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 cardiovascular disease or multiple cardiovascular risk factors. As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use 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 is 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 cardiovascular disease or multiple cardiovascular risk factors. ( 1 ) As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 ) Not recommended for use to improve glycemic control in 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 )

2 DOSAGE AND ADMINISTRATION Assess renal function prior to initiation and then as clinically indicated. Assess volume status and correct volume depletion before initiating. ( 2.1 ) To improve glycemic control, the recommended starting dosage is 5 mg orally once daily. Dosage can be increased to 10 mg orally once daily for additional glycemic control. ( 2.2 ) To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. The recommended dosage is 10 mg orally once daily. ( 2.3 ) See full prescribing information for dosage recommendations in patients with renal impairment. ( 2.2 , 2.3 ) Withhold dapagliflozin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. ( 2.4 ) 2.1 Testing Prior to Initiation of Dapagliflozin Tablets Assess renal function prior to initiation of dapagliflozin tablets and then as clinically indicated [see Warnings and Precautions ( 5.2 )] . Assess volume status. In patients with volume depletion, correct this condition before initiating dapagliflozin tablets [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.5 , 8.6 )] . 2.2 Recommended Dosage for Glycemic Control in Adults with Type 2 Diabetes Mellitus In adults with type 2 diabetes mellitus, the recommended starting dosage of dapagliflozin tablets is 5 mg orally once daily to improve glycemic control. For additional glycemic control, the dosage can be increased to 10 mg orally once daily. For Adult Patients with Type 2 Diabetes Mellitus and Renal Impairment : The recommended dosage for dapagliflozin tablets in patients with an eGFR greater than or equal to 45 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function. 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 to improve glycemic control 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. 2.3 Recommended Dosage for Other Indication in Adults The recommended dosage of dapagliflozin tablets is 10 mg orally once daily in adults for the following indication: To reduce the risk of hHF in patients with type 2 diabetes mellitus and either established CV disease or multiple CV risk factors. For Adults with Renal Impairment Receiving Dapagliflozin Tablets for Indication Other than Glycemic Control: The recommended dosage of dapagliflozin tablets in patients with an eGFR greater than or equal to 25 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function. Initiation with dapagliflozin tablets is not recommended in patients with an eGFR less than 25 mL/min/1.73 m 2 . 2.4 Temporary Interruption for Surgery Withhold dapagliflozin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume dapagliflozin tablets when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.2 )] .

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 )] Urosepsis and Pyelonephritis [see Warnings and Precautions ( 5.3 )] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ( 5.4 )] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions ( 5.5 )] Genital Mycotic Infections [see Warnings and Precautions ( 5.6 )] 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 Teva at 1-888-838-2872 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 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 was used as monotherapy, and in 8 trials dapagliflozin 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 2,338 adult patients to dapagliflozin with a mean exposure duration of 21 weeks. Patients received placebo (N=1,393), dapagliflozin 5 mg (N=1,145), or dapagliflozin 10 mg (N=1,193) 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. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg. Table 1: Adverse Reactions in Placebo-Controlled Trials of Glycemic Control Reported in ≥2% of Adults Treated with Dapagliflozin Adverse Reaction % of Patients Pool of 12 Placebo-Controlled Trials Placebo N=1,393 Dapagliflozin 5 mg N=1,145 Dapagliflozin 10 mg N=1,193 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 * 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 5 mg=581, dapagliflozin 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, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595). Pool of 13 Placebo-Controlled Adult Trials for Dapagliflozin 10 mg for Glycemic Control Dapagliflozin 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, 2,360 patients were treated once daily with dapagliflozin 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 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* in Clinical Trials in Adults with Type 2 Diabetes Mellitus with Dapagliflozin Pool of 12 Placebo-Controlled Trials Pool of 13 Placebo- Controlled Trials DECLARE Trial Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg Overall population N (%) N=1,393 5 (0.4%) N=1,145 7 (0.6%) N=1,193 9 (0.8%) N=2,295 17 (0.7%) N=2,360 27 (1.1%) N=8,569 207 (2.4%) N=8,574 213 (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 55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 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-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 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-treated and the placebo groups, respectively. Decrease in Serum Bicarbonate In a trial of concomitant therapy of dapagliflozin 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 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 in patients with diabetes mellitus. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: Necrotizing fasciitis of the perineum (Fournier’s Gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis Renal and Urinary Disorders: Acute kidney injury Skin and Subcutaneous Tissue Disorders: Rash

7 DRUG INTERACTIONS Table 4: Clinically Relevant Interactions with Dapagliflozin Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when dapagliflozin is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions ( 5.4 )] . Intervention Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during dapagliflozin initiation and dosage changes. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. See full prescribing information for information on drug interactions and interference of dapagliflozin with laboratory tests. ( 7 )

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Dapagliflozin tablets have markings on both sides and are available in the strengths and packages listed in Table 18. Table 18: Dapagliflozin Tablet Presentations Tablet Strength Film-Coated Tablet Color/Shape Tablet Markings Package Size NDC Code 5 mg yellow, round debossed with “TV” on one side and “5D” on the other side Bottles of 30 Bottles of 90 Bottles of 500 0480-3527-56 0480-3527-98 0480-3527-05 10 mg yellow, oval debossed with “TV” on one side and “1D” on the other side Bottles of 30 Bottles of 90 Bottles of 500 0480-3528-56 0480-3528-98 0480-3528-05 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].