2.1 Prior to Initiation of XIGDUO XR

•

Assess renal function before initiating XIGDUO XR therapy and periodically thereafter [see Warnings and Precautions (5.1, 5.3)].

•

Assess volume status. In patients with volume depletion, correct this condition before initiating XIGDUO XR [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5, 8.6)].

2.2 Recommended Administration

•

Take XIGDUO XR orally once daily in the morning with food.

•

Swallow XIGDUO XR tablets whole and never crush, cut, or chew.

2.3 Recommended Dosage

•

Individualize the starting dose of XIGDUO XR based upon the patient’s current regimen. Patients taking an evening dose of metformin extended-release should skip their last dose before starting XIGDUO XR.

•

To improve glycemic control in patients not already taking dapagliflozin, the recommended starting dose for dapagliflozin is 5 mg once daily.

•

For indications related to heart failure and chronic kidney disease the recommended dose for dapagliflozin is 10 mg once daily.

•

Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 10 mg dapagliflozin and 2,000 mg metformin hydrochloride (HCl) extended-release.

2.4 Patients with Renal Impairment

•

No dose adjustment for XIGDUO XR is needed in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m2.

•

Initiation of XIGDUO XR is not recommended in patients with an eGFR between 30 and 45 mL/min/1.73 m2. Assess the benefit and risk of continuing therapy if eGFR falls persistently below this level.

o

Dapagliflozin is likely to be ineffective to improve glycemic control in patients with eGFR less than 45 mL/min/1.73 m2.

o

Metformin initiation is not recommended for patients with eGFR less than 45 mL/min/1.73 m2.

•

XIGDUO XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2, end-stage renal disease, or on dialysis due to the metformin component [see Contraindications (4),  Warnings and Precautions  (5.1, 5.2), and Use in Specific Populations (8.6)].

2.5 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart XIGDUO XR if renal function is stable [see Warnings and Precautions (5.1)].

2.6 Temporary Interruption for Surgery

Withhold XIGDUO XR for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume XIGDUO XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

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 XIGDUO XR.

In XIGDUO 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 HCl is dialyzable, with a clearance of up to 170 mL/min 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 XIGDUO 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 based upon the patient’s renal function include [see Dosage and Administration (2.1 and 2.4) and Clinical Pharmacology (12.3)]:

•

Before initiating XIGDUO XR, obtain an estimated glomerular filtration rate (eGFR).

•

XIGDUO XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].

•

Obtain an eGFR at least annually in all patients taking XIGDUO XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions: The concomitant use of XIGDUO 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 Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop XIGDUO 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 XIGDUO 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. XIGDUO 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 XIGDUO 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 XIGDUO 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 XIGDUO XR in patients with clinical or laboratory evidence of hepatic disease.

5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, dapagliflozin, a component of XIGDUO XR, significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium-glucose cotransporter 2 (SGLT2) inhibitors compared to patients who received placebo. XIGDUO XR is not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including dapagliflozin.

Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing XIGDUO XR [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue XIGDUO XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting XIGDUO XR.

Withhold XIGDUO XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume XIGDUO XR when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.6)].

Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue XIGDUO XR and seek medical attention immediately if signs and symptoms occur.

5.3 Volume Depletion

Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating XIGDUO XR in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension and renal function after initiating therapy.

5.4 Urosepsis and Pyelonephritis

Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported 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)].

5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

5.6 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 XIGDUO 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 XIGDUO XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.7 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. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on XIGDUO XR and manage any abnormalities [see Adverse Reactions (6.1)].

5.8 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.

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.

6.2 Postmarketing Experience

Dapagliflozin

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

Infections: Necrotizing fasciitis of the perineum (Fournier’s Gangrene), urosepsis and pyelonephritis

Metabolism and Nutrition Disorders: Ketoacidosis

Renal and Urinary Disorders: Acute kidney injury

Skin and Subcutaneous Tissue Disorders: Rash

Metformin HCl

Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

8.1 Pregnancy

Risk Summary

Based on animal data showing adverse renal effects, XIGDUO XR is not recommended during the second and third trimesters of pregnancy.

Limited data with XIGDUO XR or dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).

In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data).

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data

Dapagliflozin

Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.

In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats 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 21-day-old pups 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 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development.

In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC).

Metformin HCl

Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

8.2 Lactation

Risk Summary

There is no information regarding the presence of XIGDUO XR or dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production.

Limited published studies report that metformin is present in human milk (see Data). However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Dapagliflozin is present in the milk of lactating rats (see Data). However, due to species specific differences in lactation physiology, the clinical relevance of these data is not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.

Because of the potential for serious adverse reactions in breastfed infants, advise women that use of XIGDUO XR is not recommended while breastfeeding.

Data

Dapagliflozin

Dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.

Metformin HCl

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

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. More frequent assessment of renal function is recommended in elderly patients.

Dapagliflozin

A total of 1424 (24%) of the 5936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. 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 for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

In both the DAPA-HF and DAPA-CKD studies, safety and efficacy were similar for patients age 65 years and younger and those older than 65 in both the overall population and the patients with type 2 diabetes mellitus. In the DAPA-HF study, 2714 (57%) out of 4744 patients with heart failure with reduced ejection fraction (HFrEF) were older than 65 years. Out of 2139 patients with HFrEF and type 2 diabetes mellitus, 1211 (57%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with chronic kidney disease were older than 65 years. Out of 2906 patients with chronic kidney disease and type 2 diabetes mellitus, 1399 (48%) were older than 65 years.

Metformin HCl

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.1)].

8.6 Renal Impairment

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. XIGDUO XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

Dapagliflozin

In the event of an overdose, contact the Poison Control Center. The removal of dapagliflozin by hemodialysis has not been studied.

Metformin HCl

Overdose of metformin HCl has occurred, including ingestion of amounts >50 grams. 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.

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 2.5 mg dapagliflozin as dapagliflozin propanediol and 1000 mg metformin hydrochloride which is equivalent to 779.86 mg metformin base (XIGDUO XR 2.5 mg/1,000 mg), 5 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin hydrochloride which is equivalent to 389.9 mg metformin base (XIGDUO XR 5 mg/500 mg), the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin hydrochloride which is equivalent to 779.86 mg metformin base (XIGDUO XR 5 mg/1,000 mg), the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin hydrochloride which is equivalent to 389.9 mg metformin base (XIGDUO XR 10 mg/500 mg), or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin hydrochloride which is equivalent to 779.86 mg metformin base (XIGDUO XR 10 mg/1,000 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.

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. The film coating for the XIGDUO XR 2.5 mg/1,000 mg, 5 mg/1000 mg, 10 mg/500 mg, and 10 mg/1,000 mg tablets contains iron oxides.

12.1 Mechanism of Action

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)]. After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose.

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)

12.3 Pharmacokinetics

XIGDUO XR

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 HCl

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 HCl

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Glycemic Control

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 mellitus 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 body mass index (BMI).

Initial Combination Therapy with Metformin Extended-Release

A total of 1236 treatment-naive patients with inadequately controlled type 2 diabetes mellitus (HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled studies of 24-week duration to evaluate initial therapy with dapagliflozin 5 mg (NCT00643851) or 10 mg (NCT00859898) in combination with metformin extended-release (XR) formulation.

In one study, 638 patients randomized to 1 of 3 treatment arms following a 1-week lead-in period received: 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 non-inferior to metformin XR monotherapy in lowering HbA1c.

Table 11: Results at Week 24 (LOCF*) in an Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XR

* 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. ¶ Non-inferior versus metformin XR. # p-value <0.05.
Efficacy Parameter	Dapagliflozin 10 mg + Metformin XR N=211†	Dapagliflozin 10 mg   N=219†	Metformin XR 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)

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

* 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.
Efficacy Parameter	Dapagliflozin 5 mg + Metformin XR N=194†	Dapagliflozin 5 mg   N=203†	Metformin XR 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)

Add-On to Metformin Immediate-Release

A total of 546 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled study to evaluate dapagliflozin in combination with metformin (NCT00528879). 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 from baseline in 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

* 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 versus placebo + metformin. ¶ p-value <0.05 versus placebo + 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)

Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Placebo-Controlled Study of Dapagliflozin in Combination with Metformin

14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus

Dapagliflozin Effect on Cardiovascular Events (DECLARE, NCT01730534) was an international, multicenter, randomized, double-blind, placebo-controlled, clinical study conducted to determine the effect of dapagliflozin 10 mg relative to placebo on cardiovascular (CV) outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either established CV disease or two or more additional CV risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidemia, hypertension, or current tobacco use). Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186 (59.4%) did not have established CV disease. A total of 8582 patients were randomized to dapagliflozin 10 mg, 8578 to placebo, and patients were followed for a median of 4.2 years.

Approximately 80% of the trial population was White, 4% Black or African American, and 13% Asian. The mean age was 64 years, and approximately 63% were male.

Mean duration of diabetes was 11.9 years and 22.4% of patients had diabetes for less than 5 years. Mean eGFR was 85.2 mL/min/1.73 m2. At baseline, 23.5% of patients had microalbuminuria (UACR ≥30 to ≤300 mg/g) and 6.8% had macroalbuminuria (UACR >300 mg/g). Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m2. At baseline, 10% of patients had a history of heart failure.

Most patients (98.1%) used one or more antihyperglycemic medications at baseline. 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with a sulfonylurea, 16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 receptor agonist.

Approximately 81.3% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics, and 10.5% with loop diuretics.

A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio (HR) of the composite of CV death, myocardial infarction (MI), or ischemic stroke (MACE) and if non-inferiority was demonstrated, to test for superiority on the two primary endpoints: 1) the composite of hospitalization for heart failure or CV death, and 2) MACE.

The incidence rate of MACE was similar in both treatment arms: 2.30 MACE events per 100 patient-years on dapagliflozin vs 2.46 MACE events per 100 patient-years on placebo. The estimated hazard ratio of MACE associated with dapagliflozin relative to placebo was 0.93 with a 95% CI of (0.84, 1.03). The upper bound of this confidence interval, 1.03, excluded the pre-specified non-inferiority margin of 1.3.

Dapagliflozin 10 mg was superior to placebo in reducing the incidence of the primary composite endpoint of hospitalization for heart failure or CV death (HR 0.83 [95% CI 0.73, 0.95]).

The treatment effect was due to a significant reduction in the risk of hospitalization for heart failure in subjects randomized to dapagliflozin 10 mg (HR 0.73 [95% CI 0.61, 0.88]), with no change in the risk of CV death (Table 16 and Figures 4 and 5).

Figure 4: Time to First Occurrence of Hospitalization for Heart Failure or CV Death in the DECLARE Study

Figure 5: Time to First Occurrence of Hospitalization for Heart Failure in the DECLARE Study

14.3 Heart Failure with Reduced Ejection Fraction

Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF, NCT03036124) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with heart failure (New York Heart Association [NYHA] functional class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] 40% or less) to determine whether dapagliflozin reduces the risk of cardiovascular death and hospitalization for heart failure.

Of 4744 patients, 2373 were randomized to dapagliflozin 10 mg and 2371 to placebo and were followed for a median of 18 months. The study included patients with type 2 diabetes mellitus (n=2139) and patients without diabetes (n=2605). The mean age of the study population was 66 years, 77% were male and 70% were White, 5% Black or African American, and 24% Asian. At baseline, 68% patients were classified as NYHA class II, 32% class III, and 1% class IV; median LVEF was 32%. At baseline, 94% of patients were treated with ACEi, ARB or angiotensin receptor-neprilysin inhibitor (ARNI, including sacubitril/valsartan 11%), 96% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 93% with diuretic, and 26% had an implantable device (with defibrillator function). Patients with eGFR 30 mL/min/1.73 m2 or greater at enrollment were included in the study.

History of type 2 diabetes mellitus was present in 42%, and an additional 3% had type 2 diabetes mellitus based on a HbA1c ≥6.5% at both enrollment and randomization, totaling to 1075 patients in the dapagliflozin group and 1064 in the placebo group. At baseline of the patients with type 2 diabetes mellitus, 48% were treated with metformin (505 patients on dapagliflozin 10 mg and 515 on placebo) and 25% were treated with insulin.

The mean age of the type 2 diabetes mellitus population was 67 years, 78% were male, 70% White, 6% Black or African American and 23% Asian. At baseline, 64% patients were classified as NYHA class II, 35% class III and 1% class IV, median LVEF was 32%. Patients were on standard of care therapy; 93% of type 2 diabetes mellitus patients were treated with ACEi, ARB, or angiotensin receptor-neprilysin inhibitor (ARNI, 11%), 97% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 95% with diuretic and 27% had an implantable device (with defibrillator function). In these patients, mean eGFR was 63 mL/min/1.73 m2.

Dapagliflozin 10 mg reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit in overall population (HR 0.74 [95% CI 0.65, 0.85]; p<0.0001). All three components of the primary composite endpoint individually contributed to the treatment effect. There were few urgent heart failure visits. The Kaplan–Meier curves for dapagliflozin 10 mg and placebo separated early and continued to diverge over the study period (Table 17 and Figure 6).

The treatment benefit of dapagliflozin 10 mg in reducing the incidence of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus (HR 0.75 [95% CI 0.63, 0.90]), and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.67 [95% CI 0.51, 0.88]).

Figure 6: Time to the First Occurrence of the Composite of Cardiovascular Death, Hospitalization for Heart Failure or Urgent Heart Failure Visit in the DAPA-HF Study

14.4 Chronic Kidney Disease

The Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA-CKD, NCT03036150) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with chronic kidney disease (CKD) (eGFR between 25 and 75 mL/min/1.73 m2) and albuminuria (urine albumin creatinine ratio [UACR] between 200 and 5000 mg/g) who were receiving standard of care background therapy, including a maximally tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The trial excluded patients with autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis and patients requiring cytotoxic, immunosuppressive, or immunomodulatory therapies in the preceding 6 months.

The primary objective was to determine whether dapagliflozin 10 mg reduces the incidence of the composite endpoint of ≥50% sustained decline in eGFR, progression to end-stage kidney disease (ESKD) (defined as sustained eGFR<15 mL/min/1.73 m2, initiation of chronic dialysis treatment or renal transplant), CV or renal death.

A total of 4304 patients were randomized equally to dapagliflozin 10 mg or placebo and were followed for a median of 28.5 months. The study included patients with type 2 diabetes mellitus (n=2906) and patients without diabetes (n=1398). The mean age of the study population was 62 years and 67% were male. The population was 53% White, 4% Black or African American, and 34% Asian; 25% were of Hispanic or Latino ethnicity. At baseline, mean eGFR was 43 mL/min/1.73 m2, 44% of patients had an eGFR 30 mL/min/1.73m2 to less than 45 mL/min/1.73m2, and 15% of patients had an eGFR less than 30 mL/min/1.73m2. Median UACR was 950 mg/g. The most common etiologies of CKD were diabetic nephropathy (58%), ischemic/hypertensive nephropathy (16%), and IgA nephropathy (6%). At baseline, 97% of patients were treated with ACEi or ARB. Approximately 44% were taking antiplatelet agents, and 65% were on a statin.

Out of 2906 (68%) patients who had type 2 diabetes mellitus at randomization, 1455 patients received dapagliflozin 10 mg and 1451 received placebo. At baseline of the patients with type 2 diabetes mellitus, 43% were being treated with metformin (631 patients on dapagliflozin 10 mg and 613 on placebo) and 55% were treated with insulin.

The mean age of the type 2 diabetes mellitus study population was 64 years, 67% were male, 53% White, 5% Black or African American and 32% Asian, 27% were of Hispanic or Latino ethnicity. In these patients, mean eGFR was 44 mL/min/1.73 m2, 43% of patients had an eGFR 30 mL/min/1.73 m2 to below 45 mL/min/1.73 m2, and 14% of patients had an eGFR below 30 mL/min/1.73 m2. Median UACR was 1017 mg/g. The most common etiologies of CKD in this group were diabetic nephropathy (86%) and ischemic/hypertensive nephropathy (7%).

Dapagliflozin 10 mg reduced the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, progression to ESKD, CV or renal death in overall population (HR 0.61 [95% CI 0.51,0.72]; p<0.0001). The dapagliflozin 10 mg and placebo event curves separate by Month 4 and continue to diverge over the study period. The treatment effect reflected a reduction in ≥50% sustained decline in eGFR, progression to ESKD, and CV death. There were few renal deaths during the trial (Table 18 and Figure 7).

The treatment benefit of dapagliflozin 10 mg was consistent in reducing the incidence of the primary composite endpoint in patients with type 2 diabetes mellitus (HR 0.64 [95% CI 0.52, 0.79]) and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.74 [95% CI 0.53, 1.03]).

The treatment benefit of dapagliflozin 10 mg was consistent in reducing the incidence of the composite endpoint of CV death or hospitalization for heart failure and all-cause mortality in patients with type 2 diabetes mellitus (HR 0.70 [95% CI 0.53, 0.92] and HR 0.74 [95% CI 0.56, 0.98], respectively) and in patients with type 2 diabetes mellitus and metformin as background therapy (HR 0.59 [95% CI 0.38, 0.91] and HR 0.71 [95% CI 0.46, 1.10]).

Figure 7: Time to First Occurrence of the Primary Composite Endpoint, ≥50% Sustained Decline in eGFR, ESKD, CV or Renal Death (DAPA-CKD Study)

DAPA-CKD enrolled a population with relatively advanced CKD at high risk of progression. Exploratory analyses of a randomized, double-blind, placebo-controlled trial conducted to determine the effect of dapagliflozin 10 mg on CV outcomes (the DECLARE trial) support the conclusion that dapagliflozin 10 mg is also likely to be effective in patients with less advanced CKD.