openFDA 收录的达格列净片（dapagliflozin，Farxiga 仿制药）常规说明书全文更新，为标签文本记录而非任何新增市场事件

['11 DESCRIPTION Dapagliflozin, an inhibitor of SGLT2, is described chemically as (2S,3R,4R,5S,6R)-2-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-6-(hydroxymethyl)oxane-3,4,5-triol. The molecular formula is C 21 H 25 ClO 6 and the molecular weight is 408.88. The structural formula is: Dapagliflozin tablets are available as a film-coated tablet for oral administration containing 5 mg dapagliflozin or 10 mg dapagliflozin, and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, crospovidone, microcrystalline cellulose, sodium lauryl sulfate, sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: iron oxide yellow, polyethylene glycol 3350, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.']

['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 (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 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 (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 )']

['4 CONTRAINDICATIONS Dapagliflozin is contraindicated in patients with a history of a serious hypersensitivity reaction to dapagliflozin or any of the excipients in dapagliflozin. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin [see Adverse Reactions ( 6.1 )] . History of serious hypersensitivity reaction to dapagliflozin or any of the excipients in dapagliflozin. ( 4 )']

['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 Secretagogues [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 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 <60 mL/min/1.73 m 2 n=107 2 (1.9%) n=107 1 (0.9%) n=89 1 (1.1%) n=268 4 (1.5%) n=265 5 (1.9%) n=658 30 (4.6%) n=604 35 (5.8%) Patients ≥65 years of age n=276 1 (0.4%) n=216 1 (0.5%) n=204 3 (1.5%) n=711 6 (0.8%) n=665 11 (1.7%) n=3950 121 (3.1%) n=3948 117 (3.0%) * Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. 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 was added to sulfonylurea or insulin [see Warnings and Precautions ( 5.4 ) ] . Table 3: Incidence of Severe Hypoglycemia* and Hypoglycemia with Glucose <54 mg/dL† in Controlled Glycemic Control Clinical Trials in Adults with Type 2 Diabetes Mellitus Placebo/Active Control Dapagliflozin 5 mg Dapagliflozin 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 ‡ (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) * 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. 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 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 treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 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 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 5 mg, and dapagliflozin 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 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 and <0.1% of patients treated with placebo. Hypersensitivity Reactions Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin 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-treated patients. If hypersensitivity reactions occur, discontinue use of dapagliflozin; 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-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 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. 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-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 10 mg group. By Week 24, hematocrit values >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. 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 )']

['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 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 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 )] . 2.5 Recommendations Regarding Missed Dose If a dose is missed, instruct patients to take the dose as soon as possible. Advise patients not to double up the next dose.']

['12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity. 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 dosage of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases in urinary volume [see Adverse Reactions ( 6.1 )] . After discontinuation of dapagliflozin, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for the 10 mg dosage. 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) 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 (C max ) is usually attained within 2 hours under fasting state. The C max 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 C max by up to 50% and prolongs T max 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 [ 14 C]-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 [ 14 C]-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 (t 1/2 ) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg. Specific Populations 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. Patients with Renal Impairment At steady-state (20 mg once daily dapagliflozin for 7 days), adult patients with type 2 diabetes with mild, moderate, or severe renal impairment (as determined by eGFR) had geometric mean systemic exposures of dapagliflozin that were 45%, 100%, and 200% higher, respectively, as compared to patients with type 2 diabetes mellitus with normal renal function. Higher systemic exposure of dapagliflozin in patients with type 2 diabetes mellitus with renal impairment did not result in a correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type 2 diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 2 diabetes mellitus with normal renal function. The impact of hemodialysis on dapagliflozin exposure is not known [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.6 ), and Clinical Studies ( 14 )] . Patients with Hepatic Impairment In adult subjects with mild and moderate hepatic impairment (Child-Pugh classes A and B), mean C max 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 adult patients with severe hepatic impairment (Child-Pugh class C), mean C max 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 )] . 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 5 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin in adults. No dose adjustments are recommended for dapagliflozin. Table 5: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure Coadministered Drug (Dose Regimen) * Dapagliflozin (Dose Regimen) * Effect on Dapagliflozin Exposure [% Change (90% CI)] C max AUC† 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). * Single dose unless otherwise noted. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. Effects of Dapagliflozin on Other Drugs Table 6 shows the effect of dapagliflozin on other coadministered drugs in adults. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs. Table 6: 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)] C max AUC † 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). * Single dose unless otherwise noted. † AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. 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.']

['16 HOW SUPPLIED/STORAGE AND HANDLING Dapagliflozin 10 mg Tablets are yellow, oval, debossed with “TV” on one side and “1D” on the other side. NDC 71335-3176-1: 30 TABLETs in a BOTTLE NDC 71335-3176-2: 90 TABLETs in a BOTTLE 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]. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504']