dapagliflozin

1 INDICATIONS AND USAGE DAPAGLIFLOZIN TABLETS are indicated:

• To reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.
• To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure.
• To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.
• As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older 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 ] .
• DAPAGLIFLOZIN TABLETS are not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2 . DAPAGLIFLOZIN TABLETS are likely to be ineffective in this setting based upon its mechanism of action.
• DAPAGLIFLOZIN TABLETS are not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. DAPAGLIFLOZIN TABLETS are not expected to be effective in these DAPAGLIFLOZIN TABLETS a sodium-glucose cotransporter 2 (SGLT2) inhibitor, are indicated:
• To reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.
• To reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure.
• To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors.
• As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Limitations of use:
• Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.
• 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.
• Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for the treatment of kidney disease. DAPAGLIFLOZIN TABLETS are not expected to be effective in these populations.

• Assess renal function prior to initiation and then as clinically indicated. Assess volume status and correct volume depletion before initiating.
• 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.
• For all other indications, the recommended dosage is 10 mg orally once daily.
• See full prescribing information for dosage recommendations in patients with renal impairment.
• Withhold DAPAGLIFLOZIN TABLETS for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting.

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 ].
• Assess volume status. In patients with volume depletion, correct this condition before initiating DAPAGLIFLOZIN TABLETS [see Warnings and Precautions and Use in Specific Populations ] . 2. 2 Recommended Dosage for Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus In adults and pediatric patients aged 10 years and older 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 and Pediatric 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 is 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 is likely to be ineffective to improve glycemic control in this setting based upon its mechanism of action. 2.3 Recommended Dosage for Other Indications in Adults The recommended dosage of DAPAGLIFLOZIN TABLETS is 10 mg orally once daily in adults for the following indications:
• To reduce the risk of sustained eGFR decline, end stage kidney disease (ESKD), cardiovascular (CV) death, and hospitalization for heart failure (hHF) in patients with chronic kidney disease at risk of progression.
• To reduce the risk of CV death, hHF, and urgent heart failure visit in patients with heart failure.
• 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 Indications 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 .
• If the eGFR falls below 25 mL/min/1.73 m 2 while receiving treatment with DAPAGLIFLOZIN TABLETS, patients may continue DAPAGLIFLOZIN TABLETS 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death and hHF. 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 and Clinical Pharmacology ].

12.1 Mechanism of Action Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity, and decreased intraglomerular pressure which is believed to be mediated by increased tubuloglomerular feedback.

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 ]
• Volume Depletion [see Warnings and Precautions ]
• Urosepsis and Pyelonephritis [see Warnings and Precautions ]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ]
• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions ]
• Genital Mycotic Infections [see Warnings and Precautions ]
• Most common adverse reactions (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 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 and pediatric patients aged 10 years and older with type 2 diabetes mellitus, in adult patients with heart failure, and in adult patients with chronic kidney disease. The overall safety profile of dapagliflozin was consistent across the studied indications. No new adverse reactions were identified in the DAPA-HF and DELIVER heart failure trials, or in the DAPA-CKD trial in patients with chronic kidney disease. 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 ]. These data reflect exposure of 2338 adult patients to dapagliflozin with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin 5 mg (N=1145), or dapagliflozin 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. 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=1393 Dapagliflozin 5 mg N=1145 Dapagliflozin 10 mg 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 5 mg=581, dapagliflozin 10 mg=598). 1.5 8.4

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

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 5 mg=564, dapagliflozin 10 mg=595). 0.3 2.8

Nausea 2.4 2.8

Influenza 2.3 2.7

Dyslipidemia 1.5 2.1

Constipation 1.5 2.2

Discomfort with urination 0.7 1.6

Pain in extremity 1.4 2.0

1.7 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, 2360 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 ]. 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 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=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 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 ] , 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 ]. Clinical Trial in Pediatric Patients with Type 2 Diabetes Mellitus The dapagliflozin safety profile observed in a 26-week placebo-controlled clinical trial with a 26-week extension in 157 pediatric patients aged 10 years and older with type 2 diabetes mellitus was similar to that observed in adults [see Clinical Studies ]. 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

Table 4: Clinically Relevant Interactions with DAPAGLIFLOZIN TABLETS Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when DAPAGLIFLOZIN TABLETS are used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions ] . 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 TABLETS 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 TABLETS with laboratory tests.

• Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters.
• Lactation: Not recommended when breastfeeding.
• Geriatrics: Higher incidence of adverse reactions related to hypotension.
• Renal Impairment: Higher incidence of adverse reactions related to volume depletion. 8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, DAPAGLIFLOZIN TABLETS are not recommended during the second and third trimesters of pregnancy. Limited data with dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure in pregnancy (see Clinical Considerations ) . In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose ( see Data ). The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development. In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1441-times the 10 mg clinical dose, based on AUC). Dose-related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity. No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1191-times the 10 mg clinical dose, based on AUC). 8.2 Lactation Risk Summary There is no information regarding the presence of dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Dapagliflozin is present in the milk of lactating rats (see Data ) . However, due to species-specific differences in lactation physiology, the clinical relevance of these data is not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in breastfed infants, advise women that use of DAPAGLIFLOZIN TABLETS 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 The safety and effectiveness of DAPAGLIFLOZIN TABLETS as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients aged 10 years and older. Use of DAPAGLIFLOZIN TABLETS for this indication is supported by a 26-week placebo-controlled trial with a 26-week extension in 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus, pediatric pharmacokinetic data, and trials in adults with type 2 diabetes mellitus [see Clinical Pharmacology and Clinical Studies ] . The safety profile observed in the placebo-controlled trial in pediatric patients with type 2 diabetes mellitus was similar to that observed in adults [see Adverse Reactions ]. The safety and effectiveness of DAPAGLIFLOZIN TABLETS for glycemic control in type 2 diabetes mellitus have not been established in pediatric patients less than 10 years of age. The safety and effectiveness of DAPAGLIFLOZIN TABLETS have not been established in pediatric patients to reduce the risk of [see Indications and Usage ] :
• sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression.
• cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure.
• hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. 8.5 Geriatric Use No DAPAGLIFLOZIN TABLETS dosage change is recommended based on age. A total of 1424 (24%) of the 5936 dapagliflozin-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 trials assessing the efficacy of dapagliflozin in improving glycemic control in type 2 diabetes mellitus. After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin for glycemic control had adverse reactions of hypotension [see Warnings and Precautions and Adverse Reactions ] . In the DAPA-CKD, DAPA-HF and DELIVER trials, safety and efficacy were similar for patients aged 65 years and younger and those older than 65. In the DAPA-HF study, 2714 (57%) out of 4744 patients with HFrEF were older than 65 years. In the DELIVER study, 4759 (76%) out of 6263 patients with heart failure (LVEF >40%) were older than 65 years. In the DAPA-CKD study, 1818 (42%) out of 4304 patients with CKD were older than 65 years. 8.6 Renal Impairment Dapagliflozin was evaluated in 4304 adult patients with chronic kidney disease (eGFR 25 to 75 mL/min/1.73 m 2 ) in the DAPA-CKD trial. Dapagliflozin was also evaluated in 1926 adult patients with an eGFR of 30 to 60 mL/min/1.73 m 2 in the DAPA-HF trial. The safety profile of dapagliflozin across eGFR subgroups in these studies was consistent with the known safety profile [see Adverse Reactions and Clinical Studies ] . Dapagliflozin was evaluated in two glycemic control adult trials that included patients with type 2 diabetes mellitus with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m 2 [see Clinical Studies ] , and an eGFR of 30 to less than 60 mL/min/1.73 m 2 , respectively). Patients with diabetes and renal impairment using dapagliflozin may be more likely to experience hypotension and may be at higher risk for acute kidney injury secondary to volume depletion. In the trial of adult patients with an eGFR 30 to less than 60 mL/min/1.73 m 2 , 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo. Use of DAPAGLIFLOZIN TABLETS for glycemic control in patients without established CV disease or CV risk factors is not recommended when eGFR is less than 45 mL/min/1.73 m 2 [see Dosage and Administration ] . Efficacy and safety trials with dapagliflozin did not enroll patients with an eGFR less than 25 mL/min/1.73 m 2 or on dialysis. Once enrolled in the DAPA-CKD and DELIVER trials, adult patients were not required to discontinue therapy if eGFR fell below 25 mL/min/1.73 m 2 or if dialysis was initiated. Once enrolled in the DAPA-HF trial, adult patients were not required to discontinue therapy if eGFR fell below 30 mL/min/1.73 m 2 or if dialysis was initiated [see Dosage and Administration and Clinical Studies ]. 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 ] .