DAPAGLIFLOZIN

1 INDICATIONS AND USAGE Dapagliflozin tablets are indicated: To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established CV disease or multiple CV risk factors. As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1) ]. Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2 . Dapagliflozin tablets are likely to be ineffective in this setting based upon its mechanism of action. Pediatric use information is approved for AstraZeneca AB's Farxiga ® (dapagliflozin) Tablets. However, due to AstraZeneca AB's marketing exclusivity rights, this drug product is not labeled with that information. Dapagliflozin tablets are a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated: To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established CV disease or multiple CV risk factors. ( 1 ) As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 ) Not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2 . Dapagliflozin tablets are likely to be ineffective in this setting based upon its mechanism of action. ( 1 )

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions ( 5.1 )] Volume Depletion [see Warnings and Precautions ( 5.2 )] Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections [see Warnings and Precautions ( 5.3 )] Hypoglycemia with Concomitant Use with Insulin and Insulin Secret agogues [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Florida Pharmaceutical Products, LLC at 1-800-315-0985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Dapagliflozin has been evaluated in clinical trials in adult patients with type 2 diabetes mellitus. The overall safety profile of dapagliflozin was consistent across the studied indications. Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus. Clinical Trials for Glycemic Control in Adult Patients with Type 2 Diabetes Mellitus Pool of 12 Placebo-Controlled Adult Trials for Dapagliflozin tablets 5 and 10 mg for Glycemic Control The data in Table 1 is derived from 12 glycemic control placebo-controlled trials in adult patients with type 2 diabetes mellitus ranging from 12 to 24 weeks. In 4 trials dapagliflozin tablets was used as monotherapy, and in 8 trials dapagliflozin tablets 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 adult patients to dapagliflozin tablets with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin tablets 5 mg (N=1145), or dapagliflozin tablets 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 m 2 ). Table 1 shows common adverse reactions in adults associated with the use of dapagliflozin tablets. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin tablets than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin tablets 5 mg or dapagliflozin tablets 10 mg. Table 1: Adverse Reactions in Placebo-Controlled Trials of Glycemic Control Reported in ≥2% of Adults Treated with Dapagliflozin Tablets Adverse Reaction % of Patients Pool of 12 Placebo-Controlled Trials Placebo Dapagliflozin Tablets 5 mg Dapagliflozin Tablets 10 mg N=1393 N=1145 N=1193 Female genital mycotic infections Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin tablets 5 mg=581, dapagliflozin tablets 10 mg=598). 1.5 8.4 6.9 Nasopharyngitis 6.2 6.6 6.3 Urinary tract infections 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. 3.7 5.7 4.3 Back pain 3.2 3.1 4.2 Increased urination Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. 1.7 2.9 3.8 Male genital mycotic infections 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, dapagliflozin tablets 5 mg=564, dapagliflozin tablets 10 mg=595). 0.3 2.8 2.7 Nausea 2.4 2.8 2.5 Influenza 2.3 2.7 2.3 Dyslipidemia 1.5 2.1 2.5 Constipation 1.5 2.2 1.9 Discomfort with urination 0.7 1.6 2.1 Pain in extremity 1.4 2.0 1.7 Pool of 13 Placebo-Controlled Adult Trials for Dapagliflozin Tablets 10 mg for Glycemic Control Dapagliflozin tablets 10 mg was also evaluated in a larger glycemic control placebo-controlled trial pool in adult patients with type 2 diabetes mellitus. This pool combined 13 placebo-controlled trials, including 3 monotherapy trials, 9 add-on to background antidiabetic therapy trials, and an initial combination with metformin trial. Across these 13 trials, 2360 patients were treated once daily with dapagliflozin tablets 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 m 2 ). Other Adverse Reactions in Adult Patients with Type 2 Diabetes Mellitus Volume Depletion Dapagliflozin tablets causes an osmotic diuresis, which may lead to a reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) in adult patients with type 2 diabetes mellitus for the 12-trial and 13-trial, short-term, placebo-controlled pools and for the DECLARE trial are shown in Table 2 [see Warnings and Precautions ( 5.2 )] . Table 2: Adverse Reactions Related to Volume Depletion Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. in Clinical Trials in Adults with Type 2 Diabetes Mellitus with Dapagliflozin Tablets Pool of 12 Placebo-Controlled Trials Pool of 13 Placebo- Controlled Trials DECLARE Trial Placebo Dapagliflozin Tablets 5 mg Dapagliflozin Tablets 10 mg Placebo Dapagliflozin Tablets 10 mg Placebo Dapagliflozin Tablets 10 mg Overall N=1393 N=1145 N=1193 N=2295 N=2360 N=8569 N=8574 population N (%) 5 7 9 17 27 207 213 (0.4%) (0.6%) (0.8%) (0.7%) (1.1%) (2.4%) (2.5%) Patient Subgroup n (%) Patients on loop n=55 n=40 n=31 n=267 n=236 n=934 n=866 diuretics 1 0 3 4 6 57 57 (1.8%) (9.7%) (1.5%) (2.5%) (6.1%) (6.6%) Patients with n=107 n=107 n=89 n=268 n=265 n=658 n=604 moderate renal 2 1 1 4 5 30 35 impairment with (1.9%) (0.9%) (1.1%) (1.5%) (1.9%) (4.6%) (5.8%) eGFR ≥30 and <60 mL/min/1.73 m 2 Patients ≥65 years n=276 n=216 n=204 n=711 n=665 n=3950 n=3948 of age 1 1 3 6 11 121 117 (0.4%) (0.5%) (1.5%) (0.8%) (1.7%) (3.1%) (3.0%) Hypoglycemia The frequency of hypoglycemia by trial in adult patients with type 2 diabetes mellitus [see Clinical Studies ( 14.1 )] is shown in Table 3. Hypoglycemia was more frequent when dapagliflozin tablets was added to sulfonylurea or insulin [see Warnings and Precautions ( 5.4 )] . Table 3: Incidence of Severe Hypoglycemia 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. and Hypoglycemia with Glucose <54 mg/dL 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. in Controlled Glycemic Control Clinical Trials in Adults with Type 2 Diabetes Mellitus Placebo/Active Control Dapagliflozin Tablets 5 mg Dapagliflozin Tablets 10 mg Monotherapy (24 weeks) N=75 N=64 N=70 Severe [n (%)] 0 0 0 Glucose <54 mg/dL [n (%)] 0 0 0 Add-on to Metformin (24 weeks) N=137 N=137 N=135 Severe [n (%)] 0 0 0 Glucose <54 mg/dL [n (%)] 0 0 0 Add-on to Glimepiride (24 weeks) N=146 N=145 N=151 Severe [n (%)] 0 0 0 Glucose <54 mg/dL [n (%)] 1 (0.7) 3 (2.1) 5 (3.3) Add-on to Metformin and a Sulfonylurea (24 Weeks) N=109 - N=109 Severe [n (%)] 0 - 0 Glucose <54 mg/dL [n (%)] 3 (2.8) - 7 (6.4) Add-on to Pioglitazone (24 weeks) N=139 N=141 N=140 Severe [n (%)] 0 0 0 Glucose <54 mg/dL [n (%)] 0 1 (0.7) 0 Add-on to DPP4 inhibitor (24 weeks) N=226 – N=225 Severe [n (%)] 0 – 1 (0.4) Glucose <54 mg/dL [n (%)] 1 (0.4) – 1 (0.4) Add-on to Insulin with or without other OADs OAD = oral antidiabetic therapy. (24 weeks) N=197 N=212 N=196 Severe [n (%)] 1 (0.5) 2 (0.9) 2 (1.0) Glucose <54 mg/dL [n (%)] 43 (21.8) 55 (25.9) 45 (23.0) In the DECLARE trial [see Clinical Studies ( 14.3 )] , severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 adult patients treated with dapagliflozin tablets and 83 (1.0%) out of 8569 adult patients treated with placebo. Genital Mycotic Infections In the glycemic control trials in adults, genital mycotic infections were more frequent with dapagliflozin tablets treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin tablets 5 mg, and 4.8% on dapagliflozin tablets 10 mg, in the 12-trial placebo-controlled pool. Discontinuation from trial due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin tablets 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 trial than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin tablets 5 mg, and dapagliflozin tablets 10 mg, respectively). In the DECLARE trial [see Clinical Studies ( 14.3 )] , serious genital mycotic infections were reported in <0.1% of patients treated with dapagliflozin tablets and <0.1% of patients treated with placebo. Genital mycotic infections that caused trial drug discontinuation were reported in 0.9% of patients treated with dapagliflozin tablets and <0.1% of patients treated with placebo. Hypersensitivity Reactions Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin tablets treatment. In glycemic control trials in adults, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of dapagliflozin tablets -treated patients. If hypersensitivity reactions occur, discontinue use of dapagliflozin tablets; treat per standard of care and monitor until signs and symptoms resolve. Ketoacidosis in Patients with Diabetes Mellitus In the DECLARE trial [see Clinical Studies ( 14.3 )] , events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 adult patients in the dapagliflozin tablets -treated group and 12 out of 8569 adult patients in the placebo group. The events were evenly distributed over the trial period. Laboratory Tests in Adult Patients with Type 2 Diabetes Mellitus Increases in Serum Creatinine and Decreases in eGFR Initiation of SGLT2 inhibitors, including dapagliflozin tablets causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions ( 5.2 )] . In two trials that included adult patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with dapagliflozin tablets. Increase in Hematocrit In the pool of 13 placebo-controlled trials of glycemic control, increases from baseline in mean hematocrit values were observed in dapagliflozin tablets -treated adult patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and 2.30% in the dapagliflozin tablets 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin tablets 10 mg-treated patients. Increase in Low-Density Lipoprotein Cholesterol In the pool of 13 placebo-controlled trials of glycemic control, changes from baseline in mean lipid values were reported in dapagliflozin tablets -treated adult 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 dapagliflozin tablets 10 mg groups, respectively. In the DECLARE trial [see Clinical Studies ( 14.3 )] , 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 dapagliflozin tablets -treated and the placebo groups, respectively. Decrease in Serum Bicarbonate In a trial of concomitant therapy of dapagliflozin tablets 10 mg with exenatide extended-release (on a background of metformin) in adults, 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 dapagliflozin tablets and exenatide-extended release treatment groups [see Warnings and Precautions ( 5.1 )] . Pediatric use information is approved for AstraZeneca AB's Farxiga ® (dapagliflozin) Tablets. However, due to AstraZeneca AB's marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of dapagliflozin tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: Necrotizing fasciitis of the perineum (Fournier's Gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis Renal and Urinary Disorders: Acute kidney injury Skin and Subcutaneous Tissue Disorders: Rash