high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was 27% increase in the AUC of saxagliptin when given with meal as compared to fasted conditions. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as saxagliptin and metformin hydrochloride extended-release combination tablets.. Metformin HCl 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 Cmax and Tmax 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.. Distribution. Saxagliptin 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.. Metformin HCl 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 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.. Elimination. Metabolism. SaxagliptinThe metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions (7.1) ].Metformin HClIntravenous 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.. Excretion. SaxagliptinSaxagliptin is eliminated by both renal and hepatic pathways. Following single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~ 230 mL/min) was greater than the average estimated glomerular filtration rate (~ 120 mL/min), suggesting some active renal excretion. total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following single oral dose of saxagliptin mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.Metformin HClRenal 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 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 compartment of distribution.. Specific Populations. Geriatric Patients SaxagliptinNo dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.Metformin HClLimited 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 Cmax 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 change in renal function.. Male and Female Patients SaxagliptinNo dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.Metformin HClMetformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type diabetes mellitus when analyzed according to gender (males 19, females 16). Similarly, in controlled clinical studies in patients with type diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.. Racial or Ethnic Groups SaxagliptinNo 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.Metformin HClNo studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n 249), Black or African American (n 51), and Hispanic or Latino ethnicity (n 24).. Patients with Renal Impairment SaxagliptinA single-dose, open-label trial was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment with eGFR 30 to less than 45 mL/min/1.73 m2, severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were 2 fold higher than AUC values in subjects with normal renal function.Metformin HClIn 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) ].. Patients with Hepatic Impairment No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. Body Mass Index SaxagliptinNo dosage adjustment is recommended based on body mass index (BMI) which was not identified as significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis.. Drug Interaction Studies. 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 Vitro Assessment of Drug Interactions 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 P-glycoprotein (P-gp) substrate, but is not significant inhibitor or inducer of P-gp.. In Vivo Assessment of Drug Interactions Table 3: Effect of Coadministered Drug on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinND not determined; QD once daily; q6h every hours; q12h every 12 hours; BID twice daily; LA long acting.Coadministered DrugDosage of Coadministered DrugSingle dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage.Dosage of SaxagliptinGeometric Mean Ratio(ratio with/without coadministered drug)No Effect 1.00AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.Cmax No dosing adjustments required for the following:Metformin1,000 mg100 mgsaxagliptin0.980.795-hydroxy saxagliptin0.990.88Glyburide5 mg10 mgsaxagliptin0.981.085-hydroxy saxagliptinNDNDPioglitazoneResults exclude one patient. 45 mg QD for 10 days10 mg QD for dayssaxagliptin1.111.115-hydroxy saxagliptinNDNDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QD for dayssaxagliptin1.050.995-hydroxy saxagliptin1.061.02Dapagliflozin10 mg single dose5 mg single dosesaxagliptin 1% 7%5-hydroxy saxagliptin 9% 6%Simvastatin40 mg QD for days10 mg QD for dayssaxagliptin1.121.215-hydroxy saxagliptin1.021.08Diltiazem360 mg LA QD for days10 mgsaxagliptin2.091.635-hydroxy saxagliptin0.660.57RifampinThe plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over 24-hour dose interval was not affected by rifampin. 600 mg QD for days5 mgsaxagliptin0.240.475-hydroxy saxagliptin1.031.39Omeprazole40 mg QD for days10 mgsaxagliptin1.130.985-hydroxy saxagliptinNDNDAluminum hydroxide magnesium hydroxide simethiconealuminum hydroxide: 2400 mgmagnesium hydroxide: 2400 mgsimethicone: 240 mg10 mgsaxagliptin0.970.745-hydroxy saxagliptinNDNDFamotidine40 mg10 mgsaxagliptin1.031.145-hydroxy saxagliptinNDNDLimit saxagliptin and metformin hydrochloride extended-release tablet dose to 2.5 mg/1,000 mg once daily when coadministered with strong CYP3A4/5 inhibitors [see Drug Interactions (7.1) and Dosage and Administration (2.2) ]:Ketoconazole200 mg BID for days100 mgsaxagliptin2.451.625-hydroxy saxagliptin0.120.05Ketoconazole200 mg BID for days20 mgsaxagliptin3.672.445-hydroxy saxagliptinNDND Table 4: Effect of Saxagliptin on Systemic Exposures of Coadministered DrugsND not determined; QD once daily; q6h every hours; q12h every 12 hours; BID twice daily; LA long acting.Coadministered DrugDosage of Coadministered DrugSingle dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage.Dosage of SaxagliptinGeometric Mean Ratio(ratio with/without saxagliptin)No Effect 1.00AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.Cmax No dosing adjustments required for the following:Metformin1,000 mg100 mgmetformin1.201.09Glyburide5 mg10 mgglyburide1.061.16PioglitazoneResults include all patients. 45 mg QD for 10 days10 mg QD for dayspioglitazone1.081.14hydroxy-pioglitazoneNDNDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QD for daysdigoxin1.061.09Simvastatin40 mg QD for days10 mg QD for dayssimvastatin1.040.88simvastatin acid1.161.00Diltiazem360 mg LA QD for days10 mgdiltiazem1.101.16Ketoconazole200 mg BID for days100 mgketoconazole0.870.84Ethinyl estradiol and norgestimateethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days5 mg QD for 21 daysethinyl estradiol1.070.98norelgestromin1.101.09norgestrel1.131.17 Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic ExposureCoadministered DrugDose of Coadministered DrugAll metformin and coadministered drugs were given as single doses.Dose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No Effect 1.00AUCAUC AUC(INF).Cmax No dosing adjustments required for the following:Glyburide5 mg850 mgmetformin0.91Ratio of arithmetic means. 0.93 Furosemide40 mg850 mgmetformin1.09 1.22 Nifedipine10 mg850 mgmetformin1.161.21Propranolol40 mg850 mgmetformin0.900.94Ibuprofen400 mg850 mgmetformin1.05 1.07 Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7.3) ].Cimetidine400 mg850 mgmetformin1.401.61 Table 6: Effect of Metformin on Coadministered Drug Systemic ExposureCoadministeredDrugDose ofCoadministered DrugAll metformin and coadministered drugs were given as single doses.Dose ofMetforminGeometric Mean Ratio(ratio with/without metformin)No Effect 1.00AUCAUC AUC(INF) unless otherwise noted.Cmax No dosing adjustments required for the following:Glyburide5 mg850 mgglyburide0.78Ratio of arithmetic means, p-value of difference 0.05. 0.63 Furosemide40 mg850 mgfurosemide0.87 0.69 Nifedipine10 mg850 mgnifedipine1.10AUC(0-24 hr) reported. 1.08Propranolol40 mg850 mgpropranolol1.01 1.02Ibuprofen400 mg850 mgibuprofen0.97Ratio of arithmetic means. 1.01 Cimetidine400 mg850 mgcimetidine0.95 1.01.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1Glycemic Efficacy Trials The effectiveness of saxagliptin and metformin hydrochloride extended-release tablets has been established in clinical trials of coadministration of oral saxagliptin and metformin HCl immediate-release tablets in adults with type diabetes mellitus inadequately controlled on metformin HCl 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 HCl immediate-release tablets at all doses produced statistically significant improvements in A1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following standard oral glucose tolerance test (OGTT), compared to control. Reductions in A1C were seen across subgroups including gender, age, race, and baseline BMI.In these two trials, decrease in body weight in the treatment groups given saxagliptin in combination with metformin HCl immediate-release was similar to that in the groups given metformin HCl immediate-release alone. Saxagliptin plus metformin HCl immediate-release was not associated with significant changes from baseline in fasting serum lipids compared to metformin HCl alone.The coadministration of saxagliptin and metformin HCl 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 HCl alone, in placebo-controlled trial where subgroup of 314 patients inadequately controlled on insulin plus metformin HCl received add-on therapy with saxagliptin or placebo, trial comparing saxagliptin to placebo in 257 patients inadequately controlled on metformin HCl plus sulfonylurea, and trial comparing saxagliptin to placebo in 315 patients inadequately controlled on dapagliflozin and metformin HCl.In 24-week, double-blind, randomized trial, patients treated with metformin HCl immediate-release 500 mg twice daily for at least weeks were randomized to continued treatment with metformin HCl immediate-release 500 mg twice daily or to metformin HCl extended-release either 1,000 mg once daily or 1,500 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 HCl immediate-release treatment arm, 0.3% (95% confidence interval 0.1%, 0.4%) for the 1,000 mg metformin HCl extended-release treatment arm, and 0.1% (95% confidence interval 0%, 0.3%) for the 1,500 mg metformin HCl extended-release treatment arm. Results of this trial suggest that patients receiving metformin HCl immediate-release treatment may be safely switched to metformin HCl extended-release once daily at the same total daily dose, up to 2,000 mg once daily. Following switch from metformin HCl immediate-release to metformin HCl extended-release, glycemic control should be closely monitored and dosage adjustments made accordingly.. Saxagliptin Morning and Evening Dosing. 24-week monotherapy trial was conducted to assess range of dosing regimens for saxagliptin. Treatment-naive patients with inadequately controlled diabetes (A1C >= 7% to <= 10%) underwent 2-week, single-blind diet, exercise, and placebo lead-in period. total of 365 patients were randomized to 2.5 mg every morning, mg every morning, 2.5 mg with possible titration to mg every morning, or mg every evening of saxagliptin, or placebo. Patients who failed to meet specific glycemic goals during the trial were treated with metformin HCl rescue therapy added on to placebo or saxagliptin; the number of patients randomized per treatment group ranged from 71 to 74.Treatment with either saxagliptin mg every morning or mg every evening provided significant improvements in A1C versus placebo (mean placebo-corrected reductions of -0.4% and -0.3%, respectively).Coadministration of Saxagliptin with Metformin HCl Immediate-Release in Treatment-Naive PatientsA total of 1306 treatment-naive patients with type diabetes mellitus participated in this 24-week, randomized, double-blind, active-controlled trial to evaluate the efficacy and safety of saxagliptin coadministered with metformin HCl 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 trial.Patients who met eligibility criteria were enrolled in single-blind, 1-week, dietary and exercise placebo lead-in period. Patients were randomized to one of four treatment arms: saxagliptin mg metformin HCl immediate-release 500 mg, saxagliptin 10 mg metformin HCl immediate-release 500 mg, saxagliptin 10 mg placebo, or metformin HCl immediate-release 500 mg placebo (the maximum recommended approved saxagliptin dose is mg daily; the 10 mg daily dose of saxagliptin does not provide greater efficacy than the mg daily dose and the 10 mg saxagliptin dosage is not an approved dosage). Saxagliptin was dosed once daily. In the treatment groups using metformin HCl immediate-release, the metformin HCl dose was up-titrated weekly in 500 mg per day increments, as tolerated, to maximum of 2,000 mg per day based on FPG. Patients who failed to meet specific glycemic goals during this trial were treated with pioglitazone rescue as add-on therapy.Coadministration of saxagliptin mg plus metformin HCl immediate-release provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin HCl immediate-release (Table 7).Table 7: Glycemic Parameters at Week 24 in Placebo-Controlled Trial of Saxagliptin Coadministration with Metformin HCl Immediate-Release in Treatment-Naive PatientsIntent-to-treat population using last observation on trial or last observation prior to pioglitazone rescue therapy for patients needing rescue. Efficacy ParameterSaxagliptin mg+Metformin HClN 320Placebo+Metformin HClN 328Hemoglobin A1C (%)N 306N 313 Baseline (mean)9.49.4 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)-2.5-2.0 Difference from placebo metformin HCl (adjusted mean)-0.5p-value 0.0001 compared to placebo metformin HCl. 95% Confidence Interval(-0.7, -0.4) Percent of patients achieving A1C 7%60% (185/307)41% (129/314)Fasting Plasma Glucose (mg/dL)N 315N 320 Baseline (mean)199199 Change from baseline (adjusted mean)-60-47 Difference from placebo metformin HCl (adjusted mean)-13p-value 0.05 compared to placebo metformin HCl. 95% Confidence Interval(-19, -6)2-hour Postprandial Glucose (mg/dL)N 146N 141 Baseline (mean)340355 Change from baseline (adjusted mean)-138-97 Difference from placebo metformin HCl (adjusted mean)-41 95% Confidence Interval(-57, -25)Addition of Saxagliptin to Metformin HCl Immediate-ReleaseA total of 743 patients with type diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with metformin HCl immediate-release in patients with inadequate glycemic control (A1C >= 7% and <= 10%) on metformin HCl alone. To qualify for enrollment, patients were required to be on stable dose of metformin HCl (1,500-2,550 mg daily) for at least weeks. Patients who met eligibility criteria were enrolled in single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin HCl immediate-release at their pre-trial dose, up to 2500 mg daily, for the duration of the trial. Following the lead-in period, eligible patients were randomized to 2.5 mg, mg, or 10 mg of saxagliptin or placebo in addition to their current dose of open-label metformin HCl immediate-release (the maximum recommended approved saxagliptin dose is mg daily; the 10 mg daily dose of saxagliptin does not provide greater efficacy than the mg daily dose and the 10 mg dosage is not an approved dosage). Patients who failed to meet specific glycemic goals during the trial were treated with pioglitazone rescue therapy, added on to existing trial medications. Dose titrations of saxagliptin and metformin HCl immediate-release were not permitted.Saxagliptin 2.5 mg and mg add-on to metformin HCl immediate-release provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin HCl 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 HCl immediate-release group, 13% in the saxagliptin mg add-on to metformin HCl immediate-release group, and 27% in the placebo add-on to metformin HCl immediate-release group.Table 8: Glycemic Parameters at Week 24 in Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin HCl Immediate-ReleaseIntent-to-treat population using last observation on trial or last observation prior to pioglitazone rescue therapy for patients needing rescue. Efficacy ParameterSaxagliptin 2.5 mg+Metformin HClN 192Saxagliptin mg+Metformin HClN 191Placebo+Metformin HClN 179Hemoglobin A1C (%)N 186N 186N 175 Baseline (mean)8.18.18.1 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)-0.6-0.7+0.1 Difference from placebo (adjusted mean)-0.7p-value 0.0001 compared to placebo metformin HCl. -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 HCl. (69/186)44% (81/186)17% (29/175)Fasting Plasma Glucose (mg/dL)N 188N 187N 176 Baseline (mean)174179175 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 155N 155N 135 Baseline (mean)294296295 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 Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin HCl Immediate-Release Saxagliptin Add-On Combination Therapy with Metformin HCl Immediate-Release versus Glipizide Add-On Combination Therapy with Metformin HCl Immediate-ReleaseIn this 52-week, active-controlled trial, total of 858 patients with type diabetes mellitus and inadequate glycemic control (A1C 6.5% and <= 10%) on metformin HCl immediate-release alone were randomized to double-blind add-on therapy with saxagliptin or glipizide. Patients were required to be on stable dose of metformin HCl immediate-release (at least 1,500 mg daily) for at least weeks prior to enrollment.Patients who met eligibility criteria were enrolled in single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin HCl immediate-release (1,500-3,000 mg based on their pre-trial dose). Following the lead-in period, eligible patients were randomized to mg of saxagliptin or mg of glipizide in addition to their current dose of open-label metformin HCl immediate-release. Patients in the glipizide plus metformin HCl immediate-release group underwent blinded titration of the glipizide dose during the first 18 weeks of the trial up to maximum glipizide dose of 20 mg per day. Titration was based on goal FPG <= 110 mg/dL or the highest tolerable glipizide dose. Fifty percent (50%) of the glipizide-treated patients were titrated to the 20-mg daily dose; 21% of the glipizide-treated patients had final daily glipizide dose of mg or less. The mean final daily dose of glipizide was 15 mg.After 52 weeks of treatment, saxagliptin and glipizide resulted in similar mean reductions from baseline in A1C when added to metformin HCl 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 baseline mean body weight of 89 kg, there was statistically significant mean reduction of 1.1 kg in patients treated with saxagliptin compared to mean weight gain of 1.1 kg in patients treated with glipizide (p 0.0001).Table 9: Glycemic Parameters at Week 52 in an Active-Controlled Trial of Saxagliptin versus Glipizide in Combination with Metformin HCl Immediate-ReleaseIntent-to-treat population using last observation on trial. Efficacy ParameterSaxagliptin mg+Metformin HClN 428Titrated Glipizide+Metformin HClN 430Hemoglobin A1C (%)N 423N 423 Baseline (mean)7.77.6 Change from baseline (adjusted mean)-0.6-0.7 Difference from glipizide metformin HCl (adjusted meanLeast squares mean adjusted for baseline value.)0.1 95% Confidence Interval(-0.02, 0.2)Saxagliptin metformin HCl is considered non-inferior to glipizide metformin HCl 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 420N 420 Baseline (mean)162161 Change from baseline (adjusted mean)-9-16 Difference from glipizide metformin HCl (adjusted mean)6 95% Confidence Interval(2, 11)Significance not tested. Saxagliptin Add-On Combination Therapy with Insulin (with or without Metformin HCl Immediate-Release)A total of 455 patients with type diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with insulin in patients with inadequate glycemic control (A1C >= 7.5% and <= 11%) on insulin alone (N 141) or on insulin in combination with stable dose of metformin HCl immediate-release (N 314). Patients were required to be on stable dose of insulin (>= 30 units to <= 150 units daily) with <= 20% variation in total daily dose for >= weeks prior to screening. Patients entered the trial on intermediate- or long-acting (basal) insulin or premixed insulin. Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of premixed insulin.Patients who met eligibility criteria were enrolled in single-blind, four-week, dietary and exercise placebo lead-in period during which patients received insulin (and metformin HCl 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 mg or placebo. Doses of the antidiabetic therapies were to remain stable but patients were rescued and allowed to adjust the insulin regimen if specific glycemic goals were not met or if the investigator learned that the patient had self-increased the insulin dose by 20%. Data after rescue were excluded from the primary efficacy analyses.Add-on therapy with saxagliptin mg provided significant improvements from baseline to Week 24 in A1C and PPG compared with add-on placebo (Table 10). Similar mean reductions in A1C versus placebo were observed for patients using saxagliptin mg add-on to insulin alone and saxagliptin mg add-on to insulin in combination with metformin HCl 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 mg and 55 units in patients treated with placebo. The mean change from baseline in daily dose of insulin was units for the saxagliptin mg group and units for the placebo group.Table 10: Glycemic Parameters at Week 24 in Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with InsulinIntent-to-treat population using last observation on trial or last observation prior to insulin rescue therapy for patients needing rescue. Efficacy ParameterSaxagliptin mg+Insulin(+/- Metformin HCl)N 304Placebo+Insulin(+/- Metformin HCl)N 151Hemoglobin A1C (%)N 300N 149 Baseline (mean)8.78.7 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value and metformin HCl use at baseline.)-0.7-0.3 Difference from placebo (adjusted mean)-0.4p-value 0.0001 compared to placebo insulin. 95% Confidence Interval(-0.6, -0.2)2-hour Postprandial Glucose (mg/dL)N 262N 129 Baseline (mean)251255 Change from baseline (adjusted mean)-27-4 Difference from placebo (adjusted mean)-23p-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.Saxagliptin Add-On Combination Therapy with Metformin HCl plus SulfonylureaA total of 257 patients with type diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with metformin HCl plus sulfonylurea in patients with inadequate glycemic control (A1C >= 7% and <= 10%). Patients were to be on stable combined dose of metformin HCl extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1,500 mg) and sulfonylurea (at maximum tolerated dose, with minimum dose for enrollment being >= 50% of the maximum recommended dose) for >= weeks prior to enrollment.Patients who met eligibility criteria were entered in 2-week enrollment period to allow assessment of inclusion/exclusion criteria. Following the 2-week enrollment period, eligible patients were randomized to either double-blind saxagliptin (5 mg once daily) or double-blind matching placebo for 24 weeks. During the 24-week double-blind treatment period, patients were to receive metformin HCl and sulfonylurea at the same constant dose ascertained during enrollment. Sulfonylurea dose could be down titrated once in the case of major hypoglycemic event or recurring minor hypoglycemic events. In the absence of hypoglycemia, titration (up or down) of trial medication during the treatment period was prohibited.Saxagliptin in combination with metformin HCl plus sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin HCl plus sulfonylurea (Table 11). The percentage of patients who discontinued for lack of glycemic control was 6% in the saxagliptin group and 5% in the placebo group.Table 11: Glycemic Parameters at Week 24 in Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin HCl plus SulfonylureaIntent-to-treat population using last observation prior to discontinuation. Efficacy ParameterSaxagliptin mg+Metformin HCl plus SulfonylureaN 129Placebo+Metformin HCl plus SulfonylureaN 128Hemoglobin A1C (%)N 127N 127 Baseline (mean)8.48.2 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)-0.7-0.1 Difference from placebo (adjusted mean)-0.7p-value 0.0001 compared to placebo metformin HCl plus sulfonylurea. 95% Confidence Interval(-0.9, -0.5)2-hour Postprandial Glucose (mg/dL)N 115N 113 Baseline (mean)268262 Change from baseline (adjusted mean)-125 Difference from placebo (adjusted mean)-17p-value 0.05 compared to placebo metformin HCl 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 HCl plus sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.Saxagliptin Add-on Combination Therapy with Metformin HCl plus an SGLT2 InhibitorA total of 315 patients with type diabetes mellitus 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 HCl in patients with baseline of HbA1c >= 7% to <= 10.5%. The mean age of these patients was 54.6 years, 1.6% were 75 years or older and 52.7% were female. The population was 87.9% White, 6.3% Black or African American, 4.1% Asian, and 1.6% other races. At baseline the population had diabetes for an average of 7.7 years and mean HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m2. Patients were required to be on stable dose of metformin HCl (>= 1,500 mg per day) for at least weeks prior to enrollment. Eligible patients who completed the screening period entered the lead-in treatment period, which included 16 weeks of open-label metformin HCl and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to saxagliptin mg (N 153) or placebo (N 162).The group treated with add-on saxagliptin had statistically significant greater reductions in HbA1c from baseline versus the group treated with placebo (see Table 12).Table 12: HbA1c Change from Baseline at Week 24 in Placebo-Controlled Trial of Saxagliptin as Add-On to Dapagliflozin and Metformin HClThere were 6.5% (n 10) of randomized patients 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 patients who discontinued trial 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 mg(N 153)Number of randomized and treated patients.Placebo(N 162)In combination with Dapagliflozin and MetforminHemoglobin 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 patients having missing Week 24 data.Baseline (mean)8.07.9Change from baseline (adjusted meanLeast 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-0.4p-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.. Figure 1: Mean Change from Baseline in A1C in Placebo-Controlled Trial of Saxagliptin as Add-On Combination Therapy with Metformin HCl Immediate-Release. 14.2Cardiovascular Safety Trial The cardiovascular risk of saxagliptin was evaluated in SAVOR, multicenter, multinational, randomized, double-blind trial comparing saxagliptin (N 8280) to placebo (N 8212), both administered in combination with standard of care, in adult patients with type diabetes mellitus at high risk for atherosclerotic cardiovascular disease. Of the randomized trial patients, 97.5% completed the trial, and the median duration of follow-up was approximately years. The trial was event-driven, and patients were followed until sufficient number of events were accrued.Patients were at least 40 years of age, had A1C >= 6.5%, and multiple risk factors (21% of randomized patients) 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 patients) cardiovascular disease defined as history of ischemic heart disease, peripheral vascular disease, or ischemic stroke. The majority of patients were male (67%) and White (75%) with 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 prior history of heart failure. Patients had median duration of type diabetes mellitus of approximately 10 years, and mean baseline A1C level of 8.0%. Approximately 5% of patients 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 Major Adverse Cardiac Event (MACE). major adverse cardiac event in SAVOR was defined as cardiovascular death, or nonfatal myocardial infarction (MI) or nonfatal ischemic stroke. The trial was designed as non-inferiority trial with pre-specified risk margin of 1.3 for the hazard ratio of MACE, and was also powered for superiority comparison if non-inferiority was demonstrated.The results of SAVOR, including the contribution of each component to the primary composite endpoint are shown in Table 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 95.1% confidence interval of (0.89, 1.12). The upper bound of this confidence interval, 1.12, excluded risk margin larger than 1.3.Table 13: Major Adverse Cardiovascular Events (MACE) by Treatment Group in the SAVOR TrialSaxagliptinPlaceboHazard RatioNumber ofPatients (%)Rate per 100 PYNumber ofPatients (%)Rate per 100PY(95.1% CI)Composite of first event of CV death, non-fatal MI or non-fatal ischemic stroke (MACE)N 8280Total PY 16308.8N 8212Total PY 16156.0613 (7.4)3.8609 (7.4)3.81.00 (0.89, 1.12) CV death245 (3.0)1.5234 (2.8)1.4 Non-fatal MI233 (2.8)1.4260 (3.2)1.6 Non-fatal ischemic stroke135 (1.6)0.8115 (1.4)0.7The Kaplan-Meier-based cumulative event probability is presented in Figure for time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for both saxagliptin and placebo arms are close together throughout the duration of the trial. The estimated cumulative event probability is approximately linear for both arms, indicating that the incidence of MACE for both arms was constant over the trial duration.Figure 2: Cumulative Percent of Time to First MACEVital status was obtained for 99% of patients 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 TrialSaxagliptinPlaceboHazard RatioNumber ofPatients (%)Rate per 100PYNumber ofPatients (%)Rate per 100PY(95.1% CI)N 8280PY 16645.3N 8212PY 16531.5All-causemortality420 (5.1)2.5378 (4.6)2.31.11 (0.96, 1.27) CV death269 (3.2)1.6260 (3.2)1.6 Non-CV death151 (1.8)0.9118 (1.4)0.7 Figure 2: Cumulative Percent of Time to First MACE.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with:oSevere renal impairment (eGFR below 30 mL/min/1.73 m2).oAcute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.oA history of serious hypersensitivity reaction to saxagliptin, metformin HCl, or any of the ingredients in saxagliptin and metformin hydrochloride extended-release tablets. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported [see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ].. oSevere renal impairment (eGFR below 30 mL/min/1.73 m2).. oAcute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.. oA history of serious hypersensitivity reaction to saxagliptin, metformin HCl, or any of the ingredients in saxagliptin and metformin hydrochloride extended-release tablets. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported [see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ].. oSevere renal impairment (eGFR below 30 mL/min/1.73 m2). (4)oMetabolic acidosis, including diabetic ketoacidosis. (4)oHistory of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin, metformin HCl, or any of the ingredients in saxagliptin and metformin hydrochloride extended-release tablets. (4). oSevere renal impairment (eGFR below 30 mL/min/1.73 m2). (4). oMetabolic acidosis, including diabetic ketoacidosis. (4). oHistory of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin, metformin HCl, or any of the ingredients in saxagliptin and metformin hydrochloride extended-release tablets. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Saxagliptin and metformin hydrochloride extended-release tablets contain two oral antihyperglycemic medications used in the management of type diabetes mellitus: saxagliptin and metformin HCl.SaxagliptinSaxagliptin 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[3.3.1.13,7]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 empirical formula is C18H25N3O2oHClo2 H2O and the molecular weight is 387.92. The structural formula is:Saxagliptin hydrochloride dihydrate is white to off white, non-hygroscopic, crystalline powder. It is sparingly soluble in water at 24C +- 3C, slightly soluble in ethyl acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400).Metformin HClMetformin hydrochloride, USP (1,1-Dimethylbiguanide monohydrochloride) is white, crystalline powder with molecular formula of C4H11N5oHCl and molecular weight of 165.62. Metformin HCl 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 1% aqueous solution of metformin HCl is 6.36. The structural formula is:Saxagliptin and Metformin Hydrochloride Extended-Release TabletsSaxagliptin and metformin hydrochloride extended-release tablets are available for oral administration as tablets containing either 6.149 mg saxagliptin hydrochloride dihydrate equivalent to mg saxagliptin and 500 mg metformin hydrochloride (saxagliptin and metformin hydrochloride extended-release tablets mg/500 mg), or 6.149 mg saxagliptin hydrochloride dihydrate equivalent to mg saxagliptin and 1000 mg metformin hydrochloride (saxagliptin and metformin hydrochloride extended-release tablets 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 soft, hydrated mass.. Saxagliptin Hydrochloride Dihydrate Structural Formula. Metformin Hydrochloride Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oAdminister once daily with the evening meal. (2.1)oIndividualize the starting dosage based on the patients current regimen then adjust the dosage based on effectiveness and tolerability. (2.1)oDo not exceed daily dosage of mg saxagliptin/2,000 mg metformin HCl extended-release. (2.1)oSwallow whole. Never crush, cut, or chew. (2.1)oLimit the saxagliptin dosage to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole). (2.3, 7.1)oAssess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and periodically thereafter. (2.2)oDo not use in patients with eGFR below 30 mL/min/1.73 m2.oInitiation is not recommended in patients with eGFR between 30 45 mL/min/1.73 m2.oAssess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m2.oLimit the saxagliptin component to 2.5 mg daily if eGFR is less than 45 mL/min/1.73 m2.oDiscontinue if eGFR falls below 30 mL/min/1.73 m2.oSaxagliptin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.4). oAdminister once daily with the evening meal. (2.1). oIndividualize the starting dosage based on the patients current regimen then adjust the dosage based on effectiveness and tolerability. (2.1). oDo not exceed daily dosage of mg saxagliptin/2,000 mg metformin HCl extended-release. (2.1). oSwallow whole. Never crush, cut, or chew. (2.1). oLimit the saxagliptin dosage to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole). (2.3, 7.1). oAssess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and periodically thereafter. (2.2)oDo not use in patients with eGFR below 30 mL/min/1.73 m2.oInitiation is not recommended in patients with eGFR between 30 45 mL/min/1.73 m2.oAssess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m2.oLimit the saxagliptin component to 2.5 mg daily if eGFR is less than 45 mL/min/1.73 m2.oDiscontinue if eGFR falls below 30 mL/min/1.73 m2.. oDo not use in patients with eGFR below 30 mL/min/1.73 m2.. oInitiation is not recommended in patients with eGFR between 30 45 mL/min/1.73 m2.. oAssess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m2.. oLimit the saxagliptin component to 2.5 mg daily if eGFR is less than 45 mL/min/1.73 m2.. oDiscontinue if eGFR falls below 30 mL/min/1.73 m2.. oSaxagliptin and metformin hydrochloride extended-release tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.4). 2.1Recommended Dosage and Administration Individualize the starting dosage of saxagliptin and metformin hydrochloride extended-release tablets based on the patients current regimen and the available strengths of saxagliptin and metformin hydrochloride extended-release tablets [see Dosage Forms and Strengths (3) ].Administer saxagliptin and metformin hydrochloride extended-release tablets once daily with the evening meal, with gradual dose titration to reduce the gastrointestinal side effects associated with metformin HCl [see Adverse Reactions (6.1) ].The recommended starting dosage of saxagliptin and metformin hydrochloride extended-release tablets in patients who need mg of saxagliptin and who are not currently treated with metformin HCl is one saxagliptin and metformin hydrochloride extended-release tablet containing mg saxagliptin and 500 mg metformin HCl extended-release once daily with gradual dose escalation to reduce the gastrointestinal side effects due to metformin HCl.In patients treated with metformin HCl, the recommended starting dosage of saxagliptin and metformin hydrochloride extended-release tablets should provide metformin HCl at the dose already being taken, or the nearest therapeutically appropriate dose. Following switch from metformin HCl immediate-release to saxagliptin and metformin hydrochloride extended-release tablets, closely monitor glycemic control and adjust the dosage accordingly.Patients who need 2.5 mg saxagliptin in combination with metformin HCl extended-release may be treated with saxagliptin and metformin hydrochloride extended-release tablets 2.5 mg/1,000 mg. Patients who need 2.5 mg saxagliptin who are either metformin HCl naive or who require dose of metformin HCl higher than 1,000 mg should use the individual components.Gradually titrate the dosage of saxagliptin and metformin hydrochloride extended-release tablets, as needed, after assessing therapeutic response and tolerability, up to maximum recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets (5 mg for saxagliptin and 2,000 mg for metformin HCl extended-release orally once daily).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 soft, hydrated mass that may resemble the original tablet.If dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose.. 2.2Recommendations for Dosage and Administration in Renal Impairment Assess renal function prior to initiation of saxagliptin and metformin hydrochloride extended-release tablets and then as clinically indicated [see Use in Specific Populations (8.6) ].The recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/minute/1.73 m2 is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration (2.1) ].In patients taking saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit risk of continuing therapy and limit dose of the saxagliptin component to 2.5 mg once daily.Initiation of saxagliptin and metformin hydrochloride extended-release tablets in patients with an eGFR between 30 45 mL/minute/1.73 m2 is not recommended.Saxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR below 30 mL/minute/1.73 m2.Discontinue saxagliptin and metformin hydrochloride extended-release tablets if the patients eGFR later falls below 30 mL/minute/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1) ].. 2.3Dosage Modifications with Concomitant Use of Strong CYP3A4/5 Inhibitors The maximum recommended dosage of saxagliptin and metformin hydrochloride extended-release tablets is 2.5 mg of saxagliptin and 1,000 mg of metformin HCl given orally once daily when used concomitantly with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [see Dosage and Administration (2.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].. 2.4Discontinuation for Iodinated Contrast Imaging Procedures 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 less than 60 mL/min/1.73 m2; 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) ].

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of saxagliptin and metformin hydrochloride extended-release tablets as an adjunct to diet and exercise to improve glycemic control in patients with type diabetes mellitus have not been established in pediatric patients.Effectiveness of saxagliptin was not demonstrated in 26-week, placebo-controlled, double-blind randomized clinical trial with 26-week safety extension (NCT03199053) in 164 pediatric patients aged 10 to 17 years with inadequately controlled type diabetes mellitus.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Extended-Release Tablets:oSaxagliptin and Metformin Hydrochloride Extended-Release Tablets, mg/500 mg, are pink, film-coated, round, unscored tablets imprinted with SM3 over in black ink on one side of the tablet and blank on the other side. oSaxagliptin and Metformin Hydrochloride Extended-Release Tablets, mg/1000 mg, are pink, film-coated, capsule shaped, unscored tablets imprinted with SM6 over in black ink on one side of the tablet and blank on the other side. oSaxagliptin and Metformin Hydrochloride Extended-Release Tablets, 2.5 mg/1000 mg, are light peach, film-coated, capsule shaped, unscored tablets imprinted with SM4 over in black ink on one side of the tablet and blank on the other side. oSaxagliptin and Metformin Hydrochloride Extended-Release Tablets, mg/500 mg, are pink, film-coated, round, unscored tablets imprinted with SM3 over in black ink on one side of the tablet and blank on the other side. oSaxagliptin and Metformin Hydrochloride Extended-Release Tablets, mg/1000 mg, are pink, film-coated, capsule shaped, unscored tablets imprinted with SM6 over in black ink on one side of the tablet and blank on the other side. oSaxagliptin and Metformin Hydrochloride Extended-Release Tablets, 2.5 mg/1000 mg, are light peach, film-coated, capsule shaped, unscored tablets imprinted with SM4 over in black ink on one side of the tablet and blank on the other side. o5 mg saxagliptin/500 mg metformin HCl extended-release (3) o5 mg saxagliptin/1000 mg metformin HCl extended-release (3) o2.5 mg saxagliptin/1000 mg metformin HCl extended-release (3) o5 mg saxagliptin/500 mg metformin HCl extended-release (3) o5 mg saxagliptin/1000 mg metformin HCl extended-release (3) o2.5 mg saxagliptin/1000 mg metformin HCl extended-release (3).

DRUG INTERACTIONS SECTION.

Drug Interactions. 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 SECTION.

8.5 Geriatric Use Saxagliptin and Metformin Hydrochloride Extended-Release Tablets. 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) ].. Saxagliptin. In the seven, double-blind, controlled clinical safety and efficacy trials of saxagliptin, 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 patients 65 years of age and older and younger adult patients.. Metformin HCl. Controlled clinical trials of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. 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 Warnings and Precautions (5.1) ].

HEPATIC IMPAIRMENT SUBSECTION.

Hepatic Impairment. 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.

HOW SUPPLIED SECTION.

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

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Saxagliptin and metformin hydrochloride extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus [see Clinical Studies (14) ].. Saxagliptin and metformin hydrochloride extended-release tablets are combination of saxagliptin, dipeptidyl peptidase-4 (DPP4) inhibitor, and metformin hydrochloride (HCl), biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. (1)Limitations of Use:oNot recommended for the treatment of type diabetes mellitus or diabetic ketoacidosis. (1.1). oNot recommended for the treatment of type diabetes mellitus or diabetic ketoacidosis. (1.1). 1.1Limitations of Use Saxagliptin and metformin hydrochloride extended-release tablets are not recommended for the treatment of type diabetes mellitus or diabetic ketoacidosis.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).Lactic AcidosisThe risks of lactic acidosis due to the metformin component, its symptoms and conditions that predispose to its development, as noted in Warnings and Precautions (5.1), should be explained to patients. Patients should be advised to discontinue saxagliptin and metformin hydrochloride extended-release tablets immediately and to promptly notify their health care provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of saxagliptin and metformin hydrochloride extended-release tablet therapy; however, patients should consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.Patients should be counseled against excessive alcohol intake while receiving saxagliptin and metformin hydrochloride extended-release tablets.Patients should be informed about the importance of regular testing of renal function and hematological parameters when receiving treatment with saxagliptin and metformin hydrochloride extended-release tablets.Instruct patients to inform their doctor that they are taking saxagliptin and metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation of saxagliptin and metformin hydrochloride extended-release tablets may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1) ].PancreatitisInform patients that acute pancreatitis has been reported during post-marketing use of saxagliptin. Educate patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets and contact their health care provider if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2) ].Heart FailureInform patients of the signs and symptoms of heart failure. Before initiating saxagliptin and metformin hydrochloride extended-release tablets, ask patients if they have history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their health care provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.3) ].Hypoglycemia with Concomitant Use with Insulin or Insulin SecretagoguesInform patients that hypoglycemia can occur, particularly when insulin or an insulin secretagogue is used in combination with saxagliptin and metformin hydrochloride extended-release tablets. Educate patients about the risks, symptoms and appropriate management of hypoglycemia [see Warnings and Precautions (5.5) ].Hypersensitivity ReactionsPatients should be informed that serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions, have been reported during post-marketing use of saxagliptin. If symptoms of these allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking saxagliptin and metformin hydrochloride extended-release tablets and seek medical advice promptly [see Warnings and Precautions (5.6) ].Severe and Disabling ArthralgiaInform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.7) ].Bullous PemphigoidInform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.8) ].Administration InstructionsPatients should be informed that saxagliptin and metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as soft mass that may resemble the original tablet.Missed DoseIf dose is missed, advise patients to take saxagliptin and metformin hydrochloride extended-release tablets as soon as they remember unless it is time for their next dose. Instruct patients not to take two doses of saxagliptin and metformin hydrochloride extended-release tablets at the same time.

LABORATORY TESTS SECTION.

Laboratory Tests. Absolute Lymphocyte CountsSaxagliptinThere was dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. From baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in pooled analysis of five placebo-controlled clinical trials. Similar effects were observed when saxagliptin mg and metformin HCl were coadministered in treatment-naive patients compared to placebo and metformin HCl. There was no difference observed for saxagliptin 2.5 mg relative to placebo. The proportion of patients who were reported to have lymphocyte count <= 750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the saxagliptin 2.5 mg, mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg saxagliptin dosage is not an approved dosage.In the SAVOR trial mean decreases of approximately 84 cells/microL with saxagliptin relative to placebo was observed. The proportion of patients who experienced decrease in lymphocyte counts to count of <= 750 cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on saxagliptin and placebo, respectively.The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.Vitamin B12 ConcentrationsMetformin HClIn metformin clinical trials of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.

LACTATION SECTION.

8.2 Lactation Risk Summary. 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 mothers 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.. Data. Human Data 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 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.. Animal Data 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 1:1 ratio with plasma drug concentrations.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Saxagliptin and Metformin Hydrochloride Extended-Release Tablets. Saxagliptin and metformin hydrochloride extended-release tablets contain two antihyperglycemic medications: saxagliptin, dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin HCl, biguanide.. Saxagliptin. Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in glucose-dependent manner in patients with type diabetes mellitus.. Metformin HCl. Metformin improves glucose tolerance in patients with type diabetes mellitus, 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 diabetes mellitus or in healthy subjects except in unusual circumstances [see Warnings and Precautions (5.5)] 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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Saxagliptin and Metformin Hydrochloride Extended-Release Tablets. 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.. Saxagliptin. CarcinogenesisCarcinogenicity 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 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 mg/day clinical dose, based on AUC.MutagenesisSaxagliptin was not mutagenic or clastogenic in battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNA repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.Impairment of FertilitySaxagliptin administered to rats had no effect on fertility or the ability to maintain litter at exposures up to 603-times and 776-times the mg clinical dose in males and females, based on AUC.. Metformin HCl. CarcinogenesisLong-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 1,500 mg/kg/day, respectively. These doses are both approximately times the maximum recommended human daily dose of 2,000 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.MutagenesisThere was no evidence of 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.Impairment of FertilityFertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately times the maximum recommended human daily dose based on body surface area comparisons.. 13.2 Animal Toxicology and/or Pharmacology Saxagliptin. Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposure approximately 20-times the mg clinical dose, but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.

OVERDOSAGE SECTION.

10 OVERDOSAGE SaxagliptinIn controlled clinical trial, once-daily, orally administered saxagliptin in healthy subjects at doses up to 400 mg daily for weeks (80-times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate.In the event of an overdose, initiate appropriate supportive treatment as dictated by the patients clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over hours). Contact the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations.Metformin HClOverdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1) ]. Metformin is dialyzable with clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 5 mg/500 mg NDC 0378-8175-93Saxagliptin and Metformin HClExtended-Release Tablets5 mg/500 mgPHARMACIST: Dispense the accompanyingMedication Guide to each patient.Do not crush, cut, or chew tablets.Tablets must be swallowed whole.Rx only 30 TabletsEach film-coated extended-release tabletcontains 6.149 mg saxagliptin hydrochloridedihydrate equivalent to mg saxagliptin and500 mg metformin hydrochloride, USP.Usual Dosage: See accompanyingprescribing information.Keep this and all medication out ofthe reach of children.Store at 20 to 25C (68 to 77F). [SeeUSP Controlled Room Temperature.]Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in IndiaMylan.comRMXA8175H1Dispense in tight, light-resistantcontainer as defined in the USPusing child-resistant closure.Keep container tightly closed.Code No.: MH/DRUGS/AD/089. Saxagliptin and Metformin HCl Extended-Release Tablets mg/500 mg Bottle Label.

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Saxagliptin and Metformin Hydrochloride Extended-Release Tablets. 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(R)) and metformin HCl extended-release as individual tablets under fed conditions.. Saxagliptin. The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ngoh/mL and 214 ngoh/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.. Metformin HCl. Metformin extended-release Cmax is achieved with median value of hours and range of to hours. At steady state, the AUC and Cmax are less than dose proportional for metformin extended-release within the range of 500 to 2,000 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.. Absorption. Saxagliptin The median time to maximum concentration (Tmax) following the mg once daily dose was hours for saxagliptin and hours for its active metabolite. Metformin HCl Following single oral dose of metformin extended-release, Cmax is achieved with median value of hours and range of to hours.. Effect of Food. Saxagliptin Administration with high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was 27% increase in the AUC of saxagliptin when given with meal as compared to fasted conditions. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as saxagliptin and metformin hydrochloride extended-release combination tablets.. Metformin HCl 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 Cmax and Tmax 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.. Distribution. Saxagliptin 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.. Metformin HCl 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 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.. Elimination. Metabolism. SaxagliptinThe metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions (7.1) ].Metformin HClIntravenous 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.. Excretion. SaxagliptinSaxagliptin is eliminated by both renal and hepatic pathways. Following single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~ 230 mL/min) was greater than the average estimated glomerular filtration rate (~ 120 mL/min), suggesting some active renal excretion. total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following single oral dose of saxagliptin mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.Metformin HClRenal 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 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 compartment of distribution.. Specific Populations. Geriatric Patients SaxagliptinNo dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.Metformin HClLimited 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 Cmax 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 change in renal function.. Male and Female Patients SaxagliptinNo dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.Metformin HClMetformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type diabetes mellitus when analyzed according to gender (males 19, females 16). Similarly, in controlled clinical studies in patients with type diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.. Racial or Ethnic Groups SaxagliptinNo 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.Metformin HClNo studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n 249), Black or African American (n 51), and Hispanic or Latino ethnicity (n 24).. Patients with Renal Impairment SaxagliptinA single-dose, open-label trial was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment with eGFR 30 to less than 45 mL/min/1.73 m2, severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were 2 fold higher than AUC values in subjects with normal renal function.Metformin HClIn 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) ].. Patients with Hepatic Impairment No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment. Body Mass Index SaxagliptinNo dosage adjustment is recommended based on body mass index (BMI) which was not identified as significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis.. Drug Interaction Studies. 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 Vitro Assessment of Drug Interactions 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 P-glycoprotein (P-gp) substrate, but is not significant inhibitor or inducer of P-gp.. In Vivo Assessment of Drug Interactions Table 3: Effect of Coadministered Drug on Systemic Exposures of Saxagliptin and its Active Metabolite, 5-hydroxy SaxagliptinND not determined; QD once daily; q6h every hours; q12h every 12 hours; BID twice daily; LA long acting.Coadministered DrugDosage of Coadministered DrugSingle dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage.Dosage of SaxagliptinGeometric Mean Ratio(ratio with/without coadministered drug)No Effect 1.00AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.Cmax No dosing adjustments required for the following:Metformin1,000 mg100 mgsaxagliptin0.980.795-hydroxy saxagliptin0.990.88Glyburide5 mg10 mgsaxagliptin0.981.085-hydroxy saxagliptinNDNDPioglitazoneResults exclude one patient. 45 mg QD for 10 days10 mg QD for dayssaxagliptin1.111.115-hydroxy saxagliptinNDNDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QD for dayssaxagliptin1.050.995-hydroxy saxagliptin1.061.02Dapagliflozin10 mg single dose5 mg single dosesaxagliptin 1% 7%5-hydroxy saxagliptin 9% 6%Simvastatin40 mg QD for days10 mg QD for dayssaxagliptin1.121.215-hydroxy saxagliptin1.021.08Diltiazem360 mg LA QD for days10 mgsaxagliptin2.091.635-hydroxy saxagliptin0.660.57RifampinThe plasma dipeptidyl peptidase-4 (DPP4) activity inhibition over 24-hour dose interval was not affected by rifampin. 600 mg QD for days5 mgsaxagliptin0.240.475-hydroxy saxagliptin1.031.39Omeprazole40 mg QD for days10 mgsaxagliptin1.130.985-hydroxy saxagliptinNDNDAluminum hydroxide magnesium hydroxide simethiconealuminum hydroxide: 2400 mgmagnesium hydroxide: 2400 mgsimethicone: 240 mg10 mgsaxagliptin0.970.745-hydroxy saxagliptinNDNDFamotidine40 mg10 mgsaxagliptin1.031.145-hydroxy saxagliptinNDNDLimit saxagliptin and metformin hydrochloride extended-release tablet dose to 2.5 mg/1,000 mg once daily when coadministered with strong CYP3A4/5 inhibitors [see Drug Interactions (7.1) and Dosage and Administration (2.2) ]:Ketoconazole200 mg BID for days100 mgsaxagliptin2.451.625-hydroxy saxagliptin0.120.05Ketoconazole200 mg BID for days20 mgsaxagliptin3.672.445-hydroxy saxagliptinNDND Table 4: Effect of Saxagliptin on Systemic Exposures of Coadministered DrugsND not determined; QD once daily; q6h every hours; q12h every 12 hours; BID twice daily; LA long acting.Coadministered DrugDosage of Coadministered DrugSingle dose unless otherwise noted. The 10 mg saxagliptin dose is not an approved dosage.Dosage of SaxagliptinGeometric Mean Ratio(ratio with/without saxagliptin)No Effect 1.00AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.Cmax No dosing adjustments required for the following:Metformin1,000 mg100 mgmetformin1.201.09Glyburide5 mg10 mgglyburide1.061.16PioglitazoneResults include all patients. 45 mg QD for 10 days10 mg QD for dayspioglitazone1.081.14hydroxy-pioglitazoneNDNDDigoxin0.25 mg q6h first day followed by q12h second day followed by QD for days10 mg QD for daysdigoxin1.061.09Simvastatin40 mg QD for days10 mg QD for dayssimvastatin1.040.88simvastatin acid1.161.00Diltiazem360 mg LA QD for days10 mgdiltiazem1.101.16Ketoconazole200 mg BID for days100 mgketoconazole0.870.84Ethinyl estradiol and norgestimateethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days5 mg QD for 21 daysethinyl estradiol1.070.98norelgestromin1.101.09norgestrel1.131.17 Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic ExposureCoadministered DrugDose of Coadministered DrugAll metformin and coadministered drugs were given as single doses.Dose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No Effect 1.00AUCAUC AUC(INF).Cmax No dosing adjustments required for the following:Glyburide5 mg850 mgmetformin0.91Ratio of arithmetic means. 0.93 Furosemide40 mg850 mgmetformin1.09 1.22 Nifedipine10 mg850 mgmetformin1.161.21Propranolol40 mg850 mgmetformin0.900.94Ibuprofen400 mg850 mgmetformin1.05 1.07 Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7.3) ].Cimetidine400 mg850 mgmetformin1.401.61 Table 6: Effect of Metformin on Coadministered Drug Systemic ExposureCoadministeredDrugDose ofCoadministered DrugAll metformin and coadministered drugs were given as single doses.Dose ofMetforminGeometric Mean Ratio(ratio with/without metformin)No Effect 1.00AUCAUC AUC(INF) unless otherwise noted.Cmax No dosing adjustments required for the following:Glyburide5 mg850 mgglyburide0.78Ratio of arithmetic means, p-value of difference 0.05. 0.63 Furosemide40 mg850 mgfurosemide0.87 0.69 Nifedipine10 mg850 mgnifedipine1.10AUC(0-24 hr) reported. 1.08Propranolol40 mg850 mgpropranolol1.01 1.02Ibuprofen400 mg850 mgibuprofen0.97Ratio of arithmetic means. 1.01 Cimetidine400 mg850 mgcimetidine0.95 1.01.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. Limited available data with saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin in pregnant women are not sufficient to determine drug-associated risk for major birth defects and miscarriage. Published trials with metformin use during pregnancy have not reported 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 to 10% in women with pre-gestational diabetes with an HbA1c greater than and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Animal Data SaxagliptinIn embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.In prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day through lactation day 21 at exposures up to 470-times the mg clinical dose, based on AUC.Metformin HClMetformin HCl 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 2,000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.Saxagliptin and MetforminSaxagliptin 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 mg saxagliptin and 2,000 mg metformin. Minor skeletal abnormalities associated with maternal toxicity were observed in rats. In rabbits, coadministration was poorly tolerated in 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 low incidence of delayed ossification of the fetal hyoid bone.

RECENT MAJOR CHANGES SECTION.

Boxed Warning 6/2026Warnings and Precautions, Lactic Acidosis (5.1) 6/2026.

RENAL IMPAIRMENT SUBSECTION.

Renal Impairment. 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 patients renal function include [see Clinical Pharmacology (12.3) ]:oBefore initiating saxagliptin and metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).oSaxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4) ].oInitiation of saxagliptin and metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m2.oObtain 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.oIn patients taking saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit and risk of continuing therapy.. oBefore initiating saxagliptin and metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).. oSaxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4) ].. oInitiation of saxagliptin and metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m2.. oObtain 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.. oIn patients taking saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit and risk of continuing therapy.

RISKS.

Risk Summary. Limited available data with saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin in pregnant women are not sufficient to determine drug-associated risk for major birth defects and miscarriage. Published trials with metformin use during pregnancy have not reported 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 to 10% in women with pre-gestational diabetes with an HbA1c greater than and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.

SPL MEDGUIDE SECTION.

Medication Guide Saxagliptin and Metformin Hydrochloride Extended-Release Tablets, for oral use (sax glip tin met for min hye droe klor ide)What is the most important information should know about saxagliptin and metformin hydrochloride extended-release tablets Serious side effects can happen in people taking saxagliptin and metformin hydrochloride extended-release tablets, including:1.Lactic acidosis. Metformin, one of the medicines in saxagliptin and metformin hydrochloride extended-release tablets, can cause rare but serious condition called lactic acidosis (a build-up of an acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. Stop taking saxagliptin and metformin hydrochloride extended-release tablets and call your healthcare provider right away or go to the nearest hospital emergency room if you have any of the following symptoms of lactic acidosis:ofeel very weak or tiredoyou have unusual (not normal) muscle painoyou have trouble breathingoyou have stomach pains, nausea,vomiting or diarrheaohave unusual sleepiness or sleep longer than usualofeel cold, especially in your arms and legsofeel dizzy or lightheadedohave slow or irregular heartbeatMost people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have higher chance for getting lactic acidosis with saxagliptin and metformin hydrochloride extended-release tablets if you: ohave severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dyeohave liver problemsodrink alcohol very often, or drink lot of alcohol in short-term binge drinkingoget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluidsoare 65 years of age or olderohave genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD).ohave surgeryohave heart attack, severe infection, or strokeThe best way to keep from having problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your saxagliptin and metformin hydrochloride extended-release tablets for while if you have any of these things. Saxagliptin and metformin hydrochloride extended-release tablets can have other serious side effects. See What are the possible side effects of saxagliptin and metformin hydrochloride extended-release tablets.2.Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking saxagliptin and metformin hydrochloride extended-release tablets: Tell your healthcare provider if you have ever had:oinflammation of your pancreas (pancreatitis)oa history of alcoholismostones in your gallbladder (gallstones)ohigh blood triglyceride levels Stop taking saxagliptin and metformin hydrochloride extended-release tablets and contact your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis. 3.Heart failure. Heart failure means your heart does not pump blood well enough. Before you start taking saxagliptin and metformin hydrochloride extended-release tablets: Tell your healthcare provider if you:ohave ever had heart failure or have problems with your kidneys. Contact your healthcare provider right away if you have any of the following symptoms:oincreasing shortness of breath or trouble breathing, especially when you lie downoswelling or fluid retention, especially in the feet, ankles or legsoan unusually fast increase in weightounusual tiredness These may be symptoms of heart failure. What are saxagliptin and metformin hydrochloride extended-release tabletsoSaxagliptin and metformin hydrochloride extended-release tablets are prescription medicine that contains saxagliptin and metformin hydrochloride (HCl). Saxagliptin and metformin hydrochloride extended-release tablets are used along with diet and exercise to help control high blood sugar in adults with type diabetes.oSaxagliptin and metformin hydrochloride extended-release tablets are not recommended for people with type diabetes.oSaxagliptin and metformin hydrochloride extended-release tablets are not recommended for people with diabetic ketoacidosis (increased ketones in your blood or urine).It is not known if saxagliptin and metformin hydrochloride extended-release tablets are safe and effective in children.Who should not take saxagliptin and metformin hydrochloride extended-release tablets Do not take saxagliptin and metformin hydrochloride extended-release tablets if you:ohave kidney problems.ohave condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine).oare allergic to metformin HCl, saxagliptin, or any of the ingredients in saxagliptin and metformin hydrochloride extended-release tablets. See the end of this Medication Guide for complete list of ingredients in saxagliptin and metformin hydrochloride extended-release tablets. Symptoms of serious allergic reaction to saxagliptin and metformin hydrochloride extended-release tablets may include:oswelling of your face, lips, throat, and other areas on your skinoraised, red areas on your skin (hives)odifficulty with swallowing or breathingoskin rash, itching, flaking, or peeling If you have these symptoms, stop taking saxagliptin and metformin hydrochloride extended-release tablets and contact your healthcare provider right away.Before taking saxagliptin and metformin hydrochloride extended-release tablets, tell your healthcare provider about all of your medical conditions, including if you:ohave type diabetes or have had diabetic ketoacidosis.ohave kidney problems.ohave liver problems.ohave heart problems, including congestive heart failure.oare older than 80 years. If you are over 80 years old you should not take saxagliptin and metformin hydrochloride extended-release tablets unless your kidneys have been checked and they are normal.odrink alcohol very often, or drink lot of alcohol in short-term binge drinking.oare going to get an injection of dye or contrast agents for an x-ray procedure or if you are going to have surgery and will not be able to eat or drink much. In these situations, saxagliptin and metformin hydrochloride extended-release tablets may need to be stopped for short time. Talk to your healthcare provider about when you should stop saxagliptin and metformin hydrochloride extended-release tablets and when you should start saxagliptin and metformin hydrochloride extended-release tablets again. See What is the most important information should know about saxagliptin and metformin hydrochloride extended-release tablets.ohave low levels of vitamin B12 in your blood.oare pregnant or plan to become pregnant. It is not known if saxagliptin and metformin hydrochloride extended-release tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.oare breastfeeding or plan to breastfeed. It is not known if saxagliptin and metformin pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take saxagliptin and metformin hydrochloride extended-release tablets.ohave genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as MELAS syndrome and MIDD.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine. Saxagliptin and metformin hydrochloride extended-release tablets may affect the way other medicines work, and other medicines may affect how saxagliptin and metformin hydrochloride extended-release tablets work. Tell your healthcare provider if you will be starting or stopping certain other types of medicines, such as antibiotics, or medicines that treat fungus or HIV/AIDS, because your dose of saxagliptin and metformin hydrochloride extended-release tablets might need to be changed.How should take saxagliptin and metformin hydrochloride extended-release tabletsoTake saxagliptin and metformin hydrochloride extended-release tablets exactly as your healthcare provider tells you.oSaxagliptin and metformin hydrochloride extended-release tablets should be taken with meals to help lessen an upset stomach side effect.oSwallow saxagliptin and metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew saxagliptin and metformin hydrochloride extended-release tablets. oYou may sometimes pass soft mass in your stools (bowel movement) that looks like saxagliptin and metformin hydrochloride extended-release tablets.oYour healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with saxagliptin and metformin hydrochloride extended-release tablets.oCheck your blood sugar as your healthcare provider tells you to.oStay on your prescribed diet and exercise program while taking saxagliptin and metformin hydrochloride extended-release tablets.oIf you miss dose of saxagliptin and metformin hydrochloride extended-release tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take your next dose as prescribed. Do not take doses of saxagliptin and metformin hydrochloride extended-release tablets at the same time.oIf you take too many saxagliptin and metformin hydrochloride extended-release tablets, contact the Poison Help line at 1-800-222-1222 or get medical help right away. Advice is also available online at poisonhelp.org.What are the possible side effects of saxagliptin and metformin hydrochloride extended-release tablets Saxagliptin and metformin hydrochloride extended-release tablets can cause serious side effects, including:oSee What is the most important information should know about saxagliptin and metformin hydrochloride extended-release tablets.oLow vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels.oLow blood sugar (hypoglycemia). If you take saxagliptin and metformin hydrochloride extended-release tablets with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take saxagliptin and metformin hydrochloride extended-release tablets.Symptoms of low blood sugar include:oshakingohungerosweatingoheadacheorapid heartbeatochange in moodochange in visionoAllergic (hypersensitivity) reactions, such as:oswelling of your face, lips, throat, and other areas on your skinoraised, red areas on your skin (hives)odifficulty with swallowing or breathingoskin rash, itching, flaking, or peeling If you have these symptoms, stop taking saxagliptin and metformin hydrochloride extended-release tablets and contact your healthcare provider right away.oJoint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in saxagliptin and metformin hydrochloride extended-release tablets, may develop joint pain that can be severe. Call your healthcare provider if you have severe joint pain.oSkin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in saxagliptin and metformin hydrochloride extended-release tablets, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your healthcare provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to stop taking saxagliptin and metformin hydrochloride extended-release tablets. Common side effects of saxagliptin and metformin hydrochloride extended-release tablets include:oupper respiratory tract infectionoheadacheostuffy or runny nose and sore throatodiarrheaourinary tract infectiononausea and vomitingSwelling or fluid retention in your hands, feet, or ankles (peripheral edema) may become worse in people who also take thiazolidinedione to treat diabetes. If you do not know whether you are already on this type of medication, ask your healthcare provider. These are not all of the possible side effects of saxagliptin and metformin hydrochloride extended-release tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store saxagliptin and metformin hydrochloride extended-release tablets Store saxagliptin and metformin hydrochloride extended-release tablets between 20 to 25C (68 to 77F). Keep saxagliptin and metformin hydrochloride extended-release tablets and all medicines out of the reach of children. General information about the use of saxagliptin and metformin hydrochloride extended-release tablets Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use saxagliptin and metformin hydrochloride extended-release tablets for condition for which they were not prescribed. Do not give saxagliptin and metformin hydrochloride extended-release tablets to other people, even if they have the same symptoms you have. They may harm them. You can ask your pharmacist or healthcare provider for information about saxagliptin and metformin hydrochloride extended-release tablets that is written for health professionals. What are the ingredients of saxagliptin and metformin hydrochloride extended-release tablets Active ingredients: saxagliptin and metformin HCl. Inactive ingredients in each tablet: 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. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited, Hyderabad -- 500 096, India For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). The brands listed are trademarks of their respective owners. This Medication Guide has been approved by the U.S. Food and Drug Administration.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India75108500Revised: 6/2026MXA:SAXMET:RX3. 1.Lactic acidosis. Metformin, one of the medicines in saxagliptin and metformin hydrochloride extended-release tablets, can cause rare but serious condition called lactic acidosis (a build-up of an acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. ofeel very weak or tired. oyou have unusual (not normal) muscle pain. oyou have trouble breathing. oyou have stomach pains, nausea,vomiting or diarrhea. ohave unusual sleepiness or sleep longer than usual. ofeel cold, especially in your arms and legs. ofeel dizzy or lightheaded. ohave slow or irregular heartbeat. ohave severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. ohave liver problems. odrink alcohol very often, or drink lot of alcohol in short-term binge drinking. oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids. oare 65 years of age or older. ohave genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD).. ohave surgery. ohave heart attack, severe infection, or stroke. 2.Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis.. Before you start taking saxagliptin and metformin hydrochloride extended-release tablets: Tell your healthcare provider if you have ever had:. oinflammation of your pancreas (pancreatitis). oa history of alcoholism. ostones in your gallbladder (gallstones). ohigh blood triglyceride levels. Stop taking saxagliptin and metformin hydrochloride extended-release tablets and contact your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis. 3.Heart failure. Heart failure means your heart does not pump blood well enough. Before you start taking saxagliptin and metformin hydrochloride extended-release tablets: Tell your healthcare provider if you:. ohave ever had heart failure or have problems with your kidneys.. Contact your healthcare provider right away if you have any of the following symptoms:. oincreasing shortness of breath or trouble breathing, especially when you lie down. oswelling or fluid retention, especially in the feet, ankles or legs. oan unusually fast increase in weight. ounusual tiredness. These may be symptoms of heart failure.. oSaxagliptin and metformin hydrochloride extended-release tablets are prescription medicine that contains saxagliptin and metformin hydrochloride (HCl). Saxagliptin and metformin hydrochloride extended-release tablets are used along with diet and exercise to help control high blood sugar in adults with type diabetes.. oSaxagliptin and metformin hydrochloride extended-release tablets are not recommended for people with type diabetes.. oSaxagliptin and metformin hydrochloride extended-release tablets are not recommended for people with diabetic ketoacidosis (increased ketones in your blood or urine).. ohave kidney problems.. ohave condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine).. oare allergic to metformin HCl, saxagliptin, or any of the ingredients in saxagliptin and metformin hydrochloride extended-release tablets. See the end of this Medication Guide for complete list of ingredients in saxagliptin and metformin hydrochloride extended-release tablets. Symptoms of serious allergic reaction to saxagliptin and metformin hydrochloride extended-release tablets may include:. oswelling of your face, lips, throat, and other areas on your skin. oraised, red areas on your skin (hives). odifficulty with swallowing or breathing. oskin rash, itching, flaking, or peeling. If you have these symptoms, stop taking saxagliptin and metformin hydrochloride extended-release tablets and contact your healthcare provider right away.. ohave type diabetes or have had diabetic ketoacidosis.. ohave kidney problems.. ohave liver problems.. ohave heart problems, including congestive heart failure.. oare older than 80 years. If you are over 80 years old you should not take saxagliptin and metformin hydrochloride extended-release tablets unless your kidneys have been checked and they are normal.. odrink alcohol very often, or drink lot of alcohol in short-term binge drinking.. oare going to get an injection of dye or contrast agents for an x-ray procedure or if you are going to have surgery and will not be able to eat or drink much. In these situations, saxagliptin and metformin hydrochloride extended-release tablets may need to be stopped for short time. Talk to your healthcare provider about when you should stop saxagliptin and metformin hydrochloride extended-release tablets and when you should start saxagliptin and metformin hydrochloride extended-release tablets again. See What is the most important information should know about saxagliptin and metformin hydrochloride extended-release tablets.. ohave low levels of vitamin B12 in your blood.. oare pregnant or plan to become pregnant. It is not known if saxagliptin and metformin hydrochloride extended-release tablets will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.. oare breastfeeding or plan to breastfeed. It is not known if saxagliptin and metformin pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby while you take saxagliptin and metformin hydrochloride extended-release tablets.. ohave genetically inherited disease affecting mitochondria (the energy-producing parts within cells) such as MELAS syndrome and MIDD.. oTake saxagliptin and metformin hydrochloride extended-release tablets exactly as your healthcare provider tells you.. oSaxagliptin and metformin hydrochloride extended-release tablets should be taken with meals to help lessen an upset stomach side effect.. oSwallow saxagliptin and metformin hydrochloride extended-release tablets whole. Do not crush, cut, or chew saxagliptin and metformin hydrochloride extended-release tablets. oYou may sometimes pass soft mass in your stools (bowel movement) that looks like saxagliptin and metformin hydrochloride extended-release tablets.. oYour healthcare provider should do blood tests to check how well your kidneys are working before and during your treatment with saxagliptin and metformin hydrochloride extended-release tablets.. oCheck your blood sugar as your healthcare provider tells you to.. oStay on your prescribed diet and exercise program while taking saxagliptin and metformin hydrochloride extended-release tablets.. oIf you miss dose of saxagliptin and metformin hydrochloride extended-release tablets, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take your next dose as prescribed. Do not take doses of saxagliptin and metformin hydrochloride extended-release tablets at the same time.. oIf you take too many saxagliptin and metformin hydrochloride extended-release tablets, contact the Poison Help line at 1-800-222-1222 or get medical help right away. Advice is also available online at poisonhelp.org.. oSee What is the most important information should know about saxagliptin and metformin hydrochloride extended-release tablets.. oLow vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels.. oLow blood sugar (hypoglycemia). If you take saxagliptin and metformin hydrochloride extended-release tablets with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take saxagliptin and metformin hydrochloride extended-release tablets.Symptoms of low blood sugar include:. oshaking. ohunger. osweating. oheadache. orapid heartbeat. ochange in mood. ochange in vision. oAllergic (hypersensitivity) reactions, such as:. oswelling of your face, lips, throat, and other areas on your skin. oraised, red areas on your skin (hives). odifficulty with swallowing or breathing. oskin rash, itching, flaking, or peeling. If you have these symptoms, stop taking saxagliptin and metformin hydrochloride extended-release tablets and contact your healthcare provider right away.. oJoint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in saxagliptin and metformin hydrochloride extended-release tablets, may develop joint pain that can be severe. Call your healthcare provider if you have severe joint pain.. oSkin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in saxagliptin and metformin hydrochloride extended-release tablets, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your healthcare provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to stop taking saxagliptin and metformin hydrochloride extended-release tablets. oupper respiratory tract infection. oheadache. ostuffy or runny nose and sore throat. odiarrhea. ourinary tract infection. onausea and vomiting.

SPL UNCLASSIFIED SECTION.

1.1Limitations of Use Saxagliptin and metformin hydrochloride extended-release tablets are not recommended for the treatment of type diabetes mellitus or diabetic ketoacidosis.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oGeriatric Use: Assess renal function more frequently. (8.5)oHepatic Impairment: Avoid use in patients with hepatic impairment. (8.7). oGeriatric Use: Assess renal function more frequently. (8.5). oHepatic Impairment: Avoid use in patients with hepatic impairment. (8.7). 8.1 Pregnancy Risk Summary. Limited available data with saxagliptin and metformin hydrochloride extended-release tablets or saxagliptin in pregnant women are not sufficient to determine drug-associated risk for major birth defects and miscarriage. Published trials with metformin use during pregnancy have not reported 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 to 10% in women with pre-gestational diabetes with an HbA1c greater than and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Animal Data SaxagliptinIn embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.In prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day through lactation day 21 at exposures up to 470-times the mg clinical dose, based on AUC.Metformin HClMetformin HCl 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 2,000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.Saxagliptin and MetforminSaxagliptin 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 mg saxagliptin and 2,000 mg metformin. Minor skeletal abnormalities associated with maternal toxicity were observed in rats. In rabbits, coadministration was poorly tolerated in 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 low incidence of delayed ossification of the fetal hyoid bone.. 8.2 Lactation Risk Summary. 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 mothers 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.. Data. Human Data 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 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.. Animal Data 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 1:1 ratio with plasma drug concentrations.. 8.4 Pediatric Use The safety and effectiveness of saxagliptin and metformin hydrochloride extended-release tablets as an adjunct to diet and exercise to improve glycemic control in patients with type diabetes mellitus have not been established in pediatric patients.Effectiveness of saxagliptin was not demonstrated in 26-week, placebo-controlled, double-blind randomized clinical trial with 26-week safety extension (NCT03199053) in 164 pediatric patients aged 10 to 17 years with inadequately controlled type diabetes mellitus.. 8.5 Geriatric Use Saxagliptin and Metformin Hydrochloride Extended-Release Tablets. 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) ].. Saxagliptin. In the seven, double-blind, controlled clinical safety and efficacy trials of saxagliptin, 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 patients 65 years of age and older and younger adult patients.. Metformin HCl. Controlled clinical trials of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. 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 Warnings and Precautions (5.1) ].. 8.6Renal Impairment Saxagliptin. In 12-week randomized placebo-controlled trial, saxagliptin 2.5 mg was administered to 85 patients 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 patients treated with saxagliptin 2.5 mg and 22% among patients treated with placebo. Four saxagliptin-treated patients (4.7%) and three placebo-treated patients (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose <= 50 mg/dL).. Metformin HCl. 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 m2 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ].. 8.7Hepatic Impairment 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) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oPancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets. (5.2)oHeart 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)oVitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually. (5.4)oHypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues: Consider lower dosage of insulin or insulin secretagogue when used in combination with saxagliptin and metformin hydrochloride extended-release tablets. (5.5)oHypersensitivity-Related Events: There have been post-marketing reports of serious hypersensitivity reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions in patients treated with saxagliptin. If hypersensitivity reactions occur, discontinue saxagliptin and metformin hydrochloride extended-release tablets, treat promptly, and monitor until signs and symptoms resolve. (5.6)oArthralgia: Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.7)oBullous 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 and metformin hydrochloride extended-release tablets (5.8).. oPancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue saxagliptin and metformin hydrochloride extended-release tablets. (5.2). oHeart 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). oVitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually. (5.4). oHypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues: Consider lower dosage of insulin or insulin secretagogue when used in combination with saxagliptin and metformin hydrochloride extended-release tablets. (5.5). oHypersensitivity-Related Events: There have been post-marketing reports of serious hypersensitivity reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions in patients treated with saxagliptin. If hypersensitivity reactions occur, discontinue saxagliptin and metformin hydrochloride extended-release tablets, treat promptly, and monitor until signs and symptoms resolve. (5.6). oArthralgia: Severe and disabling arthralgia has been reported in patients taking DPP4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.7). oBullous 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 and metformin hydrochloride extended-release tablets (5.8).. 5.1Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had 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 (> 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 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 diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with 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 health care 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:. Renal Impairment. 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 patients renal function include [see Clinical Pharmacology (12.3) ]:oBefore initiating saxagliptin and metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).oSaxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4) ].oInitiation of saxagliptin and metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m2.oObtain 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.oIn patients taking saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit and risk of continuing therapy.. oBefore initiating saxagliptin and metformin hydrochloride extended-release tablets, obtain an estimated glomerular filtration rate (eGFR).. oSaxagliptin and metformin hydrochloride extended-release tablets are contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4) ].. oInitiation of saxagliptin and metformin hydrochloride extended-release tablets is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m2.. oObtain 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.. oIn patients taking saxagliptin and metformin hydrochloride extended-release tablets whose eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit and risk of continuing therapy.. Drug Interactions. 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.. Age 65 or Greater. The risk of metformin-associated lactic acidosis increases with the patients age because elderly patients have 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) ].. Radiological Studies with Contrast. 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 m2; in patients with 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.. Surgery and Other Procedures. 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.. Hypoxic States. 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.. Excessive Alcohol Intake. 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.. Hepatic Impairment. 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.. Mitochondrial Diseases. Metformin may increase the risk of lactic acidosis in patients with mitochondrial diseases such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD). Saxagliptin and metformin hydrochloride extended-release tablets are not recommended in patients with mitochondrial diseases such as MELAS syndrome and MIDD.If patient taking saxagliptin and metformin hydrochloride extended-release tablets develops elevated lactic acid levels (with or without accompanying neurologic signs and symptoms), discontinue saxagliptin and metformin hydrochloride extended-release tablets. Depending on the clinical context, consider evaluating the patient for MELAS, MIDD, or other mitochondrial disease.. 5.2Pancreatitis There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin. In cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin compared to 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 history of pancreatitis are at increased risk for the development of pancreatitis while using saxagliptin and metformin hydrochloride extended-release tablets.. 5.3Heart Failure In 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 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). Patients with prior history of heart failure and patients with renal impairment had 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 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.. 5.4Vitamin B12 Concentrations In controlled clinical trials of metformin of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on saxagliptin and metformin hydrochloride extended-release tablets and manage any abnormalities [see Adverse Reactions (6.1) ].. 5.5Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues Saxagliptin. When saxagliptin was 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, lower dosage of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with saxagliptin and metformin hydrochloride extended-release tablets.. Metformin HCl. 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.Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.. 5.6Hypersensitivity Reactions There have been post-marketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If serious hypersensitivity reaction is suspected, discontinue saxagliptin 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 patient with history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with saxagliptin and metformin hydrochloride extended-release tablets.. 5.7Severe and Disabling Arthralgia There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. subset of patients experienced recurrence of symptoms when restarting the same drug or different DPP4 inhibitor. Consider DPP4 inhibitors as possible cause for severe joint pain and discontinue drug if appropriate.. 5.8Bullous 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 and metformin hydrochloride extended-release tablets. If bullous pemphigoid is suspected, saxagliptin and metformin hydrochloride extended-release tablets should be discontinued and referral to dermatologist should be considered for diagnosis and appropriate treatment.