FARXIGA- dapagliflozin tablet, film coated

FARXIGA by

Drug Labeling and Warnings

FARXIGA by is a Prescription medication manufactured, distributed, or labeled by A-S Medication Solutions. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    FARXIGA (dapagliflozin) is indicated:

    • as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
    • to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.

    Limitations of Use

    FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Prior to Initiation of FARXIGA

    Assess renal function prior to initiation of FARXIGA therapy and periodically thereafter [see Warnings and Precautions (5.3)].

    In patients with volume depletion, correct this condition prior to initiation of FARXIGA [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].

    2.2 Recommended Dosage

    To improve glycemic control, the recommended starting dose of FARXIGA is 5 mg once daily, taken in the morning, with or without food. In patients tolerating FARXIGA 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily.

    To reduce the risk of hospitalization for heart failure, the recommended dose of FARXIGA is 10 mg once daily.

    2.3 Patients with Renal Impairment

    No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.

    Use of FARXIGA is not recommended when the eGFR is less than 45 mL/min/1.73 m2 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].

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

  • 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.
  • 4 CONTRAINDICATIONS

    • History of a serious hypersensitivity reaction to FARXIGA, such as anaphylactic reactions or angioedema [see Adverse Reactions (6.1)].
    • Severe renal impairment, (eGFR less than 30 mL/min/1.73 m2) end-stage renal disease (ESRD), or patients on dialysis [see Use in Specific Populations (8.6)].
  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hypotension

    FARXIGA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating FARXIGA [see Adverse Reactions (6.1)] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics. Before initiating FARXIGA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms of hypotension after initiating therapy.

    5.2 Ketoacidosis

    Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in patients with type 1 and type 2 diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors, including FARXIGA [see Adverse Reactions (6.1)]. Fatal cases of ketoacidosis have been reported in patients taking FARXIGA. FARXIGA is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].

    Patients treated with FARXIGA who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels as ketoacidosis associated with FARXIGA may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, FARXIGA should be discontinued, the patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid, and carbohydrate replacement.

    In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized, and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis, such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

    Before initiating FARXIGA, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with FARXIGA consider monitoring for ketoacidosis and temporarily discontinuing FARXIGA in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

    5.3 Acute Kidney Injury

    FARXIGA causes intravascular volume contraction [see Warning and Precautions (5.1)], and can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving FARXIGA.

    Increases in serum creatinine and decreases in estimated GFR may also be observed with initiation of FARXIGA. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating FARXIGA, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing FARXIGA in the setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue FARXIGA promptly and institute treatment.

    Renal function should be evaluated prior to initiation of FARXIGA and monitored periodically thereafter. Use of FARXIGA is not recommended when the eGFR is less than 45 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and Administration (2.3), Contraindications (4) and Use in Specific Populations (8.6)].

    5.4 Urosepsis and Pyelonephritis

    There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including 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)].

    5.5 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.

    5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

    Reports of necrotizing fasciitis of the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including 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.

    5.7 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:

    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.

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

    The data in Table 1 is derived from 12 placebo-controlled studies 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 1 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 1: Adverse Reactions in Placebo-Controlled Studies 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
  • * Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, FARXIGA 5 mg=581, FARXIGA 10 mg=598).
  • † Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.
  • ‡ Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.
  • § Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, and posthitis. (N for males: Placebo=716, FARXIGA 5 mg=564, FARXIGA 10 mg=595).
    		•

    Female genital mycotic infections*

    1.5

    8.4

    6.9

    Nasopharyngitis

    6.2

    6.6

    6.3

    Urinary tract infections†

    3.7

    5.7

    4.3

    Back pain

    3.2

    3.1

    4.2

    Increased urination‡

    1.7

    2.9

    3.8

    Male genital mycotic infections§

    0.3

    2.8

    2.7

    Nausea

    2.4

    2.8

    2.5

    Influenza

    2.3

    2.7

    2.3

    Dyslipidemia

    1.5

    2.1

    2.5

    Constipation

    1.5

    2.2

    1.9

    Discomfort with urination

    0.7

    1.6

    2.1

    Pain in extremity

    1.4

    2.0

    1.7

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

    FARXIGA 10 mg was also evaluated in a larger placebo-controlled study pool. This pool combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with 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 reductions in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) for the 12-study and 13-study, short-term, placebo-controlled pools and for the DECLARE study are shown in Table 2 [see Warnings and Precautions (5.1)].

    Table 2: Adverse Reactions of Volume Depletion* in Clinical Studies with FARXIGA
  • * Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.
    		•

    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

    (0.9%)

    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 [see Clinical Studies (14.1)] is shown in Table 3. Hypoglycemia was more frequent when FARXIGA was added to sulfonylurea or insulin [see Warnings and Precautions (5.5)].

    Table 3: Incidence of Severe Hypoglycemia* and Hypoglycemia with Glucose < 54 mg/dL† in Controlled Clinical Studies
    Placebo/Active ControlFARXIGA 5 mgFARXIGA 10 mg
  • * Severe 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.
  • † Episodes 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.
  • ‡ OAD = oral antidiabetic therapy
    		•

    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‡ (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

    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 1). 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. Across the clinical program, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of 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 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 FARXIGA causes an increase in serum creatinine and decrease in eGFR. In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline at Week 24. Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 ml/min/1.73 m2) [see Warnings and Precautions (5.3) and Mechanism of Action (12.1)].

    Increase in Hematocrit

    In the pool of 13 placebo-controlled studies, 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, 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 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 (5.2)].

    6.2 Postmarketing Experience

    Additional adverse reactions have been identified during postapproval use of FARXIGA. 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.

    • Ketoacidosis
    • Acute Kidney Injury
    • Urosepsis and Pyelonephritis
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
    • Rash
  • 7 DRUG INTERACTIONS

    7.1 Positive Urine Glucose Test

    Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.

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

    Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

  • 8 USE IN SPECIFIC POPULATIONS

    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 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 are 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. 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 had adverse reactions of hypotension [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

    8.6 Renal Impairment

    Use of FARXIGA is not recommended when eGFR is less than 45 mL/min/1.73 m2 [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)] and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or ESRD [see Contraindications (4)].

    FARXIGA was evaluated in two glycemic control studies that included patients 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). The safety profile of FARXIGA in the study of patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 was similar to the general population of patients with type 2 diabetes. Although patients in the FARXIGA arm had reduction in eGFR compared to the placebo arm, eGFR generally returned towards baseline after treatment discontinuation. Patients with renal impairment using FARXIGA for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury. 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.

    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 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.

  • 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 lowers the renal threshold for glucose, and thereby increases 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.

    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)].

    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)

    Farxiga 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%, 2.04-fold, and 3.03-fold higher, respectively, as compared to patients with type 2 diabetes with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than patients with type 2 diabetes with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see Dosage and Administration (2.2), Warnings and Precautions (5.3), 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 4 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin. No dose adjustments are recommended for dapagliflozin.

    Table 4: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure
    Coadministered Drug
    (Dose Regimen)*    		Dapagliflozin
    (Dose Regimen)*    		Effect on Dapagliflozin Exposure
    (% Change [90% CI])
    CmaxAUC†
  • * Single dose unless otherwise noted.
  • † 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 5 shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.

    Table 5: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs
    Coadministered Drug
    (Dose Regimen)*    		Dapagliflozin
    (Dose Regimen)*    		Effect on Coadministered Drug Exposure
    (% Change [90% CI])
    CmaxAUC†
  • * Single dose unless otherwise noted.
  • † 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

    Overview of Clinical Studies of FARXIGA for Type 2 Diabetes

    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 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 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 6).

    Table 6: Results at Week 24 (LOCF*) in a Placebo-Controlled Study of FARXIGA Monotherapy in Patients with Type 2 Diabetes (Main Cohort AM Doses)
    Efficacy ParameterFARXIGA 10 mg
    N=70†    		FARXIGA 5 mg
    N=64†    		Placebo
    N=75†
  • * 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. Sensitivity analyses yielded smaller estimates of treatment difference with placebo.
  • Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints.
    		•

    HbA1c (%)

      Baseline (mean)

    8.0

    7.8

    7.8

      Change from baseline (adjusted mean‡)

    −0.9

    −0.8

    −0.2

      Difference from placebo (adjusted mean‡)
      (95% CI)

    −0.7§
    (−1.0, −0.4)

    −0.5
    (−0.8, −0.2)

      Percent of patients achieving HbA1c <7%
      adjusted for baseline

    50.8%

    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 (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 7 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 noninferior to metformin XR monotherapy in lowering HbA1c.

    Table 7: Results at Week 24 (LOCF*) in an Active-Controlled Study of FARXIGA Initial Combination Therapy with Metformin XR
    Efficacy ParameterFARXIGA
    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.
  • Noninferior 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

    FARXIGA 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 8).

    Table 8: Results at Week 24 (LOCF*) in an Active-Controlled Study of FARXIGA Initial Combination Therapy with Metformin XR
    Efficacy ParameterFARXIGA
    5 mg
    + Metformin XR    		FARXIGA
    5 mg    		Metformin XR
    N=194†N=203†N=201†
  • * 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.
    		•

    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 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 9 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 9: Results of a 24-Week (LOCF*) Placebo-Controlled Study of FARXIGA in Add-On Combination with Metformin
    Efficacy ParameterFARXIGA 10 mg
    + Metformin
    N=135†    		FARXIGA 5 mg
    + Metformin
    N=137†    		Placebo
    + Metformin
    N=137†
  • * 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.
    		•

    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

    FARXIGA Figure 3

    Active Glipizide-Controlled Study Add-On to Metformin

    A total of 816 patients with type 2 diabetes with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, noninferiority study to evaluate 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 noninferiority (see Table 10). 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 10: Results at Week 52 (LOCF*) in an Active-Controlled Study Comparing FARXIGA to Glipizide as Add-On to Metformin
    Efficacy ParameterFARXIGA
    + Metformin
    N=400†    		Glipizide
    + Metformin
    N=401†
  • * LOCF: last observation carried forward.
  • † Randomized and treated patients with baseline and at least 1 postbaseline efficacy measurement.
  • ‡ Least squares mean adjusted for baseline value.
  • § Noninferior to glipizide + metformin.
  • p-value <0.0001.
    		•

    HbA1c (%)

      Baseline (mean)

    7.7

    7.7

      Change from baseline (adjusted mean‡)

    -0.5

    -0.5

      Difference from glipizide + metformin (adjusted mean‡)
      (95% CI)

    0.0§
    (-0.1, 0.1)

    Body Weight (kg)

      Baseline (mean)

    88.4

    87.6

      Change from baseline (adjusted mean‡)

    -3.2

    1.4

      Difference from glipizide + metformin (adjusted mean‡)
      (95% CI)

    -4.7
    (-5.1, -4.2)

    Add-On Combination Therapy with Other Antidiabetic Agents

    Add-On Combination Therapy with a Sulfonylurea

    A total of 597 patients with type 2 diabetes 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 11). 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 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 11). A statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with metformin and a sulfonyl urea 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 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 11) 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 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 11). 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 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 11); 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 11: Results of 24-Week (LOCF*) Placebo-Controlled Studies of FARXIGA in Combination with Antidiabetic Agents
    Efficacy ParameterFARXIGA 10 mgFARXIGA 5 mgPlacebo
  • * LOCF: last observation (prior to rescue for rescued patients) carried forward.
  • † Randomized and treated patients with baseline and at least 1 post baseline efficacy measurement.
  • ‡ Least squares mean adjusted for baseline value based on an ANCOVA model.
  • § p-value <0.0001 versus placebo.
  • 2-hour PPG level as a response to a 75-gram oral glucose tolerance test (OGTT).
  • # Least squares mean adjusted for baseline value based on a longitudinal repeated measures model.
  • Þ All randomized patients who took at least one dose of double-blind study medication during the short-term, double-blind period.
  • ß p-value <0.05 versus placebo.
  • à NT: Not formally tested because of failing to achieve a statistically significant difference in an endpoint that was earlier in the testing sequence.
    		•

    In Combination with Sulfonylurea (Glimepiride)

    Intent-to-Treat Population

    N=151†

    N=142†

    N=145†

    HbA1c (%)

    Baseline (mean)

    8.1

    8.1

    8.2

    Change from baseline (adjusted mean‡)

    -0.8

    -0.6

    -0.1

    Difference from placebo (adjusted mean‡)
    (95% CI)

    -0.7§

    (-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 (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‡#)

    -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=140Þ

    N=141Þ

    N=139Þ

    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%ß

    32.5%ß

    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

    NTà

    170.0

    Change from baseline (adjusted mean‡)

    -21.7

    NTà

    3.3

    Difference from placebo (adjusted mean‡)

    (95% CI)

    -25.0§

    (-34.3, -15.8)

    NTà

    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 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 and Moderate Renal Impairment

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

    Patients with type 2 diabetes 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 12).

    Table 12: Results at Week 24 of Placebo-Controlled Study for FARXIGA in Patients with Type 2 Diabetes and Renal Impairment (eGFR 45 to less than 60 mL/min/1.73 m2)
    FARXIGA 10 mgPlacebo
    Number of patients:N=160N=161
  • * Least 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.
  • † p-value =0.008 versus placebo.
    		•

    HbA1c (%)

    Baseline (mean)

    8.3

    8.0

    Change from baseline (adjusted mean*)

    -0.4

    -0.1

    Difference from placebo (adjusted mean*)

      (95% CI)

    -0.3†

    (-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 CV outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either established CVD 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 CVD and 10186 (59.4%) did not have established CVD. 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 diabetic 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 to test for superiority on the dual primary endpoints: the composite of hospitalization for heart failure or CV death, and MACE, if non-inferiority was demonstrated.

    The incidence rate of MACE was similar in both treatment arms: 2.3 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 95.38% confidence interval of (0.84,1.03). The upper bound of this confidence interval, 1.03, excluded a risk margin larger than 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 13 and Figures 4 and 5).

    Table 13: Treatment Effects for the Primary Endpoints* and Their Components* in the DECLARE Study
  • * Full analysis set.
  • † p-value =0.005 versus placebo.
  • ‡ total number of events presented for each component of the composite endpoints
    		•

    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†

    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 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

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

    Figure 5
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Product: 50090-3481

    NDC: 50090-3481-0 30 TABLET, FILM COATED in a BOTTLE, PLASTIC

    Product: 50090-3482

    NDC: 50090-3482-0 30 TABLET, FILM COATED in a BOTTLE, PLASTIC

  • 17 PATIENT COUNSELING INFORMATION

    Advise the patient to read the FDA-approved patient labeling (Medication Guide).

    Hypotension

    Inform patients that symptomatic hypotension may occur with FARXIGA and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.1)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

    Ketoacidosis

    Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of FARXIGA. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness and labored breathing) occur, instruct patients to discontinue FARXIGA and seek medical advice immediately [see Warnings and Precautions (5.2)].

    Acute Kidney Injury

    Inform patients that acute kidney injury has been reported during use of FARXIGA. Advise patients to seek medical advice immediately if they have reduced oral intake (due to acute illness or fasting) or increased fluid losses (due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue FARXIGA use in those settings [see Warnings and Precautions (5.3)].

    Serious Urinary Tract Infections

    Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.4)].

    Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

    Inform patients that necrotizing infections of the perineum (Fournier’s Gangrene) have occurred with FARXIGA. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.6)].

    Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

    Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)].

    Genital Mycotic Infections in Males (e.g., Balanitis)

    Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)].

    Hypersensitivity Reactions

    Inform patients that serious hypersensitivity reactions (e.g., urticarial, anaphylactic reactions, and angioedema) have been reported with FARXIGA. Advise patients to immediately report any signs or symptoms suggesting allergic reaction or angioedema, and to take no more of the drug until they have consulted prescribing physicians.

    Pregnancy

    Advise pregnant patients of the potential risk to a fetus with treatment with FARXIGA. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see Use in Specific Populations (8.1)].

    Lactation

    Advise patients that use of FARXIGA is not recommended while breastfeeding [see Use in Specific Populations (8.2)].

    Laboratory Tests

    Due to its mechanism of action, patients taking FARXIGA will test positive for glucose in their urine.

    Missed Dose

    If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of FARXIGA at the same time.

     

  • SPL UNCLASSIFIED SECTION

    Distributed by:
    AstraZeneca Pharmaceuticals LP
    Wilmington, DE 19850

    FARXIGA® is a registered trademark of the AstraZeneca group of companies.

  • MEDICATION GUIDE

    MEDICATION GUIDE
    FARXIGA® (FAR-SEE-GUH)
    (dapagliflozin)
    tablets, for oral use

    What is the most important information I should know about FARXIGA?

    FARXIGA can cause serious side effects, including:

    • Dehydration. FARXIGA can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). You may be at a higher risk of dehydration if you:
      • ∘ have low blood pressure
      • ∘ take medicines to lower your blood pressure, including water pills (diuretics)
      • ∘ are 65 years of age or older
      • ∘ are on a low salt diet
      • ∘ have kidney problems
    • Vaginal yeast infection. Women who take FARXIGA may get vaginal yeast infections. Symptoms of a vaginal yeast infection include:
      • ∘ vaginal odor
      • ∘ white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)
      • ∘ vaginal itching
    • Yeast infection of the penis (balanitis). Men who take FARXIGA may get a yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:
      • ∘ redness, itching, or swelling of the penis
      • ∘ rash of the penis
      • ∘ foul smelling discharge from the penis
      • ∘ pain in the skin around the penis

    Talk to your healthcare provider about what to do if you get symptoms of a yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medication and your symptoms do not go away.

    What is FARXIGA?

    FARXIGA is a prescription medicine used in adults with type 2 diabetes to:

    • improve blood sugar (glucose) control along with diet and exercise
    • reduce the risk of hospitalization for heart failure

    FARXIGA is not for people with type 1 diabetes.

    FARXIGA is not for people with diabetic ketoacidosis (increased ketones in your blood or urine).

    It is not known if FARXIGA is safe and effective in children younger than 18 years of age.

    Who should not take FARXIGA?

    Do not take FARXIGA if you:

    • are allergic to dapagliflozin or any of the ingredients in FARXIGA. See the end of this Medication Guide for a list of ingredients in FARXIGA. Symptoms of a serious allergic reaction to FARXIGA may include:
      • ∘ skin rash
      • ∘ raised red patches on your skin (hives)
      • ∘ swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing.
    •   If you have any of these symptoms, stop taking FARXIGA and contact your healthcare provider or go to the nearest hospital emergency room right away.
    • have severe kidney problems or are on dialysis.

    What should I tell my healthcare provider before taking FARXIGA?

    Before you take FARXIGA, tell your healthcare provider if you:

    • have type 1 diabetes or have had diabetic ketoacidosis.
    • have kidney problems.
    • have liver problems.
    • have a history of urinary tract infections or problems urinating.
    • are going to have surgery.
    • are eating less due to illness, surgery or a change in your diet.
    • have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.
    • drink alcohol very often, or drink a lot of alcohol in the short term (“binge” drinking).
    • are pregnant or plan to become pregnant. FARXIGA may harm your unborn baby. If you become pregnant while taking FARXIGA, your healthcare provider may switch you to a different medicine to control your blood sugar. Talk to your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.
    • are breastfeeding or plan to breastfeed. It is not known if FARXIGA passes into your breast milk. You should not breastfeed if you take FARXIGA.

    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    How should I take FARXIGA?

    • Take FARXIGA exactly as your healthcare provider tells you to take it.
    • Do not change your dose of FARXIGA without talking to your healthcare provider.
    • Take FARXIGA by mouth 1 time each day, with or without food.
    • When your body is under some types of stress, such as fever, trauma (such as a car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare provider’s instructions.
    • Stay on your prescribed diet and exercise program while taking FARXIGA.
    • FARXIGA will cause your urine to test positive for glucose.
    • Your healthcare provider may do certain blood tests before you start FARXIGA and during your treatment.
    • Your healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your HbA1c.
    • Follow your healthcare provider’s instructions for treating low blood sugar (hypoglycemia). Talk to your healthcare provider if low blood sugar is a problem for you.
    • If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take 2 doses of FARXIGA at the same time.
    • If you take too much FARXIGA, call your healthcare provider or go to the nearest emergency room right away.

    What are the possible side effects of FARXIGA?

    FARXIGA may cause serious side effects, including:

    See “What is the most important information I should know about FARXIGA?”

    • Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes, during treatment with FARXIGA. Ketoacidosis is a serious condition, which may need to be treated in a hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with FARXIGA even if your blood sugar is less than 250 mg/dL. Stop taking FARXIGA and call your healthcare provider right away if you get any of the following symptoms:
    • ∘ nausea
    • ∘ vomiting
    • ∘ stomach area (abdominal) pain
    • ∘ tiredness
    • ∘ trouble breathing
    •   If you get any of these symptoms during treatment with FARXIGA, if possible check for ketones in your urine, even if your blood sugar is less than 250 mg/dL.
    • Kidney problems. Sudden kidney injury has happened to people taking FARXIGA. Call your healthcare provider right away if you:
      • ∘ reduce the amount of food or liquid you drink, for example, if you are sick and cannot eat or
      • ∘ you start to lose liquids from your body, for example, from vomiting, diarrhea or being in the sun too long.
    • Serious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking FARXIGA. Tell your healthcare provider if you have any signs or symptoms of a urinary tract infection such as a burning feeling when passing urine, a need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting.
    • Low blood sugar (hypoglycemia). If you take FARXIGA with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take FARXIGA. Signs and symptoms of low blood sugar may include:
    • ∘ headache
    • ∘ shaking or feeling jittery
    • ∘ irritability
    • ∘ fast heartbeat
    • ∘ weakness
    • ∘ drowsiness
    • ∘ sweating
    • ∘ confusion
    • ∘ dizziness
    • ∘ hunger
    • A rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take FARXIGA. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired, or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals:
    • ∘ pain or tenderness
    • ∘ swelling
    • ∘ redness of skin (erythema)

    The most common side effects of FARXIGA include:

    • vaginal yeast infections and yeast infections of the penis
    • stuffy or runny nose and sore throat
    • changes in urination, including urgent need to urinate more often, in larger amounts, or at night

    These are not all the possible side effects of FARXIGA. For more information, ask your healthcare provider or pharmacist.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    How should I store FARXIGA?

    Store FARXIGA at room temperature between 68°F to 77°F (20°C to 25°C).

    General information about the safe and effective use of FARXIGA

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use FARXIGA for a condition for which it is not prescribed. Do not give FARXIGA to other people, even if they have the same symptoms you have. It may harm them.

    This Medication Guide summarizes the most important information about FARXIGA. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about FARXIGA that is written for healthcare professionals.

    For more information about FARXIGA, go to www.farxiga.com or call 1-800-236-9933.

    What are the ingredients in FARXIGA?

    Active ingredient: dapagliflozin.

    Inactive ingredients: microcrystalline cellulose, anhydrous lactose, crospovidone, silicon dioxide, and magnesium stearate. The film coating contains: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and yellow iron oxide.


    Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850

    FARXIGA is a registered trademark of the AstraZeneca group of companies.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.        Revised 10/2019

  • DAPAGLIFLOZIN

    Label Image
  • DAPAGLIFLOZIN

    Label Image
  • INGREDIENTS AND APPEARANCE
    FARXIGA 
    dapagliflozin tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 50090-3481(NDC:0310-6210)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DAPAGLIFLOZIN PROPANEDIOL (UNII: 887K2391VH) (DAPAGLIFLOZIN - UNII:1ULL0QJ8UC) DAPAGLIFLOZIN10 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    anhydrous lactose (UNII: 3SY5LH9PMK)  
    CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK)  
    silicon dioxide (UNII: ETJ7Z6XBU4)  
    magnesium stearate (UNII: 70097M6I30)  
    Product Characteristics
    ColorYELLOWScoreno score
    ShapeDIAMOND (biconvenx) Size11mm
    FlavorImprint Code 10;1428
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 50090-3481-030 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product06/15/2018
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20229301/14/2008
    FARXIGA 
    dapagliflozin tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 50090-3482(NDC:0310-6205)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DAPAGLIFLOZIN PROPANEDIOL (UNII: 887K2391VH) (DAPAGLIFLOZIN - UNII:1ULL0QJ8UC) DAPAGLIFLOZIN5 mg
    Inactive Ingredients
    Ingredient NameStrength
    MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
    anhydrous lactose (UNII: 3SY5LH9PMK)  
    CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK)  
    silicon dioxide (UNII: ETJ7Z6XBU4)  
    magnesium stearate (UNII: 70097M6I30)  
    Product Characteristics
    ColorYELLOWScoreno score
    ShapeROUND (biconvex) Size7mm
    FlavorImprint Code 5;1427
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 50090-3482-030 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product06/15/2018
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA20229301/14/2008
    Labeler - A-S Medication Solutions (830016429)
    Establishment
    NameAddressID/FEIBusiness Operations
    A-S Medication Solutions830016429RELABEL(50090-3481, 50090-3482)

    • Trademark Results [FARXIGA]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    FARXIGA
    FARXIGA
    88639033 not registered Live/Pending
    AstraZeneca AB
    2019-10-02
    FARXIGA
    FARXIGA
    86049285 4638205 Live/Registered
    Bristol-Myers Squibb Company
    2013-08-27
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