2.1 Prior to Initiation of FARXIGA

Assess renal function prior to initiation of FARXIGA therapy and then as clinically indicated [see Warnings and Precautions (5.2)].

Assess volume status. In patients with volume depletion, correct this condition before initiating FARXIGA [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)].

2.2 Recommended Dosage

See Table 1 for dosage recommendations based on estimated glomerular filtration rate (eGFR).

2.3 Temporary Interruption for Surgery

Withhold FARXIGA for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume FARXIGA when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].

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

In patients with type 1 diabetes mellitus, FARXIGA 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. FARXIGA 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 FARXIGA.

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 FARXIGA [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 with type 1 diabetes mellitus and consider ketone monitoring in others 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 FARXIGA, promptly evaluate, and treat ketoacidosis, if confirmed.Monitor patients for resolution of ketoacidosis before restarting FARXIGA.

Withhold FARXIGA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume FARXIGA when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.3)].

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

5.2 Volume Depletion

FARXIGA 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 FARXIGA. 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 FARXIGA 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.

5.3 Urosepsis and Pyelonephritis

Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including FARXIGA. 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)].

5.4 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues

Insulin and insulin secretagogues are known to cause hypoglycemia. FARXIGA may 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 FARXIGA.

5.5 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 FARXIGA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with FARXIGA 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 FARXIGA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

5.6 Genital Mycotic Infections

FARXIGA 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.

FARXIGA has been evaluated in clinical trials in patients with type 2 diabetes mellitus, in patients with heart failure, and in patients with chronic kidney disease. The overall safety profile of FARXIGA was consistent across the studied indications. Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus.

Clinical Trials in Patients with Type 2 Diabetes Mellitus

Pool of 12 Placebo-Controlled Studies for FARXIGA 5 and 10 mg for Glycemic Control

The data in Table 2 is derived from 12 glycemic control placebo-controlled studies in patients with type 2 diabetes mellitus ranging from 12 to 24 weeks. In 4 studies FARXIGA was used as monotherapy, and in 8 studies FARXIGA was used as add-on to background antidiabetic therapy or as combination therapy with metformin [see Clinical Studies (14.1)].

These data reflect exposure of 2338 patients to FARXIGA with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), FARXIGA 5 mg (N=1145), or FARXIGA 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 hemoglobin A1c (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 FARXIGA. These adverse reactions were not present at baseline, occurred more commonly on FARXIGA than on placebo, and occurred in at least 2% of patients treated with either FARXIGA 5 mg or FARXIGA 10 mg.

Pool of 13 Placebo-Controlled Studies for FARXIGA 10 mg for Glycemic Control

FARXIGA 10 mg was also evaluated in a larger glycemic control placebo-controlled study pool in patients with type 2 diabetes mellitus. 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 FARXIGA 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

FARXIGA causes an osmotic diuresis, which may lead to a reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) in patients with type 2 diabetes mellitus for the 12-study and 13-study, short-term, placebo-controlled pools and for the DECLARE study are shown in Table 3 [see Warnings and Precautions (5.2)].

Hypoglycemia

The frequency of hypoglycemia by study in patients with type 2 diabetes mellitus [see Clinical Studies (14.1)] is shown in Table 4. Hypoglycemia was more frequent when FARXIGA was added to sulfonylurea or insulin [see Warnings and Precautions (5.4)].

In the DECLARE study [see Clinical Studies (14.2)], severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 patients treated with FARXIGA and 83 (1.0%) out of 8569 patients treated with placebo.

Genital Mycotic Infections

In the glycemic control trials, genital mycotic infections were more frequent with FARXIGA treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on FARXIGA 5 mg, and 4.8% on FARXIGA 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 FARXIGA 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, FARXIGA 5 mg, and FARXIGA 10 mg, respectively). In the DECLARE study [see Clinical Studies (14.2)], serious genital mycotic infections were reported in <0.1% of patients treated with FARXIGA and <0.1% of patients treated with placebo. Genital mycotic infections that caused study drug discontinuation were reported in 0.9% of patients treated with FARXIGA and <0.1% of patients treated with placebo.

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with FARXIGA treatment. In glycemic control studies, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of FARXIGA-treated patients. If hypersensitivity reactions occur, discontinue use of FARXIGA; treat per standard of care and monitor until signs and symptoms resolve.

Ketoacidosis in Patients with Diabetes Mellitus

In the DECLARE study [see Clinical Studies (14.2)], events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 patients in the FARXIGA-treated group and 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period.

Laboratory Tests

Increases in Serum Creatinine and Decreases in eGFR

Initiation of SGLT2 inhibitors, including FARXIGA causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions (5.2)]. In two studies that included patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with FARXIGA.

Increase in Hematocrit

In the pool of 13 placebo-controlled studies of glycemic control, increases from baseline in mean hematocrit values were observed in FARXIGA-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 FARXIGA 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of FARXIGA 10 mg-treated patients.

Increase in Low-Density Lipoprotein Cholesterol

In the pool of 13 placebo-controlled studies of glycemic control, changes from baseline in mean lipid values were reported in FARXIGA-treated patients compared to placebo-treated patients. Mean percent changes 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 FARXIGA 10 mg groups, respectively. In the DECLARE study [see Clinical Studies (14.2)], mean changes from baseline after 4 years were 0.4 mg/dL versus -4.1 mg/dL for total cholesterol, and -2.5 mg/dL versus -4.4 mg/dL for LDL cholesterol, in FARXIGA-treated and the placebo groups, respectively.

Decrease in Serum Bicarbonate

In a study of concomitant therapy of FARXIGA 10 mg with exenatide extended-release (on a background of metformin), four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the FARXIGA and exenatide-extended release treatment groups [see Warnings and Precautions (5.1)].

DAPA-HF and DELIVER Heart Failure Studies

No new adverse reactions were identified in the DAPA-HF and DELIVER heart failure studies.

DAPA-CKD Chronic Kidney Disease Study

No new adverse reactions were identified in the DAPA-CKD study in patients with chronic kidney disease.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during post-approval use of FARXIGA in patients with diabetes mellitus. 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

8.1 Pregnancy

8.2 Lactation

Risk Summary

There is no information regarding the presence of dapagliflozin in human milk, the effects on the breastfed infant, or the effects 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 FARXIGA is not recommended while breastfeeding.

Data

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.

8.4 Pediatric Use

Safety and effectiveness of FARXIGA in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use

No FARXIGA dosage change is recommended based on age.

A total of 1424 (24%) of the 5936 FARXIGA-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 FARXIGA in improving glycemic control in type 2 diabetes mellitus. 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 FARXIGA for glycemic control had adverse reactions of hypotension [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

In the DAPA-CKD, DAPA-HF and DELIVER studies, safety and efficacy were similar for patients age 65 years and younger and those older than 65. In the DAPA-HF study, 2714 (57%) out of 4744 patients with HFrEF were older than 65 years. In the DELIVER study, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with CKD were older than 65 years.

8.6 Renal Impairment

FARXIGA was evaluated in 4304 patients with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m2) in the DAPA-CKD study. FARXIGA was also evaluated in 1926 patients with an eGFR of 30 to 60 mL/min/1.73 m2 in the DAPA-HF study. The safety profile of FARXIGA across eGFR subgroups in these studies was consistent with the known safety profile [see Adverse Reactions (6.1) and Clinical Studies (14.3 and 14.4)].

FARXIGA was evaluated in two glycemic control studies that included patients with type 2 diabetes mellitus with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2 [see Clinical Studies (14.1)], and an eGFR of 30 to less than 60 mL/min/1.73 m2, respectively). Patients with diabetes and renal impairment using FARXIGA may be more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients receiving FARXIGA experienced bone fractures compared to none receiving placebo. Use of FARXIGA for glycemic control in patients without established CV disease or CV risk factors is not recommended when eGFR is less than 45 mL/min/1.73 m2 [see Dosage and Administration (2.2)].

Efficacy and safety studies with FARXIGA did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis.

8.7 Hepatic Impairment

No dose adjustment is recommended for patients with mild, moderate, or severe hepatic impairment. However, the benefit-risk for the use of dapagliflozin in patients with severe hepatic impairment should be individually assessed since the safety and efficacy of dapagliflozin have not been specifically studied in this population [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

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 thereby promotes urinary glucose excretion.

Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

12.2 Pharmacodynamics

General

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 at Week 12. 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

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 per 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 per 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 greater than or equal to 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 greater than 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 less than or equal to 1708-times and 998-times the maximum recommended human dose in males and females, respectively.

14.1 Glycemic Control in Patients with Type 2 Diabetes Mellitus

Initial Combination Therapy with Metformin XR

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 FARXIGA 5 mg (NCT00643851) or 10 mg (NCT00859898) in combination with metformin extended-release (XR) formulation.

In 1 study, 638 patients randomized to 1 of 3 treatment arms following a 1-week lead-in period received: FARXIGA 10 mg plus metformin XR (up to 2000 mg per day), FARXIGA 10 mg plus placebo, or metformin XR (up to 2000 mg per 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 FARXIGA 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 9 and Figure 2). FARXIGA 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 9: Results at Week 24 (LOCF*) in an Active-Controlled Study of FARXIGA Initial Combination Therapy with Metformin XR

Efficacy Parameter	FARXIGA 10 mg + Metformin XR	FARXIGA 10 mg	Metformin XR
	N=211†	N=219†	N=208†
* 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.
HbA1c (%)
Baseline (mean)	9.1	9.0	9.0
Change from baseline (adjusted mean‡)	−2.0	−1.5	−1.4
Difference from FARXIGA (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 FARXIGA (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 FARXIGA Initial Combination Therapy with Metformin XR

In a second study, 603 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: FARXIGA 5 mg plus metformin XR (up to 2000 mg per day), FARXIGA 5 mg plus placebo, or metformin XR (up to 2000 mg per 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 FARXIGA 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 10).

Table 10: Results at Week 24 (LOCF*) in an Active-Controlled Study of FARXIGA 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	FARXIGA 5 mg + Metformin XR	FARXIGA 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 FARXIGA (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 FARXIGA (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

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 FARXIGA in combination with metformin (NCT00528879). Patients on metformin at a dose of at least 1500 mg per day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to FARXIGA 5 mg, FARXIGA 10 mg, or placebo in addition to their current dose of metformin.

As add-on treatment to metformin, FARXIGA 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 11 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 FARXIGA 5 mg and 10 mg plus metformin, respectively.

Table 11: Results of a 24-Week (LOCF*) Placebo-Controlled Study of FARXIGA 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	FARXIGA 10 mg + Metformin N=135†	FARXIGA 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 FARXIGA 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 FARXIGA 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 FARXIGA 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.

FARXIGA 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 FARXIGA (HR 0.73 [95% CI 0.61, 0.88]), with no change in the risk of CV death (Table 15 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 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 FARXIGA 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 FARXIGA 10 mg or placebo and were followed for a median of 28.5 months.

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/1.73 m2 to less than 45 mL/min/1.73 m2, and 15% of patients had an eGFR less than 30 mL/min/1.73 m2. Median UACR was 950 mg/g. A total of 68% of the patients had type 2 diabetes mellitus at randomization. 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.

FARXIGA reduced the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, progression to ESKD, CV or renal death (HR 0.61 [95% CI 0.51,0.72]; p<0.0001). The FARXIGA 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 16, Figure 6).

FARXIGA also reduced the incidence of the composite endpoint of CV death or hospitalization for heart failure (HR 0.71 [95% CI 0.55, 0.92], p=0.0089) and all-cause mortality (HR 0.69 [95% CI 0.53, 0.88], p=0.0035).

Figure 6: Time to First Occurrence of the Primary Composite Endpoint, ≥50% Sustained Decline in eGFR, ESKD, CV or Renal Death (DAPA-CKD Study)

Patients at risk is the number of subjects at risk at the beginning of the period. 1 month corresponds to 30 days. 2-sided p-value is displayed. HR, CI and p-value are from the Cox proportional hazard model.

HR=hazard ratio; CI=confidence interval; eGFR=estimated glomerular filtration rate; ESKD=end stage kidney disease; CV=cardiovascular; vs=versus.

The results of the primary composite endpoint were consistent across the subgroups examined, including CKD patients with and without type 2 diabetes mellitus, causes of CKD, age, biological sex, race, UACR, and eGFR.

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 FARXIGA on CV outcomes (the DECLARE trial) support the conclusion that FARXIGA is also likely to be effective in patients with less advanced CKD.

14.4 Heart Failure

The efficacy and safety of FARXIGA 10 mg were assessed independently in two Phase 3 studies in patients with heart failure.

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 FARXIGA reduces the risk of cardiovascular death and hospitalization for heart failure. Of 4744 patients, 2373 were randomized to FARXIGA 10 mg and 2371 to placebo and were followed for a median of 18 months.

Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure (DELIVER, NCT03619213) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients aged ≥40 years with heart failure (NYHA class II-IV) with LVEF >40% and evidence of structural heart disease to determine whether FARXIGA reduces the risk of cardiovascular death, hospitalization for heart failure or urgent heart failure visits. Of 6263 patients, 3131 were randomized to FARXIGA 10 mg and 3132 to placebo and were followed for a median of 28 months. The study included 654 (10%) heart failure patients who were randomized during hospitalization for heart failure or within 30 days of discharge.

In DAPA-HF, 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.

In DELIVER, at baseline, 77% of patients were treated with ACEi, ARB or ARNI, 83% with beta-blocker, 43% with MRA, 98% with diuretic.

In both studies, FARXIGA reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit (see Table 17).

NOTE: Time to first event was analyzed in a Cox proportional hazards model. The number of first events for the single components are the actual number of first events for each component and does not add up to the number of events in the composite endpoint. Event rates are presented as the number of subjects with event per 100 patient years of follow-up.

In both studies, all three components of the primary composite endpoint individually contributed to the treatment effect. In both studies, the FARXIGA and placebo event curves separated early and continued to diverge over the study period (see Figures 7 and 9).

Figure 7: Time to the First Occurrence of the Composite of Cardiovascular Death*, Hospitalization for Heart Failure or Urgent Heart Failure Visit

A) DAPA-HF Study

B) DELIVER Study

NOTE: An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g., in an Emergency Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).

* In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.

† Patients at risk is the number of patients at risk at the beginning of the period.

HR=Hazard ratio, CI=Confidence interval, CV=Cardiovascular.

Figure 8: Time to Cardiovascular Death*

A) DAPA-HF Study

B) DELIVER Study

* In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.

† Patients at risk is the number of patients at risk at the beginning of the period.

HR=Hazard ratio, CI=Confidence interval, CV=Cardiovascular.

Figure 9: Time to the First Occurrence of Hospitalization for Heart Failure or Urgent Heart Failure Visit

A) DAPA-HF Study

B) DELIVER Study

* Patients at risk is the number of patients at risk at the beginning of the period.

HR=Hazard ratio, CI=Confidence interval.

In DAPA-HF, FARXIGA reduced the total number of hospitalizations for heart failure (first and recurrent) events and CV death, with 567 and 742 total events in the FARXIGA-treated vs placebo group (Rate Ratio 0.75 [95% CI 0.65, 0.88]; p=0.0002).

In DELIVER, FARXIGA reduced the total number of heart failure events (first and recurrent hospitalization for heart failure or urgent heart failure visit) and CV death, with 815 and 1057 total events in the FARXIGA treated vs placebo group (Rate Ratio 0.77 [95% CI 0.67, 0.89]; p=0.0003).

In both studies, the results of the primary composite endpoint were consistent across the subgroups examined (see Figure 10).

Figure 10: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and Heart Failure Events) Subgroup Analysis

A) DAPA-HF Study

a Hazard ratio estimates are not presented for subgroups with less than 15 events in total, both arms combined.

n/N# Number of subjects with event/number of subjects in the subgroup.

NT-proBNP = N-terminal pro b-type natriuretic peptide, HF = Heart failure, MRA = mineralocorticoid receptor antagonist,

ECG = electrocardiogram, eGFR = estimated glomerular filtration rate.

Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

B) DELIVER Study

a Subacute patient defined as randomized during hospitalization for heart failure or within 30 days of discharge.

b Defined as history of type 2 diabetes mellitus. This analysis does not include type 2 diabetes mellitus as a stratification factor.

n/N# Number of subjects with event/number of subjects in the subgroup.

NT-proBNP = N-terminal pro b-type natriuretic peptide, HF = Heart failure, ECG = electrocardiogram, eGFR = estimated glomerular filtration rate, BMI = body mass index, SBP = systolic blood pressure, T2DM = type 2 diabetes mellitus.

NOTE: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

The treatment effect of FARXIGA on the composite endpoint of cardiovascular death, hospitalization for heart failure or urgent heart failure was consistent across the LVEF range as evaluated in DAPA-HF and DELIVER studies (Figure 11).

Figure 11: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and Heart Failure Events) by LVEF (DAPA-HF and DELIVER Studies)

* 1 patient in DAPA-HF study had LVEF >40. 4 patients in DELIVER study had LVEF≤40.

In DAPA-HF study, the 5% and 95% percentiles of LVEF were 20 and 40 respectively. In DELIVER study, the 5% and 95% percentiles of LVEF were 42 and 70, respectively.