2014年10月30日,　阿斯利康的糖尿病复方新药Xigduo XR（dapagliflozin/缓释二甲双胍）获FDA批准，作为一种辅助药物，结合运动和饮食，用于适合dapagliflozin和二甲双胍联合治疗的2型糖尿病成人患者。
Xigduo XR为每日1次的复方单片，由固定剂量的dapagliflozin（达帕格列净，商品名：Forxiga）和缓释型盐酸二甲双胍组成，这2种成分具有互补性的作用机制，能够帮助改善血糖控制。
此前，Xigduo（dapagliflozin/速释二甲双胍）已于2014年1月获欧盟批准，是欧盟上市的首个SGLT2抑制剂和二甲双胍复方产品。在美国，由于阿斯利康和前合作伙伴百时美的监管推迟，强生Invokamet（canagliflozin/速释二甲双胍）于今年8月率先赢得FDA批准，是美国市场中的首个SGLT2和二甲双胍复方产品。Xigduo由阿斯利康和百时美施贵宝（BMS）达成的全球糖尿病联盟开发。不过，去年12月，阿斯利康耗资41亿美元收购百时美在该联盟中的全部股份后，全面接管了该单元。
目前，SGLT2抑制剂市场已经非常拥挤，除了dapagliflozin和canagliflozin，礼来和勃林格殷格翰empagliflozin也于今年8月获FDA批准，辉瑞和默沙东的ertugliflozin已处于后期临床。
钠-葡萄糖协同转运蛋白（SGLT2）抑制剂是新一类降糖药，具有独特的作用模式，独立于胰岛素发挥作用，能够在肾脏中选择性抑制SGLT2，帮助患者从尿液中排出多余的葡萄糖。SGLT2是一类特异性分布在肾脏近曲小管S1段的葡萄糖转运体，其生理作用是促进葡萄糖在肾小球的重吸收。与非糖尿病人群相比，2型糖尿病患者的肾脏能够重吸收大量的葡萄糖进入血液，这可能会推高血糖水平。
二甲双胍则是2型糖尿病治疗的一线药物，可单独或与其他药物（包括胰岛素）联合用药。在2型糖尿病患者中，肝脏产生过量的葡萄糖（glucose），从而提高血糖水平。二甲双胍可通过降低肝脏产生葡萄糖的量、增加肌肉对葡萄糖的敏感性、延缓肠道的葡萄糖吸收，降低机体的血糖水平。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use XIGDUO XR safely and effectively. See full prescribing information for XIGDUO XR.
XIGDUO XR (dapagliflozin and metformin HCl extended-release) tablets, for oral use
Initial U.S. Approval: 2014
WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.
• Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. (5.1)
• Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. (5.1)
• If acidosis is suspected, discontinue XIGDUO XR and hospitalize the patient immediately. (5.1)
INDICATIONS AND USAGE
XIGDUO XR is a combination of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate. (1)
Limitation of use:
• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis. (1.1)
DOSAGE AND ADMINISTRATION
• Individualize the starting dose based on the patient’s current treatment. (2.1)
• Administer once daily in the morning with food. (2.1)
• Swallow whole. Never crush, cut, or chew. (2.1)
• Do not exceed a daily dose of 10 mg dapagliflozin/2000 mg metformin HCl extended-release. (2.1)
• No dosage adjustment is indicated in patients with mild renal impairment. (2.2)
• XIGDUO XR should not be used in patients with moderate to severe renal impairment (defined as eGFR <60 mL/min/1.73 m 2 or CrCl <60 mL/min) or end-stage renal disease. ( 2.2, 4, 5.3)
DOSAGE FORMS AND STRENGTHS
• 5 mg dapagliflozin/500 mg metformin HCl extended-release (3)
• 5 mg dapagliflozin/1000 mg metformin HCl extended-release (3)
• 10 mg dapagliflozin/500 mg metformin HCl extended-release (3)
• 10 mg dapagliflozin/1000 mg metformin HCl extended-release (3)
CONTRAINDICATIONS
• Moderate to severe renal impairment. ( 4, 5.3)
• History of serious hypersensitivity to dapagliflozin or hypersensitivity to metformin hydrochloride. ( 4, 6.1)
• Metabolic acidosis, including diabetic ketoacidosis. ( 4, 5.1)
WARNINGS AND PRECAUTIONS
• Lactic acidosis: Warn patients against excessive alcohol intake. XIGDUO XR should generally be avoided in hepatic impairment and contraindicated in moderate to severe renal impairment. Ensure normal or mildly impaired renal function before initiating and at least annually thereafter. Temporarily discontinue XIGDUO XR in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids. ( 2.2, 4, 5.1, 5.2, 5.3, 5.5, 5.6, 5.7, 5.8, 5.10, 5.11, 8.5, 8.6)
• Hypotension: Before initiating XIGDUO XR, assess volume status and correct hypovolemia in the elderly, in patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. ( 5.4, 6.1)
• Hypoglycemia: In patients taking insulin or an insulin secretagogue with XIGDUO XR, consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. (5.9)
• Vitamin B12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. ( 5.12, 6.1)
• Genital mycotic infections: Monitor and treat if indicated. (5.13)
• Increased LDL-C: Monitor and treat per standard of care. (5.14)
• Bladder Cancer: An imbalance in bladder cancers was observed in clinical trials. Dapagliflozin should not be used in patients with active bladder cancer and should be used with caution in patients with a prior history of bladder cancer. (5.15)
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with XIGDUO XR or any other antidiabetic drug. (5.16)
ADVERSE REACTIONS
• The most common adverse reactions associated with XIGDUO XR (5% or greater incidence) were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache. (6.1)
• Adverse reactions reported in >5% of patients treated with metformin extended-release and more commonly than in patients treated with placebo are: diarrhea and nausea/vomiting. (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.
DRUG INTERACTIONS
• Cationic drugs: eliminated by renal tubular secretion may reduce metformin elimination; use with caution. ( 5.10, 7.3)
USE IN SPECIFIC POPULATIONS
• Pregnancy: There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. (8.1)
• Nursing Mothers: Discontinue XIGDUO XR or discontinue nursing. (8.3)
• Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume. ( 5.4, 8.6)
• Renal Impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function. ( 5.3, 6.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 10/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
XIGDUO XR (dapagliflozin and metformin HCl extended-release) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both dapagliflozin and metformin is appropriate [see Clinical Studies (14)].
1.1 Limitations of Use
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
• Healthcare providers should individualize the starting dose of XIGDUO XR based on the patient’s current treatment [see Dosage Forms and Strengths (3)].
• XIGDUO XR should be taken once daily in the morning with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin.
• XIGDUO XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of XIGDUO XR will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.
• Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 10 mg dapagliflozin and 2000 mg metformin HCl.
• Patients taking an evening dose of metformin XR should skip their last dose before starting XIGDUO XR.
• In patients with volume depletion, correcting this condition prior to initiation of XIGDUO XR is recommended [see Warnings and Precautions (5.4), Use in Specific Populations (8.5), and Patient Counseling Information (17)].
2.2 Patients with Renal ImpairmentNo dosage adjustment for XIGDUO XR is indicated in patients with mild renal impairment (eGFR of 60 mL/min/1.73 m2 or greater).
Assessment of renal function is recommended prior to initiation of XIGDUO XR therapy and periodically thereafter.
XIGDUO XR should not be used in patients with moderate to severe renal impairment (defined as eGFR <60 mL/min/1.73 m2 or CrCl <60 mL/min, or end-stage renal disease [ESRD]) [see Contraindications (4), Warnings and Precautions (5.3), Adverse Reactions (6.1), and Use in Specific Populations (8.6)].
3 DOSAGE FORMS AND STRENGTHS
XIGDUO XR is a combination of dapagliflozin and metformin HCl extended-release. XIGDUO XR tablets are available in the following dosage forms and strengths:
• 5 mg/500 mg tablets are orange, biconvex, capsule-shaped, and film-coated tablets with "1070" and "5/500" debossed on one side and plain on the reverse side.
• 5 mg/1000 mg tablets are pink to dark pink, biconvex, oval-shaped, and film-coated tablets with "1071" and "5/1000" debossed on one side and plain on the reverse side.
• 10 mg/500 mg tablets are pink, biconvex, capsule-shaped, and film-coated tablets with "1072" and "10/500" debossed on one side and plain on the reverse side.
• 10 mg/1000 mg tablets are yellow to dark yellow, biconvex, oval-shaped, and film-coated tablets with "1073" and "10/1000" debossed on one side and plain on the reverse side.
4 CONTRAINDICATIONS
XIGDUO XR is contraindicated in patients with:
• Moderate to severe renal impairment (e.g., serum creatinine levels ≥1.5 mg/dL for men, ≥1.4 mg/dL for women, or eGFR <60 mL/min/1.73 m 2 or CrCl <60 mL/min), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions (5.3)].
• History of a serious hypersensitivity reaction to dapagliflozin or hypersensitivity to metformin hydrochloride [see Adverse Reactions (6.1)].
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
5 WARNINGS AND PRECAUTIONS
5.1 Lactic Acidosis
Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with XIGDUO XR; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 μg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake when taking metformin since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure [see Warnings and Precautions (5.2, 5.3, 5.5, 5.6, 5.75.11)].
The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur [see Warnings and Precautions (5.2)]. Metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal (ULN), but <5 mmol/L, in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling [see Warnings and Precautions (5.8)].
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery [see Contraindications (4) and Warnings and Precautions (5.2, 5.6, 5.7, 5.10, 5.11)].
5.2 Hypoxic States
Cardiovascular collapse (shock), acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on XIGDUO XR therapy, the drug should be promptly discontinued.
5.3 Use in Patients with Renal Impairment
Metformin is known to be substantially excreted by the kidney and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Therefore, XIGDUO XR is contraindicated in patients with moderate to severe renal impairment [see Contraindications (4)]. Also, dapagliflozin increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating XIGDUO XR [see Adverse Reactions (6.1)].
Before initiation of XIGDUO XR therapy, and at least annually thereafter, renal function should be assessed and verified as normal or mildly impaired. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and XIGDUO XR discontinued if evidence of moderate to severe renal impairment is present.
5.4 Hypotension
Dapagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating dapagliflozin [see Adverse Reactions (6.1)], particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics.
Before initiating XIGDUO XR in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms of hypotension after initiating therapy.
5.5 Impaired Hepatic Function
Metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis. Therefore, XIGDUO XR should generally be avoided in patients with hepatic impairment.
5.6 Alcohol Intake
Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving XIGDUO XR.
5.7 Surgical Procedures
Use of XIGDUO XR should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal or mildly impaired.
5.8 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes
A patient with type 2 diabetes, previously well controlled on XIGDUO XR, who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, XIGDUO XR must be stopped immediately and other appropriate corrective measures initiated.
5.9 Use with Medications Known to Cause Hypoglycemia
Dapagliflozin
Insulin and insulin secretagogues are known to cause hypoglycemia. Dapagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with XIGDUO XR.
Metformin hydrochloride
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.
5.10 Concomitant Medications Affecting Renal Function or Metformin Disposition
Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion [see Drug Interactions (7.3)], should be used with caution.
5.11 Radiologic Studies with Intravascular Iodinated Contrast Materials
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, XIGDUO XR should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal or mildly impaired.
5.12 Vitamin B12 Concentrations
In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. This decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on XIGDUO XR and any apparent abnormalities should be appropriately investigated and managed [see Adverse Reactions (6.1)].
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.
5.13 Genital Mycotic Infections
Dapagliflozin increases the risk 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.
5.14 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
Increases in LDL-C occur with dapagliflozin [see Adverse Reactions (6.1)]. Monitor LDL-C and treat per standard of care after initiating XIGDUO XR.
5.15 Bladder Cancer
Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%) treated with dapagliflozin and 1/3512 patient (0.03%) treated with placebo/comparator. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 4 cases with dapagliflozin and no cases with placebo/comparator. Bladder cancer risk factors and hematuria (a potential indicator of pre-existing tumors) were balanced between treatment arms at baseline. There were too few cases to determine whether the emergence of these events is related to dapagliflozin.
There are insufficient data to determine whether dapagliflozin has an effect on pre-existing bladder tumors. Consequently, XIGDUO XR should not be used in patients with active bladder cancer. In patients with prior history of bladder cancer, the benefits of glycemic control versus unknown risks for cancer recurrence with XIGDUO XR should be considered.
5.16 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with XIGDUO XR or any other antidiabetic drug.
6 ADVERSE REACTIONS
The following important adverse reactions are described below and elsewhere in the labeling:
• Use in Patients with Renal Impairment [see Warnings and Precautions (5.3)]
• Hypotension [see Warnings and Precautions (5.4)]
• Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.9)]
• Vitamin B 12 Concentrations [see Warnings and Precautions (5.12)]
• Genital Mycotic Infections [see Warnings and Precautions (5.13)]
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.14)]
• Bladder Cancer [see Warnings and Precautions (5.15)]
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 clinical practice.
Dapagliflozin and Metformin hydrochloride
Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin coadministered with metformin immediate- or extended-release was used to evaluate safety. This pool included several add-on studies (metformin alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin, or insulin and metformin, 2 initial combination with metformin studies, and 2 studies of patients with cardiovascular disease [CVD] and type 2 diabetes who received their usual treatment [with metformin as background therapy]). For studies that included background therapy with and without metformin, only patients who received metformin were included in the 8-study placebo-controlled pool. Across these 8 studies 983 patients were treated once daily with dapagliflozin 10 mg and metformin and 1185 were treated with placebo and metformin. These 8 studies provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and moderately impaired in 10% of patients.
The overall incidence of adverse events for the 8-study, short-term, placebo-controlled pool in patients treated with dapagliflozin 10 mg and metformin was 60.3% compared to 58.2% for the placebo and metformin group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin was 4% compared to 3.3% for the placebo and metformin group. The most commonly reported events leading to discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and metformin were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%).
Table 1 shows common adverse reactions associated with the use of dapagliflozin and metformin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin and metformin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.
Table 1: Adverse Reactions in Placebo-Controlled Studies Reported in ≥2% of Patients Treated with Dapagliflozin and Metformin 

Adverse Reaction	% of Patients
	Pool of 8 Placebo-Controlled Studies
	Placebo and Metformin N=1185	Dapagliflozin 5 mg and Metformin N=410	Dapagliflozin 10 mg and Metformin N=983
Female genital mycotic infections1	1.5	9.4	9.3
Nasopharyngitis	5.9	6.3	5.2
Urinary tract infections2	3.6	6.1	5.5
Diarrhea	5.6	5.9	4.2
Headache	2.8	5.4	3.3
Male genital mycotic infections3	0	4.3	3.6
Influenza	2.4	4.1	2.6
Nausea	2.0	3.9	2.6
Back pain	3.2	3.4	2.5
Dizziness	2.2	3.2	1.8
Cough	1.9	3.2	1.4
Constipation	1.6	2.9	1.9
Dyslipidemia	1.4	2.7	1.5
Pharyngitis	1.1	2.7	1.5
Increased urination4	1.4	2.4	2.6
Discomfort with urination	1.1	2.2	1.6

Metformin hydrochloride
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.
Pool of 12 Placebo-Controlled Studies for Dapagliflozin 5 and 10 mg
Dapagliflozin
The data in Table 2 are derived from 12 placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies dapagliflozin was used as monotherapy, and in 8 studies dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14)].
These data reflect exposure of 2338 patients to dapagliflozin with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin 5 mg (N=1145), or dapagliflozin 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 6 years, had a mean HbA1c of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m2).
Table 2 shows common adverse reactions associated with the use of dapagliflozin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.
Table 2: Adverse Reactions in Placebo-Controlled Studies Reported in ≥2% of Patients Treated with Dapagliflozin 

Adverse Reaction	% of Patients
	Pool of 12 Placebo-Controlled Studies
	Placebo N=1393	Dapagliflozin 5 mg N=1145	Dapagliflozin 10 mg N=1193
Female genital mycotic infections*	1.5	8.4	6.9
Nasopharyngitis	6.2	6.6	6.3
Urinary tract infections†	3.7	5.7	4.3
Back pain	3.2	3.1	4.2
Increased urination‡	1.7	2.9	3.8
Male genital mycotic infections§	0.3	2.8	2.7
Nausea	2.4	2.8	2.5
Influenza	2.3	2.7	2.3
Dyslipidemia	1.5	2.1	2.5
Constipation	1.5	2.2	1.9
Discomfort with urination	0.7	1.6	2.1
Pain in extremity	1.4	2.0	1.7

Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin 5 mg=581, dapagliflozin 10 mg=598). Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.
Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.
Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, posthitis. (N for males: Placebo=716, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595).
Pool of 13 Placebo-Controlled Studies for Dapagliflozin 10 mg
The safety and tolerability of dapagliflozin 10 mg was also evaluated in a larger placebo-controlled study pool. This pool combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg for a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR 82 mL/min/1.73 m2).
Volume Depletion
Dapagliflozin causes an osmotic diuresis, which may lead to reductions in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) are shown in Table 3 for the 12-study and 13-study, short-term, placebo-controlled pools [see Warnings and Precautions (5.4)].
Table 3: Adverse Reactions of Volume Depletion* in Clinical Studies with Dapagliflozin

Pool of 12 Placebo-Controlled Studies			Pool of 13 Placebo-Controlled Studies
	Placebo	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo	Dapagliflozin 10 mg
Overall population N (%)	N=1393 5 (0.4%)	N=1145 7 (0.6%)	N=1193 9 (0.8%)	N=2295 17 (0.7%)	N=2360 27 (1.1%)
Patient Subgroup n (%)
Patients on loop diuretics	n=55 1 (1.8%)	n=40 0	n=31 3 (9.7%)	n=267 4 (1.5%)	n=236 6 (2.5%)
Patients with moderate renal impairment with eGFR ≥30 and <60 mL/min/1.73 m 2	n=107 2 (1.9%)	n=107 1 (0.9%)	n=89 1 (1.1%)	n=268 4 (1.5%)	n=265 5 (1.9%)
Patients ≥65 years of age	n=276 1 (0.4%)	n=216 1 (0.5%)	n=204 3 (1.5%)	n=711 6 (0.8%)	n=665 11 (1.7%)

Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.
Impairment of Renal Function
Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 4). In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24. Renal-related adverse reactions, including renal failure and blood creatinine increase, were more frequent in patients treated with dapagliflozin (see Table 5). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions (see Table 5). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2).
Table 4: Changes in Serum Creatinine and eGFR Associated with Dapagliflozin in the Pool of 12 Placebo-Controlled Studies and Moderate Renal Impairment Study

 

Pool of 12 Placebo-Controlled Studies
		Placebo N=1393	Dapagliflozin 5 mg N=1145	Dapagliflozin 10 mg N=1193
Baseline Mean	Serum Creatinine (mg/dL)	0.853	0.860	0.847
	eGFR (mL/min/1.73 m2)	86.0	85.3	86.7
Week 1 Change	Serum Creatinine (mg/dL)	−0.003	0.029	0.041
	eGFR (mL/min/1.73 m2)	0.4	−2.9	−4.1
Week 24 Change	Serum Creatinine (mg/dL)	−0.005	−0.001	0.001
	eGFR (mL/min/1.73 m2)	0.8	0.8	0.3
		Moderate Renal Impairment Study
		Placebo N=84	Dapagliflozin 5 mg N=83	Dapagliflozin 10 mg N=85
Baseline Mean	Serum Creatinine (mg/dL)	1.46	1.53	1.52
	eGFR (mL/min/1.73 m2)	45.6	44.2	43.9
Week 1 Change	Serum Creatinine (mg/dL)	0.01	0.13	0.18
	eGFR (mL/min/1.73 m2)	0.5	−3.8	−5.5
Week 24 Change	Serum Creatinine (mg/dL)	0.02	0.08	0.16
	eGFR (mL/min/1.73 m2)	0.03	−4.0	−7.4
Week 52 Change	Serum Creatinine (mg/dL)	0.10	0.06	0.15
	eGFR (mL/min/1.73 m2)	−2.6	−4.2	−7.3

Table 5: Proportion of Patients with at Least One Renal Impairment-Related Adverse Reaction

Pool of 6 Placebo-Controlled Studies (up to 104 weeks)*			Pool of 9 Placebo-Controlled Studies (up to 104 weeks)†
Baseline Characteristic	Placebo	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo	Dapagliflozin 10 mg
Overall population Patients (%) with at least one event	n=785 13 (1.7%)	n=767 14 (1.8%)	n=859 16 (1.9%)	n=1956 82 (4.2%)	n=2026 136 (6.7%)
65 years of age and older Patients (%) with at least one event	n=190 4 (2.1%)	n=162 5 (3.1%)	n=159 6 (3.8%)	n=655 52 (7.9%)	n=620 87 (14.0%)
eGFR ≥30 and <60 mL/min/1.73 m2 Patients (%) with at least one event	n=77 5 (6.5%)	n=88 7 (8.0%)	n=75 9 (12.0%)	n=249 40 (16.1%)	n=251 71 (28.3%)
65 years of age and older and eGFR ≥30 and <60 mL/min/1.73 m2 Patients (%) with at least one event	n=41 2 (4.9%)	n=43 3 (7.0%)	n=35 4 (11.4%)	n=141 27 (19.1%)	n=134 47 (35.1%)

Subset of patients from the pool of 12 placebo-controlled studies with long-term extensions.
Subset of patients from the pool of 13 placebo-controlled studies with long-term extensions
The safety of dapagliflozin was evaluated in a study of patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2). In this study 13 patients experienced bone fractures for treatment durations up to 104 weeks. No fractures occurred in the placebo group, 5 occurred in the dapagliflozin 5 mg group, and 8 occurred in the dapagliflozin 10 mg group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to 45 mL/min/1.73 m2. Eleven of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the anatomic site of fracture.
Hypoglycemia
The frequency of hypoglycemia by study [see Clinical Studies (14)] is shown in Table 6. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see Warnings and Precautions (5.9)].
Table 6: Incidence of Major* and Minor† Hypoglycemia in Placebo-Controlled Studies 

Placebo	Dapagliflozin 5 mg	Dapagliflozin 10 mg
Add-on to Metformin* (24 weeks)	N=137	N=137	N=135
Major [n (%)]	0	0	0
Minor [n (%)]	0	2 (1.5)	1 (0.7)
Active Control Add-on to Metformin versus Glipizide (52 weeks)	N=408	–	N=406
Major [n (%)]	3 (0.7)	–	0
Minor [n (%)]	147 (36.0)	–	7 (1.7)
Add-on to DPP4 inhibitor (with or without Metformin) (24 weeks)	N=226	–	N=225
Major [n (%)]	0	–	1 (0.4)
Minor [n (%)]	3 (1.3)	–	4 (1.8)
Add-on to Insulin with or without other OADs‡ (24 weeks)	N=197	N=212	N=196
Major [n (%)]	1 (0.5)	1 (0.5)	1 (0.5)
Minor [n (%)]	67 (34.0)	92 (43.4)	79 (40.3)

Major episodes of hypoglycemia were defined as symptomatic episodes requiring external (third party) assistance due to severe impairment in consciousness or behavior with a capillary or plasma glucose value <54 mg/dL and prompt recovery after glucose or glucagon administration.
Minor episodes of hypoglycemia were defined as either a symptomatic episode with a capillary or plasma glucose measurement <63 mg/dL regardless of need for external assistance, or an asymptomatic capillary or plasma glucose measurement <63 mg/dL that does not qualify as a major episode.
OAD = oral antidiabetic therapy.
Genital Mycotic Infections
Genital mycotic infections were more frequent with dapagliflozin treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 2). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively).
Hypersensitivity Reactions
Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. Across the clinical program, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of dapagliflozin-treated patients. If hypersensitivity reactions occur, discontinue use of dapagliflozin; treat per standard of care and monitor until signs and symptoms resolve.
Laboratory Tests
Increase in Hematocrit
Dapagliflozin
In the pool of 13 placebo-controlled studies, 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 dapagliflozin 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg–treated patients.
Increase in Serum Inorganic Phosphorus
Dapagliflozin
In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10 mg–treated patients compared with placebo-treated patients (mean increases of 0.13 mg/dL versus −0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL if age 17-65 or ≥5.1 mg/dL if age ≥66) were reported in the dapagliflozin 10 mg group versus the placebo group at Week 24 (1.7% versus 0.9%, respectively).
Increase in Low -Density Lipoprotein Cholesterol Dapagliflozin
Dapagliflozin
In the pool of 13 placebo-controlled studies, changes from baseline in mean lipid values were reported in dapagliflozin-treated patients compared to placebo-treated patients. Mean percent change from baseline at Week 24 were 0.0% versus 2.5% for total cholesterol and −1.0% versus 2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively.
Vitamin B12 Concentrations
Metformin hydrochloride
Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on XIGDUO XR and any apparent abnormalities should be appropriately investigated and managed [see Warnings and Precautions (5.12)].
7 DRUG INTERACTIONS
7.1 Positive Urine Glucose Test
Dapagliflozin
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.
7.2 Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Dapagliflozin
Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
7.3 Cationic Drugs
Metformin hydrochloride
Cationic drugs (e.g., amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. A 40% increase in exposure (AUC) of metformin when coadministered with cimetidine was observed in normal healthy volunteers. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of XIGDUO XR and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
7.4 Use with Other Drugs
Metformin hydrochloride
Some medications can predispose to hyperglycemia and may lead to loss of glycemic control. These medications include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving XIGDUO XR, the patient should be observed closely for loss of glycemic control. When such drugs are withdrawn from a patient receiving XIGDUO XR, the patient should be observed closely for hypoglycemia.
In healthy volunteers, the pharmacokinetics of metformin and propranolol, and of metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of XIGDUO XR or its individual components in pregnant women. Based on results of reproductive and developmental toxicity studies in animals, dapagliflozin, a component of XIGDUO XR, may affect renal development and maturation. In a juvenile rat study, increased incidence and/or severity of renal pelvic and tubular dilatations were evident at the lowest tested dose which was approximately 15 times clinical exposure from a 10 mg dose.
These outcomes occurred with drug exposures during periods of animal development that correlate with the late second and third trimesters of human pregnancy. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. XIGDUO XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Dapagliflozin
In a juvenile toxicity study, when dapagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and renal pelvic and tubular dilatations were reported at all levels. Exposure at the lowest tested dose was 15 times the maximum clinical dose, based on AUC. The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within the approximate 1-month recovery period.
In a prenatal and postnatal development study, maternal rats were dosed from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in adult offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415 times and 137 times, respectively, the human values at the clinical dose). Dose-related reductions in pup body weights were observed at doses ≥1 mg/kg/day (approximately ≥19 times the clinical dose). No adverse effects on developmental endpoints were noted at 1 mg/kg/day, or approximately 19 times the clinical dose.
In embryo-fetal development studies in rats and rabbits, dapagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities were observed in rabbits at any dose tested. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day or 1441 times the maximum clinical dose of 10 mg. At higher doses in rats, malformations of blood vessels, ribs, vertebrae, manubria, and skeletal variations in fetuses at ≥150 mg/kg or 2344 times the 10 mg clinical dose were observed.
Metformin hydrochloride
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the MRHD of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
8.3 Nursing Mothers
It is not known whether XIGDUO XR is excreted in human milk. In studies performed with the individual components, both dapagliflozin (reaching levels 0.49 times that found in maternal plasma) and metformin are excreted in the milk of lactating rats.
Data in juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and in the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from dapagliflozin, a decision should be made whether to discontinue nursing or to discontinue XIGDUO XR, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness of XIGDUO XR in pediatric patients under 18 years of age have not been established.
8.5 Geriatric Use
XIGDUO XR
No XIGDUO XR dosage change is recommended based on age.
Dapagliflozin
A total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and over and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical safety and efficacy studies of dapagliflozin. After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin had adverse reactions related to volume depletion and renal impairment or failure compared to patients treated with placebo [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].
Metformin hydrochloride
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney and because the risk of lactic acidosis with metformin is greater in patients with moderately to severely impaired renal function, XIGDUO XR should only be used in patients with normal or mildly impaired renal function. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications (4), Warnings and Precautions (5.1, 5.3), and Clinical Pharmacology (12.3)].
8.6 Patients with Mild Renal Impairment (eGFR ≥60 to <90 mL/min/1.73 m2)
Dapagliflozin
The pool of 21 double-blind, active- and placebo-controlled clinical safety and efficacy studies (dapagliflozin as monotherapy or in combination with other antidiabetic therapies) included 53% (4906/9339) of patients with mild renal impairment. The safety profile in patients with mild renal impairment is similar to that in the overall population.
10 OVERDOSAGE
Dapagliflozin
There were no reports of overdose during the clinical development program for dapagliflozin. In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ supportive measures as dictated by the patient’s clinical status. The removal of dapagliflozin by hemodialysis has not been studied.
Metformin hydrochloride
Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride 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 a 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.
11 DESCRIPTION
XIGDUO XR (dapagliflozin and metformin HCl extended-release) tablets contain two oral antihyperglycemic medications used in the management of type 2 diabetes: dapagliflozin and metformin hydrochloride.
Dapagliflozin
Dapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical formula is C21H25ClO6•C3H8O2•H2O and the formula weight is 502.98. The structural formula is:

Metformin hydrochloride
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white to off-white crystalline compound with a molecular formula of C4H11N5•HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is:

XIGDUO XR
XIGDUO XR is available for oral administration as tablets containing the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin hydrochloride (XIGDUO XR 5 mg/500 mg), the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol and 1000 mg metformin hydrochloride (XIGDUO XR 5 mg/1000 mg), the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin hydrochloride (XIGDUO XR 10 mg/500 mg), or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 1000 mg metformin hydrochloride (XIGDUO XR 10 mg/1000 mg).
Each film-coated tablet of XIGDUO XR contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, crospovidone, silicon dioxide, magnesium stearate, carboxymethylcellulose sodium, and hypromellose 2208. The 5 mg/500 mg and 5 mg/1000 mg strength tablets of XIGDUO XR also contain hypromellose 2910.
The film coatings contain the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Additionally, the film coating for the XIGDUO XR 5 mg/500 mg tablets contains FD&C Yellow No. 6/Sunset Yellow FCF aluminum lake and the film coating for the XIGDUO XR 5 mg/1000 mg, 10 mg/500 mg, and 10 mg/1000 mg tablets contains iron oxides.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
XIGDUO XR
XIGDUO XR combines two antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes: dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride, a biguanide.
Dapagliflozin
Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.
Metformin hydrochloride
Metformin improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or in healthy subjects, except in unusual circumstances [see Warnings and Precautions (5.8)], 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
General
Dapagliflozin
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type 2 diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day. A near maximum glucose excretion was observed at the dapagliflozin daily dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions (6.1)].

Figure 1: Scatter Plot and Fitted Line of Change from Baseline in 24-Hour Urinary Glucose Amount versus Dapagliflozin Dose in Healthy Subjects and Subjects with Type 2 Diabetes Mellitus (T2DM) (Semi-Log Plot)
Cardiac Electrophysiology
Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15 times the recommended dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50 times the recommended dose) dapagliflozin in healthy subjects.
12.3 Pharmacokinetics
XIGDUO XR
XIGDUO XR combination tablets are considered to be bioequivalent to coadministration of corresponding doses of dapagliflozin (FARXIGA™) and metformin hydrochloride extended-release (GLUCOPHAGE® XR) administered together as individual tablets.
The administration of XIGDUO XR in healthy subjects after a standard meal compared to the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin extended-release. Compared to the fasted state, the standard meal resulted in 35% reduction and a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not considered to be clinically meaningful. Food has no relevant effect on the pharmacokinetics of metformin when administered as XIGDUO XR combination tablets.
Absorption
Dapagliflozin
Following oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately 1 hour, but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food.
Metformin hydrochloride
Following a single oral dose of metformin extended-release, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. 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.
Distribution
Dapagliflozin
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.
Metformin hydrochloride
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.
Metabolism
Dapagliflozin
The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.
Metformin hydrochloride
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Elimination
Dapagliflozin
Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg.
Metformin hydrochloride
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations
Renal Impairment
XIGDUO XR
Use of metformin in patients with renal impairment increases the risk for lactic acidosis. Because XIGDUO XR contains metformin, XIGDUO XR is contraindicated in patients with moderate to severe renal impairment [see Contraindications (4) and Warnings and Precautions (5.3)]. No dose adjustment of XIGDUO XR is required in patients with mild renal impairment [see Use in Specific Populations (8.6)].
Dapagliflozin
At steady-state (20 mg once-daily dapagliflozin for 7 days), patients with type 2 diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 2.04-fold, and 3.03-fold higher, respectively, as compared to patients with type 2 diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.2), Warnings and Precautions (5.3), and Use in Specific Populations (8.6)].
Metformin hydrochloride
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Hepatic Impairment
XIGDUO XR
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Because XIGDUO XR contains metformin, XIGDUO XR should generally be avoided in patients with hepatic impairment [see Warnings and Precautions (5.5)].
Dapagliflozin
In patients with mild and moderate hepatic impairment (Child-Pugh Classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh Class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls.
Metformin hydrochloride
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Geriatric
Dapagliflozin
Based on a population pharmacokinetic analysis, age does not have a clinically meaningful effect on systemic exposures of dapagliflozin; thus, no dose adjustment is recommended.
Metformin hydrochloride
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggests 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 a change in renal function.
XIGDUO XR should not be initiated in patients of any age unless measurement of creatinine clearance demonstrates that renal function is only normal or mildly impaired [see Warnings and Precautions (5.1, 5.3) and Use in Specific Populations (8.6)].
Pediatric
Pharmacokinetics of XIGDUO XR in the pediatric population has not been studied.
Gender
Dapagliflozin
Based on a population pharmacokinetic analysis, gender does not have a clinically meaningful effect on systemic exposures of dapagliflozin; thus, no dose adjustment is recommended.
Metformin hydrochloride
Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Race
Dapagliflozin
Based on a population pharmacokinetic analysis, race (White, Black, or Asian) does not have a clinically meaningful effect on systemic exposures of dapagliflozin; thus, no dose adjustment is recommended.
Metformin hydrochloride
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).
Body Weight
Dapagliflozin
Based on a population pharmacokinetic analysis, body weight does not have a clinically meaningful effect on systemic exposures of dapagliflozin; thus, no dose adjustment is recommended.
Drug Interactions
Specific pharmacokinetic drug interaction studies with XIGDUO XR have not been performed, although such studies have been conducted with the individual dapagliflozin and metformin components.
In Vitro Assessment of Drug Interactions
Dapagliflozin
In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P‑gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.
Effects of Other Drugs on Metformin
Table 7 shows the effect of other coadministered drugs on metformin.
Table 7: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure 

Coadministered Drug (Dose Regimen)*	Metformin (Dose Regimen)*	Metformin
		Change† in AUC‡	Change† in Cmax
No dosing adjustments required for the following:
Glyburide (5 mg)	850 mg	↓9%§	↓7%§
Furosemide (40 mg)	850 mg	↑15%§	↑22%§
Nifedipine (10 mg)	850 mg	↑9%	↑20%
Propranolol (40 mg)	850 mg	↓10%	↓6%
Ibuprofen (400 mg)	850 mg	↑5%§	↑7%§
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution [see Warnings and Precautions (5.10)and Drug Interactions (7.3)].
Cimetidine (400 mg)	850 mg	↑40%	↑60%

All metformin and coadministered drugs were given as single doses.
Percent change (with/without coadministered drug and no change = 0%);
↑ and ↓ indicate the exposure increase and decrease, respectively.
AUC = AUC(INF).
Ratio of arithmetic means
Effects of Metformin on Other Drugs
Table 8 shows the effect of metformin on other coadministered drugs.
Table 8: Effect of Metformin on Coadministered Drug Systemic Exposure 

Coadministered Drug (Dose Regimen)	Metformin (Dose Regimen)	Coadministered Drug
		Change† in AUC	Change† in Cmax
No dosing adjustments required for the following:
Glyburide (5 mg)	850 mg	↓22%§	↓37%§
Furosemide (40 mg)	850 mg	↓12%§	↓31%§
Nifedipine (10 mg)	850 mg	↑10%	↑8%
Propranolol (40 mg)	850 mg	↑1%	↑2%
Ibuprofen (400 mg)	850 mg	↓3%	↑1%
Cimetidine (400 mg)	850 mg	↓5%	↑1%

All metformin and coadministered drugs were given as single doses.
Percent change (with/without coadministered drug and no change = 0%);
↑and ↓indicate the exposure increase and decrease, respectively.
AUC = AUC(INF) unless otherwise noted.
Ratio of arithmetic means, p-value of difference <0.05.
AUC(0-24 hr) reported.
Ratio of arithmetic means.
Effects of Other Drugs on Dapagliflozin
Table 9 shows the effect of coadministered drugs on dapagliflozin. No dose adjustments are recommended for dapagliflozin.
Table 9: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure 

Coadministered Drug (Dose Regimen)*	Dapagliflozin (Dose Regimen)*	Dapagliflozin
		Change† in AUC‡	Change† in Cmax
No dosing adjustments required for the following:
Oral Antidiabetic Agents
Metformin (1000 mg)	20 mg	↓1%	↓7%
Pioglitazone (45 mg)	50 mg	0%	↑9%
Sitagliptin (100 mg)	20 mg	↑8%	↓4%
Glimepiride (4 mg)	20 mg	↓1%	↑1%
Voglibose (0.2 mg three times daily)	10 mg	↑1%	↑4%
Cardiovascular Agents
Hydrochlorothiazide (25 mg)	50 mg	↑7%	↓1%
Bumetanide (1 mg)	10 mg once daily for 7 days	↑5%	↑8%
Valsartan (320 mg)	20 mg	↑2%	↓12%
Simvastatin (40 mg)	20 mg	↓1%	↓2%
Anti-infective Agent
Rifampin (600 mg once daily for 6 days)	10 mg	↓22%	↓7%
Non-Steroidal Anti-inflammatory Agent
Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours)	10 mg	↑51%	↑13%

Single dose unless otherwise noted.
Percent change (with/without coadministered drug and no change = 0%);
↑ and ↓ indicate the exposure increase and decrease, respectively.
Effects of Dapagliflozin on Other Drugs
Table 10 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.
Table 10: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs

Coadministered Drug (Dose Regimen)*	Dapagliflozin (Dose Regimen)*	Coadministered Drug
		Change†inAUC‡	Change† in Cmax
No dosing adjustments required for the following:
Oral Antidiabetic Agents
Metformin (1000 mg)	20 mg	0%	↓5%
Pioglitazone (45 mg)	50 mg	0%	↓7%
Sitagliptin (100 mg)	20 mg	↑1%	↓11%
Glimepiride (4 mg)	20 mg	↑13%	↑4%
Cardiovascular Agents
Hydrochlorothiazide (25 mg)	50 mg	↓1%	↓5%
Bumetanide (1 mg)	10 mg once daily for 7 days	↑13%	↑13%
Valsartan (320 mg)	20 mg	↑5%	↓6%
Simvastatin (40 mg)	20 mg	↑19%	↓6%
Digoxin (0.25 mg)	20 mg loading dose then 10 mg once daily for 7 days	0%	↓1%
Warfarin (25 mg) S-warfarin R-warfarin	20 mg loading dose then 10 mg once daily for 7 days	↑3% ↑6%	↑7% ↑8%

Single dose unless otherwise noted.
Percent change (with/without coadministered drug and no change = 0%);
and ↓ indicate the exposure increase and decrease, respectively.
AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
XIGDUO XR
No animal studies have been conducted with XIGDUO XR to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with dapagliflozin and metformin individually.
Dapagliflozin
Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10, and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72 times (males) and 105 times (females) the clinical dose of 10 mg/day based on AUC exposure. In rats, the highest dose was approximately 131 times (males) and 186 times (females) the clinical dose of 10 mg/day based on AUC exposure.
Dapagliflozin was negative in the Ames mutagenicity assay and was positive in a series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations ≥100 μg/mL. Dapagliflozin was negative for clastogenicity in a series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples >2100 times the clinical dose.
There was no carcinogenicity or mutagenicity signal in animal studies, suggesting that dapagliflozin does not represent a genotoxic risk to humans.
Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples ≤1708 and 998 times the maximum recommended human doses in males and females, respectively.
Metformin hydrochloride
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the MRHD of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the MRHD based on body surface area comparisons.
14 CLINICAL STUDIES
There have been no clinical efficacy studies conducted with XIGDUO XR combination tablets to characterize its effect on HbA1c reduction. XIGDUO XR is considered to be bioequivalent to coadministered dapagliflozin and metformin hydrochloride extended-release (XR) tablets [see Clinical Pharmacology (12.3)]. Relative bioavailability studies between XIGDUO XR and coadministered dapagliflozin and metformin hydrochloride immediate-release (IR) tablets have not been conducted. The metformin hydrochloride XR tablets and metformin hydrochloride IR tablets have a similar extent of absorption (as measured by AUC), while peak plasma levels of XR tablets are approximately 20% lower than those of IR tablets at the same dose.
The coadministration of dapagliflozin and metformin XR tablets has been studied in treatment-naive patients inadequately controlled on diet and exercise alone. The coadministration of dapagliflozin and metformin IR or XR tablets has been studied in patients with type 2 diabetes inadequately controlled on metformin and compared with a sulfonylurea (glipizide) in combination with metformin. Treatment with dapagliflozin plus metformin at all doses produced clinically relevant and statistically significant improvements in HbA1c and fasting plasma glucose (FPG) compared to placebo in combination with metformin (initial or add-on therapy). HbA1c reductions were seen across subgroups including gender, age, race, duration of disease, and baseline BMI.
14.1 Initial Combination Therapy with Metformin Extended-Release
A total of 1241 treatment-naive patients with inadequately controlled type 2 diabetes (HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled studies of 24-week duration to evaluate the safety and efficacy of initial therapy with dapagliflozin 5 mg or 10 mg in combination with metformin XR formulation.
In 1 study, 638 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: dapagliflozin 10 mg plus metformin XR (up to 2000 mg/day), dapagliflozin 10 mg plus placebo, or metformin XR (up to 2000 mg/day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.
The combination treatment of dapagliflozin 10 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 11 and Figure 2). Dapagliflozin 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin alone and was noninferior to metformin XR monotherapy in lowering HbA1c.
Table 11: Results at Week 24 (LCOF*) in an Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XR 

Efficacy Parameter	Dapagliflozin 10 mg + Metformin XR	Dapagliflozin 10 mg	Metformin XR
	N=211†	N=219†	N=208†
HbA1c (%)
Baseline (mean)	9.1	9.0	9.0
Change from baseline (adjusted mean ‡)	−2.0	−1.5	−1.4
Difference from dapagliflozin (adjusted mean ‡) (95% CI)	−0.5§ (−0.7, −0.3)
Difference from metformin XR (adjusted mean ‡) (95% CI)	−0.5§ (−0.8, −0.3)	0.0 (−0.2, 0.2)
Percent of patients achieving HbA1c <7% adjusted for baseline	46.6%	31.7%	35.2%
FPG (mg/dL)
Baseline (mean)	189.6	197.5	189.9
Change from baseline (adjusted mean ‡)	−60.4	−46.4	−34.8
Difference from dapagliflozin (adjusted mean ‡) (95% CI)	−13.9§ (−20.9, −7.0)
Difference from metformin XR (adjusted mean ‡) (95% CI)	−25.5§ (−32.6, −18.5)	−11.6# (−18.6, −4.6)
Body Weight (kg)
Baseline (mean)	88.6	88.5	87.2
Change from baseline (adjusted mean ‡)	−3.3	−2.7	−1.4
Difference from metformin XR (adjusted mean ‡) (95% CI)	−2.0§ (−2.6, −1.3)	−1.4§ (−2.0, −0.7)

LOCF: last observation (prior to rescue for rescued patients) carried forward.
All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.
Least squares mean adjusted for baseline value.
p-value <0.0001.
Noninferior versus metformin XR.
p-value <0.05.
Figure 2: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XR

In the second study, 603 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: dapagliflozin 5 mg plus metformin XR (up to 2000 mg/day), dapagliflozin 5 mg plus placebo, or metformin XR (up to 2000 mg/day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2000 mg.
The combination treatment of dapagliflozin 5 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 12).
Table 12: Results at Week 24 (LOCF*) in an Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XR 

Efficacy Parameter	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR
	N=194†	N=203†	N=201†
HbA1c (%)
Baseline (mean)	9.2	9.1	9.1
Change from baseline (adjusted mean ‡)	−2.1	−1.2	−1.4
Difference from dapagliflozin (adjusted mean ‡) (95% CI)	−0.9§ (−1.1, −0.6)
Difference from metformin XR (adjusted mean ‡) (95% CI)	−0.7§ (−0.9, −0.5)
Percent of patients achieving HbA1c <7% adjusted for baseline	52.4%¶	22.5%	34.6%
FPG (mg/dL)
Baseline (mean)	193.4	190.8	196.7
Change from baseline (adjusted mean ‡)	−61.0	−42.0	−33.6
Difference from dapagliflozin (adjusted mean ‡) (95% CI)	−19.1§ (−26.7, −11.4)
Difference from metformin XR (adjusted mean ‡) (95% CI)	−27.5§ (−35.1, −19.8)
Body Weight (kg)
Baseline (mean)	84.2	86.2	85.8
Change from baseline (adjusted mean)	−2.7	−2.6	−1.3
Difference from metformin XR (adjusted mean) (95% CI)	−1.4 (−2.0, −0.7)

LOCF: last observation (prior to rescue for rescued patients) carried forward.
All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.
Least squares mean adjusted for baseline value.
p-value <0.0001.
p-value <0.05.
14.2 Add-On to Metformin Immediate-Release
A total of 546 patients with type 2 diabetes with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled study to evaluate dapagliflozin in combination with metformin. Patients on metformin at a dose of at least 1500 mg/day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to their current dose of metformin.
As add-on treatment to metformin, dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 13 and Figure 3). Statistically significant (p<0.05 for both doses)mean changes frombaselinein systolic blood pressure relative to placebo plus metformin were −4.5 mmHg and −5.3 mmHg with dapagliflozin 5 mg and 10 mg plus metformin, respectively.
Table 13: Results of a 24-Week (LOCF*) Placebo-Controlled Study of Dapagliflozin in Add-On Combination with Metformin 

Efficacy Parameter	Dapagliflozin 10 mg + Metformin N=135†	Dapagliflozin 5 mg + Metformin N=137†	Placebo + Metformin N=137†
HbA1c (%)
Baseline (mean)	7.9	8.2	8.1
Change from baseline (adjusted mean ‡)	−0.8	−0.7	−0.3
Difference from placebo (adjusted mean ‡) (95% CI)	−0.5§ (−0.7, −0.3)	−0.4§ (−0.6, −0.2)
Percent of patients achieving HbA1c <7% adjusted for baseline	40.6%¶	37.5%¶	25.9%
FPG (mg/dL)
Baseline (mean)	156.0	169.2	165.6
Change from baseline at Week 24 (adjusted mean ‡)	−23.5	−21.5	−6.0
Difference from placebo (adjusted mean ‡) (95% CI)	−17.5§ (−25.0, −10.0)	−15.5§ (−22.9, −8.1)
Change from baseline at Week 1 (adjusted mean ‡)	−16.5§ (N=115)	−12.0§ (N=121)	1.2 (N=126)
Body Weight (kg)
Baseline (mean)	86.3	84.7	87.7
Change from baseline (adjusted mean ‡)	−2.9	−3.0	−0.9
Difference from placebo (adjusted mean ‡) (95% CI)	−2.0§ (−2.6, −1.3)	−2.2§ (−2.8, −1.5)

LOCF: last observation (prior to rescue for rescued patients) carried forward.
All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.
Least squares mean adjusted for baseline value.
p-value <0.00001 versus placebo + metformin.
p-value <0.05 versus placebo + metformin
Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Placebo-Controlled Study of Dapagliflozin in Combination with Metformin

14.3 Active Glipizide-Controlled Study Add-On to Metformin Immediate-Release
A total of 816 patients with type 2 diabetes with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, noninferiority study to evaluate dapagliflozin as add-on therapy to metformin. Patients on metformin at a dose of at least 1500 mg/day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.
At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin treatment led to a similar mean reduction in HbA1c from baseline at Week 52, compared with glipizide, thus demonstrating noninferiority (see Table 14). Dapagliflozin treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was −5.0 mmHg with dapagliflozin plus metformin.
Table 14: Results at Week 52 (LOCF*) in an Active-Controlled Study Comparing Dapagliflozin to Glipizide as Add-On to Metformin 

Efficacy Parameter	Dapagliflozin + Metformin N=400†	Glipizide + Metformin N=401†
HbA1c (%)
Baseline (mean)	7.7	7.7
Change from baseline (adjusted mean ‡)	−0.5	−0.5
Difference from glipizide + metformin (adjusted mean ‡) (95% CI)	0.0§ (−0.1, 0.1)
Body Weight (kg)
Baseline (mean)	88.4	87.6
Change from baseline (adjusted mean ‡)	−3.2	1.4
Difference from glipizide + metformin (adjusted mean ‡) (95% CI)	−4.7 (−5.1, −4.2)

LOCF: last observation carried forward.
Randomized and treated patients with baseline and at least 1 postbaseline efficacy measurement.
Least squares mean adjusted for baseline value.
Noninferior to glipizide + metformin.
p-value <0.0001.
16 HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
XIGDUOTM XR (dapagliflozin and metformin HCl extended-release) tablets have markings on one side, are plain on the reverse side, and are available in the strengths and packages listed in Table 15.
Table 15: XIGDUO XR Tablet Presentations

Tablet Strength	Film-Coated Tablet Color/Shape	Tablet Markings	Pack Size	NDC Code
5/500 mg	orange, biconvex, capsule-shaped	"1070" and "5/500" debossed on one side and plain on the reverse side.	Bottle of 30 Bottle of 500	0310-6250-30 0310-6250-50
5/1000 mg	pink to dark pink, biconvex, oval-shaped	"1071" and "5/1000" debossed on one side and plain on the reverse side.	Bottle of 30 Bottle of 60 Bottle of 90 Bottle of 400	0310-6260-30 0310-6260-60 0310-6260-90 0310-6260-40
10/500 mg	pink, biconvex, capsule-shaped	"1072" and "10/500" debossed on one side and plain on the reverse side.	Bottle of 30 Bottle of 500	0310-6270-30 0310-6270-50
10/1000 mg	yellow to dark yellow, biconvex, oval-shaped	"1073" and "10/1000" debossed on one side and plain on the reverse side	Bottle of 30 Bottle of 90 Bottle of 400	0310-6280-30 0310-6280-90 0310-6280-40

Storage and Handling
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].