Dapagliflozin And Metformin Hydrochloride

1 INDICATIONS AND USAGE XIGDUO XR is a combination of dapagliflozin and metformin hydrochloride (HCl) extended-release, indicated 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. Dapagliflozin, when used as a component of XIGDUO XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: • 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 (CVD) or multiple cardiovascular (CV) risk factors. Limitations of Use • XIGDUO XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2) ] . • Because of the metformin HCl component, the use of XIGDUO XR is limited to patients with type 2 diabetes mellitus for all indications. • XIGDUO XR is 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. XIGDUO XR is not expected to be effective in these populations. XIGDUO XR is a combination of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated 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. ( 1 ) Dapagliflozin when used as a component of XIGDUO XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: • Sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. ( 1 ) • Cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in patients with heart failure. ( 1 ) • Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. ( 1 ) Limitations of use : • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 ) • Because of the metformin HCl component, the use of XIGDUO XR is limited to patients with type 2 diabetes mellitus for all indications. ( 1 ) • 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. XIGDUO XR is not expected to be effective in these populations. ( 1 )

2 DOSAGE AND ADMINISTRATION • Assess renal function prior to initiating and then as clinically indicated. ( 2.1 ) • Assess volume status and correct volume depletion before initiating. ( 2.1 ) • Individualize the starting dosage based on the patient’s current treatment. ( 2.3 ) • Administer orally once daily in the morning with food. ( 2.2 ) • To improve glycemic control, for patients aged 10 years and older not already taking dapagliflozin, the recommended starting dosage for dapagliflozin is 5 mg once daily. ( 2.3 ) • For indications in adults related to heart failure and chronic kidney disease the recommended dosage of dapagliflozin is 10 mg once daily. ( 2.3 ) • Do not exceed a daily dosage of 10 mg dapagliflozin/2,000 mg metformin HCl extended-release. ( 2.3 ) • See Full Prescribing Information for dosage recommendations in patients with renal impairment. ( 2.4 ) • XIGDUO XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.5 ) • Withhold XIGDUO XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 ) 2.1 Testing Prior to Initiation of XIGDUO XR • Assess renal function prior to initiating XIGDUO XR and then as clinically indicated [see Warnings and Precautions (5.1 , 5.3) ] . • Assess volume status. In patients with volume depletion, correct this condition before initiating XIGDUO XR [see Warnings and Precautions (5.3) and Use in Specific Populations (8.5 , 8.6)]. 2.2 Recommended Administration • Take XIGDUO XR orally once daily in the morning with food. • Swallow XIGDUO XR tablets whole and never crush, cut, or chew. 2.3 Recommended Dosage • Individualize the starting dosage of XIGDUO XR based upon the patient’s current regimen. Patients taking an evening dosage of metformin HCl extended‑release should skip their last dose before starting XIGDUO XR. • To improve glycemic control in adults and pediatric patients aged 10 years and older not already taking: ∘ Dapagliflozin: the recommended starting dosage of dapagliflozin in XIGDUO XR is 5 mg orally once daily. ∘ Metformin HCl extended‑release: the recommended starting dosage of metformin HCl extended‑release in XIGDUO XR is 500 mg orally once daily. • For XIGDUO XR indications in adults related to heart failure and chronic kidney disease, the recommended dosage of dapagliflozin in XIGDUO XR is 10 mg orally once daily. • For all XIGDUO XR indications, the dosage may be adjusted based on effectiveness and tolerability. The maximum recommended daily dosage of dapagliflozin is 10 mg and 2,000 mg of metformin HCl extended‑release, with gradual dosage escalation to reduce gastrointestinal adverse reactions with metformin HCl [see Adverse Reactions (6.1) ] . 2.4 Recommended Dosage in Patients with Renal Impairment • The recommended dosage of XIGDUO XR in patients with an estimated glomerular filtration rate (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. • Initiation of XIGDUO XR is not recommended in patients with an eGFR between 30 and 45 mL/min/1.73 m 2 . Assess the benefit and risk of continuing therapy if eGFR falls persistently below this level. ∘ Dapagliflozin is likely to be ineffective to improve glycemic control in patients with eGFR less than 45 mL/min/1.73 m 2 . ∘ Metformin HCl initiation is not recommended for patients with eGFR less than 45 mL/min/1.73 m 2 . • XIGDUO XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2 and end‑stage renal disease due to the metformin HCl component [ see Contraindications (4) , Warnings and Precautions (5.1 , 5.2) , and Use in Specific Populations (8.6) ] . 2.5 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m 2 , in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart XIGDUO XR if renal function is stable [see Warnings and Precautions (5.1) ] . 2.6 Temporary Interruption for Surgery Withhold XIGDUO XR for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume XIGDUO XR when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] .

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: • Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1) ] • Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions (5.2) ] • Volume Depletion [see Warnings and Precautions (5.3) ] • Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4) ] • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5) ] • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions (5.6) ] • Vitamin B 12 Concentrations [see Warnings and Precautions (5.7) ] • Genital Mycotic Infections [see Warnings and Precautions (5.8) ] • Adverse reactions reported in >5% of patients treated with XIGDUO XR were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache. ( 6.1 ) • Adverse reactions reported in >5% of patients treated with metformin extended-release are: diarrhea and nausea/vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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. Clinical Trials with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin HCl extended-release. Clinical Trials with Dapagliflozin in Adults Dapagliflozin Dapagliflozin has been evaluated in clinical trials in adult and pediatric patients 10 years of age 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, DELIVER and DAPA-CKD trials. Pools of Placebo-Controlled Clinical Trials for Glycemic Control in Adults Pool of 8 Placebo-Controlled Adult Trials for Dapagliflozin and Metformin HCl for Glycemic Control Data from a prespecified pool of adult patients from 8 short-term, placebo-controlled trials of dapagliflozin coadministered with metformin HCl immediate- or extended-release was used to evaluate safety. This pool included several add-on trials (metformin HCl alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin HCl, or insulin and metformin HCl, 2 initial combination with metformin HCl trials, and 2 trials of patients with CVD and type 2 diabetes mellitus who received their usual treatment [with metformin HCl as background therapy]). For trials that included background therapy with and without metformin HCl, only patients who received metformin HCl were included in the 8-trial placebo-controlled pool. Across these 8 trials, 983 patients were treated once daily with dapagliflozin 10 mg and metformin HCl, and 1185 were treated with placebo and metformin HCl. These 8 trials provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and moderately impaired in 10% of patients. The overall incidence of adverse events for the 8-trial, short-term, placebo-controlled pool in adult patients treated with dapagliflozin 10 mg and metformin HCl was 60.3% compared to 58.2% for the placebo and metformin HCl group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin HCl was 4% compared to 3.3% for the placebo and metformin HCl group. The most commonly reported events leading to discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and metformin HCl were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%). Table 2 shows common adverse reactions in adults associated with the use of dapagliflozin and metformin HCl. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin and metformin HCl than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg. Table 2: Adverse Reactions in Placebo-Controlled Trials Reported in ≥2% of Adult Patients Treated with Dapagliflozin and Metformin HCl Adverse Reaction % of Patients Pool of 8 Placebo-Controlled Trials Placebo and Metformin HCl N=1185 Dapagliflozin 5 mg and Metformin HCl N=410 Dapagliflozin 10 mg and Metformin HCl N=983 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, genital infection, vulvovaginitis, fungal genital infection, vulvovaginal candidiasis, vulval abscess, genital candidiasis, and vaginitis bacterial. (N for females: Placebo and metformin HCl=534, dapagliflozin 5 mg and metformin HCl=223, dapagliflozin 10 mg and metformin HCl=430). 1.5 9.4 9.3 Nasopharyngitis 5.9 6.3 5.2 Urinary tract infections Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, pyelonephritis, urethritis, and prostatitis. 3.6 6.1 5.5 Diarrhea 5.6 5.9 4.2 Headache 2.8 5.4 3.3 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, posthitis, and balanoposthitis. (N for males: Placebo and metformin HCl=651, dapagliflozin 5 mg and metformin HCl=187, dapagliflozin 10 mg and metformin HCl=553). 0 4.3 3.6 Influenza 2.4 4.1 2.6 Nausea 2.0 3.9 2.6 Back pain 3.2 3.4 2.5 Dizziness 2.2 3.2 1.8 Cough 1.9 3.2 1.4 Constipation 1.6 2.9 1.9 Dyslipidemia 1.4 2.7 1.5 Pharyngitis 1.1 2.7 1.5 Increased urination Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. 1.4 2.4 2.6 Discomfort with urination 1.1 2.2 1.6 Pool of 12 Placebo-Controlled Adult Trials for Dapagliflozin 5 and 10 mg for Glycemic Control The data in Table 3 are derived from 12 glycemic control placebo-controlled trials in adults 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 HCl [see Clinical Studies (14.1) ] . 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 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 3 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 3: 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 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 5 mg=564, dapagliflozin 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 10 mg for Glycemic Control Dapagliflozin 10 mg was also evaluated in a larger glycemic control placebo-controlled trial pool in adult patients. 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 HCl 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 with Dapagliflozin in Adults 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) for the 12-trial and 13-trial, short-term, placebo-controlled pools and for the DECLARE trial are shown in Table 4 [see Warnings and Precautions (5.3) ] . Table 4: Adverse Reactions Related to Volume Depletion Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. in Adult Clinical Trials 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 <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%) Hypoglycemia The frequency of hypoglycemia in adult patients by trial [see Clinical Studies (14.1) ] is shown in Table 5. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see Warnings and Precautions (5.5) ] . Table 5: 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 Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg Add-on to Metformin HCl (24 weeks) N=137 N=137 N=135 Severe [n (%)] 0 0 0 Glucose < 54 mg/dL [n (%)] 0 0 0 Add-on to DPP4 inhibitor (with or without Metformin HCl) (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 10 mg 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 3). 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 10 mg 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 10 mg 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 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 in 12 out of 8569 adult patients in the placebo group. The events were evenly distributed over the trial period. Laboratory Tests in Adults with Type 2 Diabetes Mellitus treated with Dapagliflozin or Metformin HCl Dapagliflozin 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 (5.3) ] . 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 10 mg‑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 HCl) 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 Warning and Precautions (5.2) ]. Metformin HCl Vitamin B 12 Concentrations In metformin clinical trials of 29‑week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Clinical Trials in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus Dapagliflozin The dapagliflozin safety profile observed in the 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 (14.2) ] . Metformin HCl In clinical trials with metformin HCl immediate-release tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post‑approval use of XIGDUO XR, dapagliflozin or metformin HCl. 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. Dapagliflozin 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 Metformin HCl Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury

12.3 Pharmacokinetics XIGDUO XR The administration of XIGDUO XR in healthy subjects after a standard meal compared to the fasted state resulted in the same extent of exposure for both dapagliflozin and metformin extended-release. Compared to the fasted state, the standard meal resulted in 35% reduction and a delay of 1 to 2 hours in the peak plasma concentrations of dapagliflozin. This effect of food is not considered to be clinically meaningful. Food has no relevant effect on the pharmacokinetics of metformin when administered as XIGDUO XR combination tablets. Absorption Dapagliflozin 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. Metformin HCl Following a single oral dose of metformin HCl extended-release, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. The extent of metformin absorption (as measured by AUC) from the metformin HCl extended-release tablet increased by approximately 50% when given with food. There was no effect of food on C max and T max of metformin. Metformin HCl extended-release tablets and metformin HCl immediate-release tablets have a similar extent of absorption (as measured by AUC), while peak plasma levels of metformin extended-release tablets are approximately 20% lower than those of metformin immediate-release tablets at the same dose. Distribution Dapagliflozin Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. Metformin HCl Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes. Metabolism Dapagliflozin 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. Metformin HCl Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted. Elimination Dapagliflozin 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 ½ ) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg . Metformin HCl Renal clearance is approximately 3.5‑times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. Specific Populations Geriatric Patients Dapagliflozin Based on a population pharmacokinetic analysis, age does not have a clinically meaningful effect on systemic exposures of dapagliflozin. Metformin HCl Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function. Pediatric Patients Dapagliflozin The pharmacokinetics and pharmacodynamics (glucosuria) of dapagliflozin in pediatric patients aged 10 to 17 years with type 2 diabetes mellitus were similar to those observed in adult patients with same renal function. Metformin HCl After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin C max and AUC differed less than 5% between pediatric type 2 diabetic patients (12-16 years of age) and gender- and weight-matched healthy adults (20-45 years of age), all with normal renal function. Male and Female Patients Dapagliflozin Based on a population pharmacokinetic analysis, gender does not have a clinically meaningful effect on systemic exposures of dapagliflozin. Metformin HCl Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females. Racial or Ethnic Groups Dapagliflozin Based on a population pharmacokinetic analysis, race (White, Black or African American, or Asian) does not have a clinically meaningful effect on systemic exposures of dapagliflozin. Metformin HCl No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Black or African Americans (n=51), and Hispanic or Latino Ethnicity (n=24). Patients with Renal Impairment Dapagliflozin At steady-state (20 mg once daily dapagliflozin for 7 days), adult patients with type 2 diabetes mellitus 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 Dosage and Administration (2.4) , Warnings and Precautions (5.3) , Use in Specific Populations (8.6) and Clinical Studies (14) ] . Metformin HCl In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1) ] . Patients with Hepatic Impairment Dapagliflozin In adult patients 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. Metformin HCl No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions (5.1) ] . Body Weight Dapagliflozin Based on a population pharmacokinetic analysis, body weight does not have a clinically meaningful effect on systemic exposures of dapagliflozin. Drug Interactions Specific pharmacokinetic drug interaction studies with XIGDUO XR have not been performed, although such studies have been conducted with the individual dapagliflozin and metformin components. In Vitro Assessment of Drug Interactions Dapagliflozin 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 Metformin Table 7 shows the effect of coadministered drugs on the pharmacokinetics of metformin in adults. Table 7: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug (Dose Regimen) All metformin and coadministered drugs were given as single doses. Metformin (Dose Regimen) Metformin Change Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. in AUC AUC = AUC(INF). Change in C max No dosing adjustments required for the following: Glyburide (5 mg) 850 mg ↓9% Ratio of arithmetic means. ↓7% Furosemide (40 mg) 850 mg ↑15% ↑22% Nifedipine (10 mg) 850 mg ↑9% ↑20% Propranolol (40 mg) 850 mg ↓10% ↓6% Ibuprofen (400 mg) 850 mg ↑5% ↑7% Drugs eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7) ] . Cimetidine (400 mg) 850 mg ↑40% ↑60% Effects of Metformin on Other Drugs Table 8 shows the effect of metformin on the pharmacokinetics of coadministered drugs in adults. Table 8: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug (Dose Regimen) All metformin and coadministered drugs were given as single doses. Metformin (Dose Regimen) Coadministered Drug Change Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. in AUC AUC = AUC(INF) unless otherwise noted. Change in C max No dosing adjustments required for the following: Glyburide (5 mg) 850 mg ↓22% Ratio of arithmetic means, p-value of difference <0.05. ↓37% Furosemide (40 mg) 850 mg ↓12% ↓31% Nifedipine (10 mg) 850 mg ↑10% AUC(0-24 hr) reported. ↑8% Propranolol (40 mg) 850 mg ↑1% ↑2% Ibuprofen (400 mg) 850 mg ↓3% Ratio of arithmetic means. ↑1% Cimetidine (400 mg) 850 mg ↓5% ↑1% Effects of Other Drugs on Dapagliflozin Table 9 shows the effect of coadministered drugs on the pharmacokinetics of dapagliflozin in adults. No dose adjustments are recommended for dapagliflozin. Table 9: Effects of Coadministered Drugs on Dapagliflozin Systemic Exposure Coadministered Drug (Dose Regimen) Single dose unless otherwise noted. Dapagliflozin (Dose Regimen) Dapagliflozin Change Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. in AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. Change in C max No dosing adjustments required for the following: Oral Antidiabetic Agents Metformin (1,000 mg) 20 mg ↓1% ↓7% Pioglitazone (45 mg) 50 mg 0% ↑9% Sitagliptin (100 mg) 20 mg ↑8% ↓4% Glimepiride (4 mg) 20 mg ↓1% ↑1% Voglibose (0.2 mg three times daily) 10 mg ↑1% ↑4% Other Medications Hydrochlorothiazide (25 mg) 50 mg ↑7% ↓1% Bumetanide (1 mg) 10 mg once daily for 7 days ↑5% ↑8% Valsartan (320 mg) 20 mg ↑2% ↓12% Simvastatin (40 mg) 20 mg ↓1% ↓2% Anti-infective Agent Rifampin (600 mg once daily for 6 days) 10 mg ↓22% ↓7% Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every 6 hours) 10 mg ↑51% ↑13% Effects of Dapagliflozin on Other Drugs Table 10 shows the effect of dapagliflozin on other coadministered drugs in adults. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs. Table 10: Effects of Dapagliflozin on the Systemic Exposures of Coadministered Drugs Coadministered Drug (Dose Regimen) Single dose unless otherwise noted. Dapagliflozin (Dose Regimen) Coadministered Drug Change Percent change (with/without coadministered drug and no change = 0%); ↑ and ↓ indicate the exposure increase and decrease, respectively. in AUC AUC = AUC(INF) for drugs given as single dose and AUC = AUC(TAU) for drugs given in multiple doses. Change in C max No dosing adjustments required for the following: Oral Antidiabetic Agents Metformin (1,000 mg) 20 mg 0% ↓5% Pioglitazone (45 mg) 50 mg 0% ↓7% Sitagliptin (100 mg) 20 mg ↑1% ↓11% Glimepiride (4 mg) 20 mg ↑13% ↑4% Other Medications Hydrochlorothiazide (25 mg) 50 mg ↓1% ↓5% Bumetanide (1 mg) 10 mg once daily for 7 days ↑13% ↑13% Valsartan (320 mg) 20 mg ↑5% ↓6% Simvastatin (40 mg) 20 mg ↑19% ↓6% Digoxin (0.25 mg) 20 mg loading dose then 10 mg once daily for 7 days 0% ↓1% Warfarin (25 mg) S-warfarin R-warfarin 20 mg loading dose then 10 mg once daily for 7 days ↑3% ↑6% ↑7% ↑8%