FDA label 52ce7560-432e-42e3-95af-4de643456437

WARNING: LACTIC ACIDOSIS • Postmarketing 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 (>5 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) ] . • Risk 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 a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. • Steps 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) ] . • If metformin-associated lactic acidosis is suspected, immediately discontinue QTERNMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see WARNINGS AND PRECAUTIONS (5.1) ] . WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning. • Postmarketing 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) • Risk 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, and hepatic impairment. 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) • If lactic acidosis is suspected, discontinue QTERNMET XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)

5 WARNINGS AND PRECAUTIONS Lactic acidosis : See boxed warning (2.2 , 4 , 5.1) Pancreatitis : If pancreatitis is suspected, promptly discontinue. (5.2 , 6.2) Heart Failure : Consider the risks and benefits of QTERNMET XR in patients who have known risk factors for heart failure. Monitor patients. (5.3) Hypotension : Before initiating QTERNMET XR, assess volume status and correct hypovolemia in the elderly, in patients with renal impairment or low systolic blood pressure, and in patients on loop diuretics. Monitor for signs and symptoms during therapy. (5.4 , 6.1) Ketoacidosis : Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis regardless of blood glucose level. If suspected, discontinue QTERNMET XR, evaluate and treat promptly. Before initiating QTERNMET XR, consider risk factors for ketoacidosis. Patients on QTERNMET XR may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. (5.5 , 6.2) Acute Kidney Injury : Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat. Monitor renal function during therapy. (5.6 , 6.2) Urosepsis and Pyelonephritis : Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.7 , 6.2) Hypoglycemia : Consider lowering the dose of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating QTERNMET XR in combination with these agents. (5.8 , 6.1) Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene ): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.9) Hypersensitivity Reactions (e.g., urticaria, facial edema) : There have been postmarketing reports of serious hypersensitivity reactions treated with saxagliptin, such as anaphylaxis, angioedema, and exfoliative skin conditions. Promptly discontinue QTERNMET XR, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.10 , 6.2) Vitamin B 12 deficiency : Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. (5.11 , 6.1) Genital Mycotic Infections : Monitor and treat if indicated. (5.12 , 6.1) Arthralgia : Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.13 , 6.1 , 6.2) Bullous Pemphigoid : There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue QTERNMET XR. (5.14) Macrovascular Outcomes : There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with QTERNMET XR. (5.15) 5.1 Lactic Acidosis There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of QTERNMET XR. In QTERNMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue QTERNMET XR and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment : The postmarketing 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 [see DOSAGE AND ADMINISTRATION (2.3) and CLINICAL PHARMACOLOGY (12.3) ] based upon the patient’s renal function include: • Before initiating QTERNMET XR, obtain an estimated glomerular filtration rate (eGFR). • Obtain an eGFR at least annually in all patients taking QTERNMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. • QTERNMET XR is contraindicated in patients with an eGFR less than 45 mL/minute/1.73 m 2 [see CONTRAINDICATIONS (4) , USE IN SPECIFIC POPULATIONS (8.6) ] . Drug Interactions : The concomitant use of QTERNMET XR 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 (e.g., cationic drugs) [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 patient’s age because elderly patients have a greater likelihood of having hepatic, renal or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see USE IN SPECIFIC POPULATIONS (8.5) ] . Radiological Studies with Contras t: 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 QTERNMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart QTERNMET XR 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. QTERNMET XR should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States : Several of the postmarketing 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 QTERNMET XR. 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 QTERNMET XR. 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 QTERNMET XR in patients with clinical or laboratory evidence of hepatic disease. 5.2 Pancreatitis There have been postmarketing reports of acute pancreatitis in patients taking saxagliptin. In a cardiovascular outcome trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin compared to 9 of 8173 (0.1%) receiving placebo. Pre-existing risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin and in 100% (9/9) of those patients receiving placebo. After initiation of QTERNMET XR, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue QTERNMET XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using QTERNMET XR. 5.3 Heart Failure In a cardiovascular outcome trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin (289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event analysis, the risk of hospitalization for heart failure was higher in the saxagliptin group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with a prior history of heart failure and subjects with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment. Consider the risks and benefits of QTERNMET XR prior to initiating treatment in patients at a higher risk of 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 QTERNMET XR. 5.4 Hypotension Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating QTERNMET XR [see ADVERSE REACTIONS (6.1) ] particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m 2 ), elderly patients or patients on loop diuretics. Before initiating QTERNMET XR, volume status should be assessed and corrected. QTERNMET XR is contraindicated in patients with an eGFR <45 mL/min/1.73 m 2 . Monitor for signs and symptoms of hypotension after initiating therapy. 5.5 Ketoacidosis Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have been identified in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose cotransporter-2 (SGLT2) inhibitors, including dapagliflozin. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. QTERNMET XR is not indicated for the treatment of patients with type 1 diabetes mellitus [see INDICATIONS AND USAGE (1) ] . Patients treated with QTERNMET XR who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with QTERNMET XR may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, QTERNMET XR should be discontinued, the patient should be evaluated and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid, and carbohydrate replacement. In many of the postmarketing reports for dapagliflozin, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized, and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis, such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified. Before initiating QTERNMET XR, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. For patients who undergo elective surgery, consider temporarily discontinuing QTERNMET XR for at least 3 days prior to surgery [see Clinical Pharmacology ( 12.2 , 12.3 )] . Consider monitoring for ketoacidosis and temporarily discontinuing QTERNMET XR in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery) [see ADVERSE REACTIONS (6.2)]. Ensure risk factors for ketoacidosis are resolved prior to restarting QTERNMET XR. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue QTERNMET XR and seek medical attention immediately if signs and symptoms occur. 5.6 Acute Kidney Injury Dapagliflozin causes intravascular volume contraction [see WARNINGS AND PRECAUTIONS (5.4) ] and can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving dapagliflozin. Increases in serum creatinine and decreases in estimated GFR may also be observed with initiation of dapagliflozin. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating QTERNMET XR, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs and NSAIDs). Consider temporarily discontinuing QTERNMET XR in the setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue QTERNMET XR promptly and institute treatment. Renal function should be evaluated prior to initiation of QTERNMET XR and monitored periodically thereafter. QTERNMET XR is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m 2 [see DOSAGE AND ADMINISTRATION (2.2) , CONTRAINDICATIONS (4) , WARNINGS AND PRECAUTIONS (5.1) and USE IN SPECIFIC POPULATIONS (8.6) ]. 5.7 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see ADVERSE REACTIONS (6.2) ] . 5.8 Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Dapagliflozin, and saxagliptin can individually increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia when these agents are used in combination with QTERNMET XR [see ADVERSE REACTIONS (6.1) ] . 5.9 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with QTERNMET XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue QTERNMET XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 5.10 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include anaphylaxis, angioedema and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue QTERNMET XR, treat per standard of care, and monitor until signs and symptoms are resolved. Assess for other potential causes for the event. Institute alternative treatment for diabetes. Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with saxagliptin. 5.11 Vitamin B 12 Concentrations In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2- to 3-year intervals in patients on QTERNMET XR and manage any abnormalities [see ADVERSE REACTIONS (6.1) ] . 5.12 Genital Mycotic Infections Dapagliflozin increases the risks of genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections [see ADVERSE REACTIONS (6.1) ] . Monitor and treat appropriately. 5.13 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate [see ADVERSE REACTIONS (6) ] . 5.14 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving QTERNMET XR. If bullous pemphigoid is suspected, QTERNMET XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment. 5.15 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with QTERNMET XR.

6 ADVERSE REACTIONS The following important adverse reactions are described below or elsewhere in the labeling: • Lactic Acidosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1) ] • Pancreatitis [see WARNINGS AND PRECAUTIONS (5.2) ] • Heart Failure [see WARNINGS AND PRECAUTIONS (5.3) ] • Hypotension [see WARNINGS AND PRECAUTIONS (5.4) ] • Ketoacidosis [see WARNINGS AND PRECAUTIONS (5.5) ] • Acute Kidney Injury [see WARNINGS AND PRECAUTIONS (5.6) ] • Urosepsis and Pyelonephritis [see WARNINGS AND PRECAUTIONS (5.7) ] • Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [see WARNINGS AND PRECAUTIONS (5.8) ] • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see WARNINGS AND PRECAUTIONS (5.9) ] • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS (5.10) ] • Vitamin B 12 Concentrations [see WARNINGS AND PRECAUTIONS (5.11) ] • Genital Mycotic Infections [see WARNINGS AND PRECAUTIONS (5.12) ] • Severe and Disabling Arthralgia [see WARNINGS AND PRECAUTIONS (5.13) ] • Bullous Pemphigoid [see WARNINGS AND PRECAUTIONS (5.14) ] Adverse reactions reported in ≥5% of subjects treated with dapagliflozin and saxagliptin plus metformin were: upper respiratory tract infection, urinary tract infection, and dyslipidemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of combined use of 10 mg dapagliflozin and 5 mg saxagliptin has been evaluated in adult subjects with type 2 diabetes in a pooled safety analysis of three phase 3 active/placebo-controlled clinical trials with a median exposure of 51 weeks. The pooled safety analysis included a total of 1169 adults: 492 patients in the combination of saxagliptin and dapagliflozin plus metformin group, 341 patients in the dapagliflozin plus metformin group, 336 patients the saxagliptin plus metformin group. The mean age of these subjects was 54 years, 0.8% were 75 years or older and 53.7% were female. The population was 80.9% White, 8.3% Black or African American, 3.7% Asian, and 6.6% Other race. At baseline the population had diabetes for an average of 7.5 years and a mean HbA1c of 8.4%. The mean eGFR at baseline was 94.4 mL/min/1.73 m 2 . The common adverse reactions were based on the pooled analyses of these studies as shown in Table 1. Table 1: Adverse Reactions Reported in ≥2% of Subjects Treated with 10 mg Dapagliflozin and 5 mg Saxagliptin plus Metformin (≥1500 mg) Adverse Reaction Preferred Term Adverse reactions that are medically related were grouped to a single preferred term. Frequency % Upper respiratory tract infection 13.6 Urinary tract infection 5.7 Dyslipidemia 5.1 Headache 4.3 Diarrhea 3.7 Back pain 3.3 Genital infection 3.0 Arthralgia 2.4 Additionally, adverse reactions reported in <5% and ≥2% from the dapagliflozin development program and ≥1% more frequently compared to placebo included increased urination and discomfort with urination. Metformin In placebo-controlled monotherapy trials of metformin 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 study medication in 0.6% of the patients treated with metformin extended-release. Hypoglycemia In the pooled analysis, the incidences of hypoglycemia (defined as blood glucose <54 mg/dL regardless of the presence or absence of symptoms) and severe hypoglycemia (events requiring assistance due to neuroglycopenia, characterized by altered mental and/or physical status) were 1% and 0.2%, respectively. Genital Mycotic Infections Genital mycotic infections were reported in 15 subjects (3%) treated with combination plus metformin therapy. Reported adverse reactions by frequency included vulvovaginal mycotic infection, balanoposthitis, genital fungal infection, vaginal infection, and vulvovaginitis. The majority of subjects (84.2%) who experienced genital infection adverse reactions were females. Urinary Tract Infections Urinary tract infections were reported in 28 subjects (5.7%) treated with combination plus metformin therapy. Reported adverse reactions by frequency included urinary tract infection, Escherichia urinary tract infection, prostatitis, and pyelonephritis. The majority of subjects (80.6%) who experienced urinary tract infection adverse reactions were females. Volume Depletion Dapagliflozin causes an osmotic diuresis, which may lead to reductions in intravascular volume. Events related to volume depletion (hypotension, dehydration, and hypovolemia) were reported in 2 subjects (0.4%) treated with dapagliflozin, saxagliptin and metformin combination therapy. Impairment of Renal Function Dapagliflozin and Saxagliptin plus Metformin Adverse reactions related to decreased renal function were reported in 10 subjects (2.0%) treated with combination plus metformin therapy. The reported adverse reactions included decreased glomerular filtration rate, renal impairment, increased blood creatinine, acute renal failure, and decreased urine output. None of the adverse reactions were reported as serious and all but one were mild to moderate in intensity. Three subjects discontinued due to decreased eGFR. Subjects with AEs of renal impairment had lower mean eGFR values at baseline of 64.4 mL/min/1.73 m 2 compared to 94.4 mL/min/1.73 m 2 in overall population treated with combination plus metformin therapy. Ketoacidosis Dapagliflozin In the cardiovascular outcome study with dapagliflozin in patients with type 2 diabetes mellitus, events of diabetic ketoacidosis were reported in 27 out of 8574 patients in the dapagliflozin-treated group and in 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period. Laboratory Findings Increases in Serum Creatinine and Decreases in eGFR Dapagliflozin Initiation of dapagliflozin causes an increase in serum creatinine and decrease in eGFR. In patients with normal or mildly impaired renal function at baseline, the serum creatinine and eGFR returned to baseline at Week 24. Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ) [see WARNINGS AND PRECAUTIONS (5.6) and MECHANISM OF ACTION (12.1) ] . Decrease in Lymphocyte Counts Saxagliptin A dose-related mean decrease in absolute lymphocyte count has been observed with saxagliptin. In a pool of 5 placebo-controlled studies, a mean decrease in absolute lymphocyte count of approximately 100 cells/microL relative to placebo was observed. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, and 0.4% in the 2.5 mg, 5 mg saxagliptin and placebo groups, respectively. The clinical significance of this decrease in lymphocyte count relative to placebo is not known. The effect of saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown. Increase in Hematocrit Dapagliflozin In a pool of 13 placebo-controlled studies with dapagliflozin, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were −0.33% in the placebo group and 2.30% in the 10 mg dapagliflozin group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of 10 mg dapagliflozin-treated patients. Increase in Low-Density Lipoprotein Cholesterol Patients treated with combination therapy demonstrated a mean percent increase from baseline LDL-cholesterol (ranging from 2.1 to 6.9%). Elevations in Creatine Kinase An imbalance in the number of subjects who experienced serum creatine kinase (CK) elevations >10x the upper limit of normal (a marker of muscle injury/necrosis) was observed in 5 subjects (1%) treated with combination therapy. The elevations were transient. Rhabdomyolysis was reported for one of those subjects for which no obvious cause was identified. Decrease in Serum Bicarbonate In a study of concomitant therapy of 10 mg dapagliflozin with exenatide extended-release (on a background of metformin), four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the dapagliflozin and exenatide-extended release treatment groups [see WARNINGS AND PRECAUTIONS (5.5 )] . Vitamin B 12 Concentrations Metformin In clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post approval use of dapagliflozin, saxagliptin, and metformin. Because the following reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dapagliflozin • Ketoacidosis • Acute Kidney Injury • Urosepsis and pyelonephritis • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) • Rash Saxagliptin • Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions • Pancreatitis • Severe and disabling arthralgia • Bullous pemphigoid • Rhabdomyolysis Metformin • Cholestatic, hepatocellular, and mixed hepatocellular liver injury

<table width="100%"><caption>Table 1: Adverse Reactions Reported in &#x2265;2% of Subjects Treated with 10 mg Dapagliflozin and 5 mg Saxagliptin plus Metformin (&#x2265;1500 mg)</caption><col width="33%"/><col width="19%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph><paragraph><content styleCode="bold">Preferred Term</content><footnote ID="_Ref475527322">Adverse reactions that are medically related were grouped to a single preferred term.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Frequency %</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper respiratory tract infection<footnoteRef IDREF="_Ref475527322"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13.6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Urinary tract infection<footnoteRef IDREF="_Ref475527322"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyslipidemia<footnoteRef IDREF="_Ref475527322"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Back pain</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Genital infection<footnoteRef IDREF="_Ref475527322"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Arthralgia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2.4</paragraph></td></tr></tbody></table>