FARXIGA (DAPAGLIFLOZIN) tablet, film coated
AstraZeneca Pharmaceuticals LP

AstraZeneca Pharmaceuticals LP
AstraZeneca PLC
FARXIGA
DAPAGLIFLOZIN
DAPAGLIFLOZIN PROPANEDIOL
dapagliflozin
MICROCRYSTALLINE CELLULOSE
anhydrous lactose
CROSPOVIDONE, UNSPECIFIED
silicon dioxide
magnesium stearate
biconvex
5;1427
FARXIGA
DAPAGLIFLOZIN
DAPAGLIFLOZIN PROPANEDIOL
dapagliflozin
MICROCRYSTALLINE CELLULOSE
anhydrous lactose
CROSPOVIDONE, UNSPECIFIED
silicon dioxide
magnesium stearate
biconvenx
10;1428

Indications and Usage (1)                                                                 09/2023

Dosage and Administration (2.3)                                                      09/2023

Warnings and Precautions (5.1)                                                        09/2023

1 INDICATIONS AND USAGE

FARXIGA (dapagliflozin) is indicated:

  • To reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.
  • To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure.
  • To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.
  • As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
  •  

Limitations of Use

  • FARXIGA is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1)].
  • FARXIGA is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. FARXIGA is likely to be ineffective in this setting based upon its mechanism of action.
  • FARXIGA is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. FARXIGA is not expected to be effective in these populations.

FARXIGA is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated:

  • To reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression. (1)
  • To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure. (1)
  • To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. (1)
  • As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1)
  •  

Limitations of use:

  • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. (1)
  • Not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. FARXIGA is likely to be ineffective in this setting based upon its mechanism of action. (1)
  • Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for the treatment of kidney disease. FARXIGA is not expected to be effective in these populations. (1)

2 DOSAGE AND ADMINISTRATION

  • Assess volume status and correct volume depletion before initiating. (2.1)

eGFR
(mL/min/1.73 m2)

Recommended Dose

eGFR 45 or greater

To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control.

For all other indications, the recommended starting dose is 10 mg orally once daily.

eGFR 25 to less than 45

10 mg orally once daily

eGFR less than 25

Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF.

  • Withhold FARXIGA for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. (2.3)

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).

Table 1: Recommended Dosage

eGFR
(mL/min/1.73 m2)

Recommended Dose

eGFR 45 or greater

To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic controlFARXIGA is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. FARXIGA is likely to be ineffective in this setting based upon its mechanism of action..

For all other indications, the recommended starting dose is 10 mg orally once daily.

eGFR 25 to less than 45

10 mg orally once daily

.

eGFR less than 25

Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF.

hHF: hospitalization for heart failure, CV: Cardiovascular, ESKD: End Stage Kidney Disease.

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)].

3 DOSAGE FORMS AND STRENGTHS

  • FARXIGA 5 mg tablets are yellow, biconvex, round, film-coated tablets with “5” engraved on one side and “1427” engraved on the other side.
  • FARXIGA 10 mg tablets are yellow, biconvex, diamond-shaped, film-coated tablets with “10” engraved on one side and “1428” engraved on the other side.
  • Tablets: 5 mg and 10 mg (3)

4 CONTRAINDICATIONS

  • History of a serious hypersensitivity reaction to FARXIGA, such as anaphylactic reactions or angioedema [see Adverse Reactions (6.1)].
  • History of serious hypersensitivity reaction to FARXIGA. (4)

5 WARNINGS AND PRECAUTIONS

  • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue FARXIGA if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. (5.1)
  • Volume depletion: Before initiating FARXIGA, assess volume status and renal function in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.2)
  • Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.3)
  • Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with FARXIGA. (5.4)
  • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in patients with diabetes, both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.5)
  • Genital Mycotic Infections: Monitor and treat if indicated. (5.6)

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 ADVERSE REACTIONS

The following important adverse reactions are described below and elsewhere in the labeling:

  • Most common adverse reactions (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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.

Table 2: Adverse Reactions in Placebo-Controlled Studies of Glycemic Control Reported in ≥2% of Patients Treated with FARXIGA
Adverse Reaction % of Patients
Pool of 12 Placebo-Controlled Studies
Placebo
N=1393
FARXIGA 5 mg
N=1145
FARXIGA 10 mg
N=1193

Female genital mycotic infectionsGenital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, FARXIGA 5 mg=581, FARXIGA 10 mg=598).

1.5

8.4

6.9

Nasopharyngitis

6.2

6.6

6.3

Urinary tract infectionsUrinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.

3.7

5.7

4.3

Back pain

3.2

3.1

4.2

Increased urinationIncreased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.

1.7

2.9

3.8

Male genital mycotic infectionsGenital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, and posthitis. (N for males: Placebo=716, FARXIGA 5 mg=564, FARXIGA 10 mg=595).

0.3

2.8

2.7

Nausea

2.4

2.8

2.5

Influenza

2.3

2.7

2.3

Dyslipidemia

1.5

2.1

2.5

Constipation

1.5

2.2

1.9

Discomfort with urination

0.7

1.6

2.1

Pain in extremity

1.4

2.0

1.7

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)].

Table 3: Adverse Reactions Related to Volume DepletionVolume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. in Clinical Studies in Patients with Type 2 Diabetes Mellitus with FARXIGA

Pool of 12 Placebo-Controlled
Studies

Pool of 13 Placebo-Controlled
Studies

DECLARE Study

Placebo

FARXIGA
5 mg

FARXIGA
10 mg

Placebo

FARXIGA
10 mg

Placebo

FARXIGA
10 mg

Overall population N (%)

N=1393
5
(0.4%)

N=1145
7
(0.6%)

N=1193
9
(0.8%)

N=2295
17
(0.7%)

N=2360
27
(1.1%)

N=8569
207
(2.4%)

N=8574
213
(2.5%)

Patient Subgroup n (%)

Patients on loop diuretics

n=55
1
(1.8%)

n=40
0

n=31
3
(9.7%)

n=267
4
(1.5%)

n=236
6
(2.5%)

n=934
57
(6.1%)

n=866
57
(6.6%)

Patients with moderate renal impairment with eGFR ≥30 and <60 mL/min/1.73 m2

n=107
2
(1.9%)

n=107
1
(0.9%)

n=89
1
(1.1%)

n=268
4
(1.5%)

n=265
5
(1.9%)

n=658
30
(4.6%)

n=604
35
(5.8%)

Patients ≥65 years of age

n=276
1
(0.4%)

n=216
1
(0.5%)

n=204
3
(1.5%)

n=711
6
(0.8%)

n=665
11
(1.7%)

n=3950
121
(3.1%)

n=3948
117
(3.0%)

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)].

Table 4: Incidence of Severe HypoglycemiaSevere episodes of hypoglycemia were defined as episodes of severe impairment in consciousness or behavior, requiring external (third party) assistance, and with prompt recovery after intervention regardless of glucose level. and Hypoglycemia with Glucose < 54 mg/dLEpisodes of hypoglycemia with glucose <54 mg/dL (3 mmol/L) were defined as reported episodes of hypoglycemia meeting the glucose criteria that did not also qualify as a severe episode. in Controlled Glycemic Control Clinical Studies in Patients with Type 2 Diabetes Mellitus
Placebo/Active Control FARXIGA
5 mg
FARXIGA
10 mg

Monotherapy (24 weeks)

N=75

N=64

N=70

  Severe [n (%)]

0

0

0

  Glucose <54 mg/dL [n (%)]

0

0

0

Add-on to Metformin (24 weeks)

N=137

N=137

N=135

  Severe [n (%)]

0

0

0

  Glucose <54 mg/dL [n (%)]

0

0

0

Add-on to Glimepiride (24 weeks)

N=146

N=145

N=151

  Severe [n (%)]

0

0

0

  Glucose <54 mg/dL [n (%)]

1 (0.7)

3 (2.1)

5 (3.3)

Add-on to Metformin and a Sulfonylurea (24 Weeks)

N=109

-

N=109

  Severe [n (%)]

0

-

0

  Glucose <54 mg/dL [n (%)]

3 (2.8)

-

7 (6.4)

Add-on to Pioglitazone (24 weeks)

N=139

N=141

N=140

  Severe [n (%)]

0

0

0

  Glucose <54 mg/dL [n (%)]

0

1 (0.7)

0

Add-on to DPP4 inhibitor (24 weeks)

N=226

N=225

  Severe [n (%)]

0

1 (0.4)

  Glucose <54 mg/dL [n (%)]

1 (0.4)

1 (0.4)

Add-on to Insulin with or without other OADs OAD = oral antidiabetic therapy. (24 weeks)

N=197

N=212

N=196

  Severe [n (%)]

1 (0.5)

2 (0.9)

2 (1.0)

  Glucose <54 mg/dL [n (%)]

43 (21.8)

55 (25.9)

45 (23.0)

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

7 DRUG INTERACTIONS

Table 5: Clinically Relevant Interactions with FARXIGA

Insulin or Insulin Secretagogues

Clinical Impact

The risk of hypoglycemia may be increased when FARXIGA is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions (5.4)].

Intervention

Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia.

Lithium

Clinical Impact

Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations.

Intervention

Monitor serum lithium concentration more frequently during FARXIGA initiation and dosage changes.

Positive Urine Glucose Test

Clinical Impact

SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.

Intervention

Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay

Clinical Impact

Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.

Intervention

Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

See full prescribing information for information on drug interactions and interference of FARXIGA with laboratory tests. (7)

8 USE IN SPECIFIC POPULATIONS

  • Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters. (8.1)
  • Lactation: Not recommended when breastfeeding. (8.2)
  • Geriatrics: Higher incidence of adverse reactions related to hypotension. (8.5)
  • Renal Impairment: Higher incidence of adverse reactions related to volume depletion. (8.6)

8.1 Pregnancy

Risk Summary

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

Limited data with FARXIGA in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure 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

Animal Data

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).

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)].

10 OVERDOSAGE

There were no reports of overdose during the clinical development program for FARXIGA.

In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ supportive measures as dictated by the patient’s clinical status. The removal of dapagliflozin by hemodialysis has not been studied.

11 DESCRIPTION

Dapagliflozin, an inhibitor of SGLT2, 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 C21H25ClO6C3H8O2H2O and the molecular weight is 502.98. The structural formula is:

Dapagliflozin Chemical Structure

FARXIGA is available as a film-coated tablet for oral administration containing the equivalent of 5 mg dapagliflozin as dapagliflozin propanediol or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol, and the following inactive ingredients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide.

Dapagliflozin Chemical Structure

12 CLINICAL PHARMACOLOGY

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)

Figure 1
Figure 1

Cardiac Electrophysiology

Dapagliflozin was not associated with clinically meaningful prolongation of QTc interval at daily doses up to 150 mg (15-times the recommended maximum dose) in a study of healthy subjects. In addition, no clinically meaningful effect on QTc interval was observed following single doses of up to 500 mg (50-times the recommended maximum dose) of dapagliflozin in healthy subjects.

12.3 Pharmacokinetics

Absorption

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.

Distribution

Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.

Metabolism

The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.

Elimination

Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [14C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t½) for dapagliflozin is approximately 12.9 hours following a single oral dose of FARXIGA 10 mg.

Specific Populations

Renal Impairment

At steady-state (20 mg once daily dapagliflozin for 7 days), patients with type 2 diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100%, and 200% higher, respectively, as compared to patients with type 2 diabetes mellitus with normal renal function. There was no meaningful difference in exposure between patients with chronic kidney disease with and without type 2 diabetes. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function.

The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) , Use in Specific Populations (8.6), and Clinical Studies (14)].

Hepatic Impairment

In subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean Cmax and AUC of dapagliflozin were up to 12% and 36% higher, respectively, as compared to healthy matched control subjects following single-dose administration of 10 mg dapagliflozin. These differences were not considered to be clinically meaningful. In patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls [see Use in Specific Populations (8.7)].

Effects of Age, Gender, Race, and Body Weight on Pharmacokinetics

Based on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a clinically meaningful effect on the pharmacokinetics of dapagliflozin and thus, no dose adjustment is recommended.

Pediatric

Pharmacokinetics in the pediatric population has not been studied.

Drug Interactions

In Vitro Assessment of Drug Interactions

In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP 1A2, 2C9, 2C19, 2D6, or 3A4, nor induced CYP 1A2, 2B6, or 3A4. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.

Effects of Other Drugs on Dapagliflozin

Table 6 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. No dose adjustments are recommended for dapagliflozin.

Table 6: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure

Coadministered Drug
(Dose Regimen) Single dose unless otherwise noted.

Dapagliflozin
(Dose Regimen)

Effect on Dapagliflozin Exposure
(% Change [90% CI])

Cmax

AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.

No dosing adjustments required for the following:

Oral Antidiabetic Agents

  Metformin (1000 mg)

20 mg

  Pioglitazone (45 mg)

50 mg

  Sitagliptin (100 mg)

20 mg

  Glimepiride (4 mg)

20 mg

  Voglibose (0.2 mg three times daily)

10 mg

Other Medications

  Hydrochlorothiazide (25 mg)

50 mg

  Bumetanide (1 mg)

10 mg once daily
for 7 days

  Valsartan (320 mg)

20 mg

↓12%
[↓3%, ↓20%]

  Simvastatin (40 mg)

20 mg

Anti-infective Agent

  Rifampin (600 mg once daily for 6 days)

10 mg

↓7%
[↓22%, ↑11%]

↓22%
[↓27%, ↓17%]

Nonsteroidal Anti-inflammatory Agent

  Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours)

10 mg

↑13%
[↑3%, ↑24%]

↑51%
[↑44%, ↑58%]

↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to dapagliflozin administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25)

Effects of Dapagliflozin on Other Drugs

Table 7 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.

Table 7: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs

Coadministered Drug
(Dose Regimen) Single dose unless otherwise noted.

Dapagliflozin
(Dose Regimen)

Effect on Coadministered Drug Exposure
(% Change [90% CI])

Cmax

AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses.

No dosing adjustments required for the following:

Oral Antidiabetic Agents

  Metformin (1000 mg)

20 mg

  Pioglitazone (45 mg)

50 mg

↓7%
[↓25%, ↑15%]

  Sitagliptin (100 mg)

20 mg

  Glimepiride (4 mg)

20 mg

↑13%
[0%, ↑29%]

Other Medications

  Hydrochlorothiazide (25 mg)

50 mg

  Bumetanide (1 mg)

10 mg once daily
for 7 days

↑13%
[↓2%, ↑31%]

↑13%
[↓1%, ↑30%]

  Valsartan (320 mg)

20 mg

↓6%
[↓24%, ↑16%]

↑5%
[↓15%, ↑29%]

  Simvastatin (40 mg)

20 mg

↑19%

  Digoxin (0.25 mg)

20 mg loading dose
then 10 mg once daily
for 7 days

  Warfarin (25 mg)

20 mg loading dose
then 10 mg once daily
for 7 days

↔ = no change (geometric mean ratio of test: reference within 0.80 to 1.25); ↓ or ↑ = parameter was lower or higher, respectively, with coadministration compared to the other medicine administered alone (geometric mean ratio of test: reference was lower than 0.80 or higher than 1.25).

13 NONCLINICAL TOXICOLOGY

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 CLINICAL STUDIES

14.1 Glycemic Control in Patients with Type 2 Diabetes Mellitus

Overview of Clinical Studies of FARXIGA for Type 2 Diabetes Mellitus

FARXIGA has been studied as monotherapy, in combination with metformin, pioglitazone, sulfonylurea (glimepiride), sitagliptin (with or without metformin), metformin plus a sulfonylurea, or insulin (with or without other oral antidiabetic therapy), compared to a sulfonylurea (glipizide), and in combination with a GLP-1 receptor agonist (exenatide extended-release) added-on to metformin. FARXIGA has also been studied in patients with type 2 diabetes mellitus and moderate renal impairment.

Treatment with FARXIGA as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control. Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).

Monotherapy

A total of 840 treatment-naive patients with inadequately controlled type 2 diabetes mellitus participated in 2 placebo-controlled studies to evaluate the safety and efficacy of monotherapy with FARXIGA.

In 1 monotherapy study, a total of 558 treatment-naive patients with inadequately controlled diabetes participated in a 24-week study (NCT00528372). Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c ≥7% and ≤10% were randomized to FARXIGA 5 mg or FARXIGA 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo.

At Week 24, treatment with FARXIGA 10 mg QAM provided significant improvements in HbA1c and the fasting plasma glucose (FPG) compared with placebo (see Table 8).

Table 8: Results at Week 24 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) in a Placebo-Controlled Study of FARXIGA Monotherapy in Patients with Type 2 Diabetes Mellitus (Main Cohort AM Doses)
Efficacy Parameter FARXIGA
10 mg
N=70 All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.
FARXIGA
5 mg
N=64
Placebo
N=75

HbA1c (%)

  Baseline (mean)

8.0

7.8

7.8

  Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)

−0.9

−0.8

−0.2

  Difference from placebo (adjusted mean

)
  (95% CI)

−0.7p-value <0.0001 versus placebo. Sensitivity analyses yielded smaller estimates of treatment difference with placebo.
(−1.0, −0.4)

−0.5
(−0.8, −0.2)

  Percent of patients achieving HbA1c <7%
  adjusted for baseline

50.8%Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints.

44.2%

31.6%

FPG (mg/dL)

  Baseline (mean)

166.6

157.2

159.9

  Change from baseline (adjusted mean

)

−28.8

−24.1

−4.1

  Difference from placebo (adjusted mean

)
  (95% CI)

−24.7


(−35.7, −13.6)

−19.9
(−31.3, −8.5)

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 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) 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 All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period. N=219
N=208

HbA1c (%)

  Baseline (mean)

9.1

9.0

9.0

  Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)

−2.0

−1.5

−1.4

  Difference from FARXIGA (adjusted mean

)
  (95% CI)

−0.5p-value <0.0001.
(−0.7, −0.3)

  Difference from metformin XR (adjusted mean

)
  (95% CI)

−0.5


(−0.8, −0.3)

0.0Non-inferior versus metformin XR.
(−0.2, 0.2)

  Percent of patients achieving HbA1c <7%
  adjusted for baseline

46.6%p-value <0.05.

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

Figure 2

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 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) in an Active-Controlled Study of FARXIGA Initial Combination Therapy with Metformin XR

Efficacy Parameter

FARXIGA
5 mg
+ Metformin XR

FARXIGA
5 mg

Metformin

XR

N=194 All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.

N=203

N=201

HbA1c (%)

  Baseline (mean)

9.2

9.1

9.1

  Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)

−2.1

−1.2

−1.4

  Difference from FARXIGA (adjusted mean

)
  (95% CI)

−0.9p-value <0.0001.
(−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%p-value <0.05.

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)

Figure 2

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 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) Placebo-Controlled Study of FARXIGA in Add-On Combination with Metformin

Efficacy Parameter

FARXIGA 10 mg
+ Metformin
N=135 All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.

FARXIGA 5 mg
+ Metformin
N=137

Placebo
+ Metformin
N=137

HbA1c (%)

  Baseline (mean)

7.9

8.2

8.1

  Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)

-0.8

-0.7

-0.3

  Difference from placebo (adjusted mean

)
  (95% CI)

-0.5p-value <0.0001 versus placebo + metformin.

(-0.7, -0.3)

-0.4

(-0.6, -0.2)

  Percent of patients achieving HbA1c <7%
  adjusted for baseline

40.6%p-value <0.05 versus placebo + metformin.

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

Figure 3
Figure 3

Active Glipizide-Controlled Study Add-On to Metformin

A total of 816 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, non-inferiority study to evaluate FARXIGA as add-on therapy to metformin (NCT00660907). Patients on metformin at a dose of at least 1500 mg per day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and FARXIGA 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.

At the end of the titration period, 87% of patients treated with FARXIGA had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). FARXIGA led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating non-inferiority (see Table 12). FARXIGA treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was -5.0 mmHg with FARXIGA plus metformin.

Table 12: Results at Week 52 (LOCFLOCF: last observation carried forward.) in an Active-Controlled Study Comparing FARXIGA to Glipizide as Add-On to Metformin
Efficacy Parameter FARXIGA
+ Metformin
N=400 Randomized and treated patients with baseline and at least 1 post-baseline efficacy measurement.
Glipizide
+ Metformin
N=401

HbA1c (%)

  Baseline (mean)

7.7

7.7

  Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.)

-0.5

-0.5

  Difference from glipizide + metformin (adjusted mean

)
  (95% CI)

0.0Non-inferior to glipizide + metformin.
(-0.1, 0.1)

Body Weight (kg)

  Baseline (mean)

88.4

87.6

  Change from baseline (adjusted mean

)

-3.2

1.4

  Difference from glipizide + metformin (adjusted mean

)
  (95% CI)

-4.7p-value <0.0001.
(-5.1, -4.2)

Add-On Combination Therapy with Other Antidiabetic Agents

Add-On Combination Therapy with a Sulfonylurea

A total of 597 patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized in this 24-week, placebo-controlled study to evaluate FARXIGA in combination with glimepiride (a sulfonylurea) (NCT00680745).

Patients on at least half the maximum recommended dose of glimepiride as monotherapy (4 mg) for at least 8 weeks lead-in were randomized to FARXIGA 5 mg, FARXIGA 10 mg, or placebo in addition to glimepiride 4 mg per day. Down-titration of glimepiride to 2 mg or 0 mg was allowed for hypoglycemia during the treatment period; no up-titration of glimepiride was allowed.

In combination with glimepiride, FARXIGA 10 mg provided statistically significant improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in body weight compared with placebo plus glimepiride at Week 24 (see Table 13). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus glimepiride were -2.8 mmHg and -3.8 mmHg with FARXIGA 5 mg and 10 mg plus glimepiride, respectively.

Add-on Combination Therapy with Metformin and a Sulfonylurea

A total of 218 patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate FARXIGA in combination with metformin and a sulfonylurea (NCT01392677). Patients on a stable dose of metformin (immediate- or extended-release formulations) ≥1500 mg/day plus maximum tolerated dose, which must be at least half the maximum dose, of a sulfonylurea for at least 8 weeks prior to enrollment were randomized after an 8-week placebo lead-in period to FARXIGA 10 mg or placebo. Dose-titration of FARXIGA or metformin was not permitted during the 24-week treatment period. Down-titration of the sulfonylurea was permitted to prevent hypoglycemia, but no up-titration was permitted. As add-on treatment to combined metformin and a sulfonylurea, treatment with FARXIGA 10 mg provided statistically significant improvements in HbA1c and FPG and statistically significant reduction in body weight compared with placebo at Week 24 (Table 13). A statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with metformin and a sulfonylurea was -3.8 mmHg with FARXIGA 10 mg in combination with metformin and a sulfonylurea at Week 8.

Add-On Combination Therapy with a Thiazolidinedione

A total of 420 patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate FARXIGA in combination with pioglitazone (a thiazolidinedione [TZD]) alone (NCT00683878). Patients on a stable dose of pioglitazone of 45 mg per day (or 30 mg per day, if 45 mg per day was not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 or 10 mg of FARXIGA or placebo in addition to their current dose of pioglitazone. Dose titration of FARXIGA or pioglitazone was not permitted during the study.

In combination with pioglitazone, treatment with FARXIGA 10 mg provided statistically significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7%, and a statistically significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (see Table 13) at Week 24. A statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with pioglitazone was -4.5 mmHg with FARXIGA 10 mg in combination with pioglitazone.

Add-On Combination Therapy with a DPP4 Inhibitor

A total of 452 patients with type 2 diabetes mellitus who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled study to evaluate FARXIGA in combination with sitagliptin (a DPP4 inhibitor) with or without metformin (NCT00984867).

Eligible patients were stratified based on the presence or absence of background metformin (≥1500 mg per day), and within each stratum were randomized to either FARXIGA 10 mg plus sitagliptin 100 mg once daily, or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for FARXIGA 10 mg versus placebo for the total study group (sitagliptin with and without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of FARXIGA, sitagliptin, or metformin was not permitted during the study.

In combination with sitagliptin (with or without metformin), FARXIGA 10 mg provided statistically significant improvements in HbA1c, FPG, and a statistically significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (see Table 13). These improvements were also seen in the stratum of patients who received FARXIGA 10 mg plus sitagliptin alone (placebo-corrected mean change for HbA1c -0.56%; n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received FARXIGA 10 mg plus sitagliptin and metformin (placebo-corrected mean change for HbA1c -0.40; n=113) compared with placebo plus sitagliptin with metformin (n=113).

Add-On Combination Therapy with Insulin

A total of 808 patients with type 2 diabetes mellitus who had inadequate glycemic control (HbA1c ≥7.5% and ≤10.5%) were randomized in a 24-week, placebo-controlled study to evaluate FARXIGA as add-on therapy to insulin (NCT00673231). Patients on a stable insulin regimen, with a mean dose of at least 30 IU of injectable insulin per day, for a period of at least 8 weeks prior to enrollment and on a maximum of 2 oral antidiabetic medications (OADs), including metformin, were randomized after completing a 2-week enrollment period to receive either FARXIGA 5 mg, FARXIGA 10 mg, or placebo in addition to their current dose of insulin and other OADs, if applicable. Patients were stratified according to the presence or absence of background OADs. Up- or down-titration of insulin was only permitted during the treatment phase in patients who failed to meet specific glycemic goals. Dose modifications of blinded study medication or OAD(s) were not allowed during the treatment phase, with the exception of decreasing OAD(s) where there were concerns over hypoglycemia after cessation of insulin therapy.

In this study, 50% of patients were on insulin monotherapy at baseline, while 50% were on 1 or 2 OADs in addition to insulin. At Week 24, FARXIGA 10 mg dose provided statistically significant improvement in HbA1c and reduction in mean insulin dose, and a statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (see Table 13); the effect of FARXIGA on HbA1c was similar in patients treated with insulin alone and patients treated with insulin plus OAD. Statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with insulin was -3.0 mmHg with FARXIGA 10 mg in combination with insulin.

At Week 24, FARXIGA 5 mg (-5.7 IU, difference from placebo) and 10 mg (-6.2 IU, difference from placebo) once daily resulted in a statistically significant reduction in mean daily insulin dose (p<0.0001 for both doses) compared to placebo in combination with insulin, and a statistically significantly higher proportion of patients on FARXIGA 10 mg (19.6%) reduced their insulin dose by at least 10% compared to placebo (11.0%).

Table 13: Results of 24-Week (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) Placebo-Controlled Studies of FARXIGA in Combination with Antidiabetic Agents

Efficacy Parameter

FARXIGA 10 mg

FARXIGA 5 mg

Placebo

In Combination with Sulfonylurea (Glimepiride)

Intent-to-Treat Population

N=151 Randomized and treated patients with baseline and at least 1 post-baseline efficacy measurement.

N=142

N=145

HbA1c (%)

  Baseline (mean)

8.1

8.1

8.2

  Change from baseline (adjusted meanLeast squares mean adjusted for baseline value based on an ANCOVA model. )

-0.8

-0.6

-0.1

  Difference from placebo (adjusted mean

)
  (95% CI)

-0.7p-value <0.0001 versus placebo.

(-0.9, -0.5)

-0.5

(-0.7, -0.3)

Percent of patients achieving HbA1c <7% adjusted for baseline

31.7%

30.3%

13.0%

FPG (mg/dL)

  Baseline (mean)

172.4

174.5

172.7

  Change from baseline (adjusted mean

)

-28.5

-21.2

-2.0

  Difference from placebo (adjusted mean

)

  (95% CI)

-26.5

(-33.5, -19.5)

-19.3

(-26.3, -12.2)

2-hour PPG 2-hour PPG level as a response to a 75-gram oral glucose tolerance test (OGTT). (mg/dL)

  Baseline (mean)

329.6

322.8

324.1

  Change from baseline (adjusted mean

)

-60.6

–54.5

-11.5

  Difference from placebo (adjusted mean

)

  (95% CI)

-49.1

(-64.1, -34.1)

-43.0

(–58.4, -27.5)

Body Weight (kg)

  Baseline (mean)

80.6

81.0

80.9

  Change from baseline (adjusted mean

)

-2.3

-1.6

-0.7

  Difference from placebo (adjusted mean

)

  (95% CI)

-1.5

(-2.2, -0.9)

-0.8

(-1.5, -0.2)

In Combination with Metformin and a Sulfonylurea

Intent-to-Treat Population

N=108

-

N=108

HbA1c (%)

  Baseline (mean)

8.08

-

8.24

  Change from baseline (adjusted mean

Least squares mean adjusted for baseline value based on a longitudinal repeated measures model.)

-0.86

-

-0.17

  Difference from placebo (adjusted mean

)

  (95% CI)

-0.69

(-0.89, -0.49)

-

  Percent of patients achieving HbA1c <7%
  adjusted for baseline

31.8%

-

11.1%

FPG (mg/dL)

  Baseline (mean)

167.4

-

180.3

  Change from baseline (adjusted mean

)

-34.2

-

-0.8

  Difference from placebo (adjusted mean

)

  (95% CI)

-33.5

(-43.1, -23.8)

-

Body Weight (kg)

  Baseline (mean)

88.57

-

90.07

  Change from baseline (adjusted mean

)

-2.65

-

-0.58

  Difference from placebo (adjusted mean

)

  (95% CI)

-2.07

(-2.79, -1.35)

-

In Combination with Thiazolidinedione (Pioglitazone)

Intent-to-Treat Population

N=140 All randomized patients who took at least one dose of double-blind study medication during the short-term, double-blind period.

N=141

N=139

HbA1c (%)

  Baseline (mean)

8.4

8.4

8.3

  Change from baseline (adjusted mean

)

-1.0

-0.8

-0.4

  Difference from placebo (adjusted mean

)

  (95% CI)

-0.6

(-0.8, -0.3)

-0.4

(-0.6, -0.2)

  Percent of patients achieving HbA1c <7%
  adjusted for baseline

38.8%p-value <0.05 versus placebo.

32.5%

22.4%

FPG (mg/dL)

  Baseline (mean)

164.9

168.3

160.7

  Change from baseline (adjusted mean

)

-29.6

-24.9

-5.5

  Difference from placebo (adjusted mean

)

  (95% CI)

-24.1

(-32.2, -16.1)

-19.5

(-27.5, -11.4)

2-hour PPG

(mg/dL)

  Baseline (mean)

308.0

284.8

293.6

  Change from baseline (adjusted mean

)

-67.5

-65.1

-14.1

  Difference from placebo (adjusted mean

)

  (95% CI)

-53.3

(-71.1, -35.6)

-51.0

(-68.7, -33.2)

Body Weight (kg)

  Baseline (mean)

84.8

87.8

86.4

  Change from baseline (adjusted mean

)

-0.1

0.1

1.6

  Difference from placebo (adjusted mean

)

  (95% CI)

-1.8

(-2.6, -1.0)

-1.6

(-2.3, -0.8)

In Combination with DPP4 Inhibitor (Sitagliptin) with or without Metformin

Intent-to-Treat Population

N=223

N=224

HbA1c (%)

  Baseline (mean)

7.90

7.97

  Change from baseline (adjusted mean

)

-0.45

0.04

  Difference from placebo (adjusted mean

)

  (95% CI)

-0.48

(-0.62, -0.34)

  Patients with HbA1c decrease ≥0.7% (adjusted percent)

35.4%

16.6%

FPG (mg/dL)

  Baseline (mean)

161.7

163.1

  Change from baseline at Week 24 (adjusted mean

)

-24.1

3.8

  Difference from placebo (adjusted mean

)

  (95% CI)

-27.9

(-34.5, -21.4)

Body Weight (kg)

  Baseline (mean)

91.02

89.23

  Change from baseline (adjusted mean

)

-2.14

-0.26

  Difference from placebo (adjusted mean

)

  (95% CI)

-1.89

(-2.37, -1.40)

In Combination with Insulin with or without up to 2 Oral Antidiabetic Therapies

Intent-to-Treat Population

N=194

N=211

N=193

HbA1c (%)

  Baseline (mean)

8.6

8.6

8.5

  Change from baseline (adjusted mean

)

-0.9

-0.8

-0.3

  Difference from placebo (adjusted mean

)

  (95% CI)

-0.6

(-0.7, -0.5)

-0.5

(-0.7, -0.4)

FPG (mg/dL)

  Baseline (mean)

173.7

NTNT: Not formally tested because of failing to achieve a statistically significant difference in an endpoint that was earlier in the testing sequence.

170.0

  Change from baseline (adjusted mean

)

-21.7

NT

3.3

  Difference from placebo (adjusted mean

)

  (95% CI)

-25.0

(-34.3, -15.8)

NT

Body Weight (kg)

  Baseline (mean)

94.6

93.2

94.2

  Change from baseline (adjusted mean

)

-1.7

-1.0

0.0

  Difference from placebo (adjusted mean

)

  (95% CI)

-1.7

(-2.2, -1.2)

-1.0

(-1.5, -0.5)

Combination Therapy with Exenatide-Extended Release as Add-On to Metformin

A total of 694 adult patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥8.0 and ≤12.0%) on metformin, were evaluated in a 28-week double-blind, active-controlled study to compare FARXIGA in combination with exenatide extended-release (a GLP-1 receptor agonist) to FARXIGA alone and exenatide extended-release alone, as add-on to metformin (NCT02229396). Patients on metformin at a dose of at least 1,500 mg per day were randomized following a 1-week placebo lead-in period to receive either FARXIGA 10 mg once daily (QD) in combination with exenatide extended-release 2 mg once weekly (QW), FARXIGA 10 mg QD, or exenatide extended–release 2 mg QW.

At Week 28, FARXIGA in combination with exenatide extended-release provided statistically significantly greater reductions in HbA1c (-1.77%) compared to FARXIGA alone (-1.32%, p=0.001) and exenatide extended-release alone (-1.42%, p=0.012). FARXIGA in combination with exenatide extended-release provided statistically significantly greater reductions in FPG (-57.35 mg/dL) compared to FARXIGA alone (-44.72 mg/dL, p=0.006) and exenatide extended-release alone (-40.53, p <0.001).

Use in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment

FARXIGA was assessed in two placebo-controlled studies of patients with type 2 diabetes mellitus and moderate renal impairment.

Patients with type 2 diabetes mellitus and an eGFR between 45 to less than 60 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in a 24-week, double-blind, placebo-controlled clinical study (NCT02413398). Patients were randomized to either FARXIGA 10 mg or placebo, administered orally once daily. At Week 24, FARXIGA provided statistically significant reductions in HbA1c compared with placebo (Table 14).

Table 14: Results at Week 24 of Placebo-Controlled Study for FARXIGA in Patients with Type 2 Diabetes Mellitus and Renal Impairment (eGFR 45 to less than 60 mL/min/1.73 m2)
FARXIGA 10 mg Placebo
Number of patients: N=160 N=161

HbA1c (%)

  Baseline (mean)

8.3

8.0

  Change from baseline (adjusted meanLeast squares mean adjusted for baseline value; at Week 24, HbA1c was missing for 5.6% and 6.8% of individuals treated with FARXIGA and placebo, respectively. Retrieved dropouts, i.e. observed HbA1c at Week 24 from subjects who discontinued treatment, were used to impute missing values in HbA1c. )

-0.4

-0.1

  Difference from placebo (adjusted mean

)

  (95% CI)

-0.3p-value =0.008 versus placebo.

(-0.5, - 0.1)

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).

Table 15: Treatment Effects for the Primary EndpointsFull analysis set. and their Components
in the DECLARE Study

Patients with events n (%)

Efficacy Variable

(time to first occurrence)

FARXIGA 10 mg

N=8582

Placebo

N=8578

Hazard ratio

(95% CI)

Primary Endpoints

Composite of Hospitalization for Heart Failure, CV Death p-value =0.005 versus placebo.

417 (4.9)

496 (5.8)

0.83 (0.73, 0.95)

Composite Endpoint of CV Death, MI, Ischemic Stroke

756 (8.8)

803 (9.4)

0.93 (0.84, 1.03)

Components of the composite endpointsTotal number of events presented for each component of the composite endpoints.

  Hospitalization for Heart Failure

212 (2.5)

286 (3.3)

0.73 (0.61, 0.88)

  CV Death

245 (2.9)

249 (2.9)

0.98 (0.82, 1.17)

  Myocardial Infarction

393 (4.6)

441 (5.1)

0.89 (0.77, 1.01)

  Ischemic Stroke

235 (2.7)

231 (2.7)

1.01 (0.84, 1.21)

N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction.

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

Figure 4