ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling:oLactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]oVolume Depletion [see Warnings and Precautions (5.2)]oKetoacidosis [see Warnings and Precautions (5.3)]oUrosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]oUse with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.5)]oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see Warnings and Precautions (5.6) oVitamin B12 Concentrations see Warnings and Precautions (5.7 )] oGenital Mycotic Infections [see Warnings and Precautions (5.8)]. oLactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]. oVolume Depletion [see Warnings and Precautions (5.2)]. oKetoacidosis [see Warnings and Precautions (5.3)]. oUrosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]. oUse with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.5)]. oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene) [see Warnings and Precautions (5.6) . oVitamin B12 Concentrations see Warnings and Precautions (5.7 )] oGenital Mycotic Infections [see Warnings and Precautions (5.8)]. oAdverse reactions reported in >5% of patients treated with XIGDUO XR were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache. (6.1)oAdverse 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. oAdverse reactions reported in >5% of patients treated with XIGDUO XR were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache. (6.1). oAdverse reactions reported in >5% of patients treated with metformin extended-release are: diarrhea and nausea/vomiting. (6.1). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 and Metformin HCl. Data from prespecified pool of patients from short-term, placebo-controlled studies of dapagliflozin coadministered with metformin immediate- or extended-release was used to evaluate safety. This pool included several add-on studies (metformin alone and in combination with dipeptidyl peptidase-4 [DPP4] inhibitor and metformin, or insulin and metformin, initial combination with metformin studies, and studies of patients with CVD and type diabetes mellitus who received their usual treatment [with metformin as background therapy]). For studies that included background therapy with and without metformin, only patients who received metformin were included in the 8-study placebo-controlled pool. Across these studies 983 patients were treated once daily with dapagliflozin 10 mg and metformin and 1185 were treated with placebo and metformin. These studies provide 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 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-study, short-term, placebo-controlled pool in patients treated with dapagliflozin 10 mg and metformin was 60.3% compared to 58.2% for the placebo and metformin group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin was 4% compared to 3.3% for the placebo and metformin group. The most commonly reported events leading to discontinuation and reported in at least patients treated with dapagliflozin 10 mg and metformin were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%).Table shows common adverse reactions associated with the use of dapagliflozin and metformin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin and metformin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin mg or dapagliflozin 10 mg.Table 1: Adverse Reactions in Placebo-Controlled Studies Reported in >=2% of Patients Treated with Dapagliflozin and MetforminAdverse Reaction% of Patients Pool of Placebo-Controlled StudiesPlacebo and MetforminN=1185Dapagliflozin5 mg and MetforminN=410Dapagliflozin10 mg and MetforminN=983Female genital mycotic infectionsGenital 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=534, dapagliflozin mg and metformin=223, dapagliflozin 10 mg and metformin=430). 1.59.49.3Nasopharyngitis5.96.35.2Urinary tract infectionsUrinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, pyelonephritis, urethritis, and prostatitis. 3.66.15.5Diarrhea5.65.94.2Headache2.85.43.3Male genital mycotic infectionsGenital 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=651, dapagliflozin mg and metformin=187, dapagliflozin 10 mg and metformin=553). 04.33.6Influenza2.44.12.6Nausea2.03.92.6Back pain3.23.42.5Dizziness2.23.21.8Cough1.93.21.4Constipation1.62.91.9Dyslipidemia1.42.71.5Pharyngitis1.12.71.5Increased urinationIncreased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. 1.42.42.6Discomfort with urination1.12.21.6. Metformin HCl. In placebo-controlled monotherapy trials of metformin 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 extended-release.. Dapagliflozin. Dapagliflozin 10 mg has been evaluated in clinical trials in patients with type diabetes mellitus and patients with heart failure. The overall safety profile of dapagliflozin was consistent across the studied indications. No new adverse reactions were identified in the DAPA-HF study.. Pool of 12 Placebo-Controlled Studies for Dapagliflozin and 10 mg for Glycemic Control. DapagliflozinThe data in Table are derived from 12 glycemic control placebo-controlled studies ranging from 12 to 24 weeks. In studies dapagliflozin was used as monotherapy, and in studies 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 2338 patients to dapagliflozin with mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin 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 years, had 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 m2).Table shows common adverse reactions 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 mg or dapagliflozin 10 mg.Table 2: Adverse Reactions in Placebo-Controlled Studies of Glycemic Control Reported in >=2% of Patients Treated with DapagliflozinAdverse Reaction% of Patients Pool of 12 Placebo-Controlled StudiesPlacebo N=1393Dapagliflozin5 mgN=1145Dapagliflozin10 mgN=1193Female genital mycotic infectionsGenital 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 mg=581, dapagliflozin 10 mg=598). 1.58.46.9Nasopharyngitis6.26.66.3Urinary tract infectionsUrinary 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. 3.75.74.3Back pain3.23.14.2Increased urinationIncreased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. 1.72.93.8Male genital mycotic infectionsGenital 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 mg=564, dapagliflozin 10 mg=595). 0.32.82.7Nausea2.42.82.5Influenza2.32.72.3Dyslipidemia1.52.12.5Constipation1.52.21.9Discomfort with urination0.71.62.1Pain in extremity1.42.01.7. Pool of 13 Placebo-Controlled Studies for Dapagliflozin 10 mg for Glycemic Control. Dapagliflozin 10 mg was also evaluated in larger glycemic control placebo-controlled study pool. This pool combined 13 placebo-controlled studies, including monotherapy studies, add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg for 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 years, had 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 m2).. Volume Depletion. Dapagliflozin causes an osmotic diuresis, which may lead to reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) for the 12-study and 13-study, short-term, placebo-controlled pools and for the DECLARE study are shown in Table [see Warnings and Precautions (5.2) ].Table 3: Adverse Reactions Related to Volume DepletionVolume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. in Clinical Studies with DapagliflozinPool of 12 Placebo-Controlled StudiesPool of 13 Placebo-Controlled StudiesDECLARE StudyPlaceboDapagliflozin5 mgDapagliflozin10 mgPlaceboDapagliflozin10 mgPlaceboDapagliflozin10 mgOverall populationN (%) N=13935(0.4%)N=11457(0.6%)N=11939(0.8%)N=229517(0.7%)N=236027(1.1%)N=8569207(2.4%)N=8574213(2.5%)Patient Subgroup (%)Patients on loop diureticsn=551(1.8%)n=400n=313(9.7%)n=2674(1.5%)n=2366(2.5%)n=93457(6.1%)n=86657(6.6%)Patients with moderate renal impairment with eGFR >=30 and <60 mL/min/1.73 m2 n=1072(1.9%)n=1071(0.9%)n=891(1.1%)n=2684(1.5%)n=2655(1.9%)n=65830(4.6%)n=60435(5.8%)Patients >=65 years of agen=2761(0.4%)n=2161(0.5%)n=2043(1.5%)n=7116(0.8%)n=66511(1.7%)n=3950121(3.1%)n=3948117(3.0%). Hypoglycemia. The frequency of hypoglycemia by study [see Clinical Studies (14.1) is shown in Table 4. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin [see Warnings and Precautions (5.5) ].Table 4: Incidence of Severe HypoglycemiaSevere 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/dLEpisodes 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 severe episode. in Controlled Glycemic Control Clinical StudiesPlaceboDapagliflozin5 mg Dapagliflozin10 mgAdd-on to Metformin (24 weeks)N=137N=137N=135 Severe [n (%)]000 Glucose 54 mg/dL [n (%)]000Add-on to DPP4 inhibitor (with or without Metformin) (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 OADsOAD oral antidiabetic therapy. (24 weeks)N=197N=212N=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 study [see Clinical Studies (14.2)], severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 patients treated with dapagliflozin 10 mg and 83 (1.0%) out of 8569 patients treated with placebo.. Genital Mycotic Infections. In the glycemic control studies, 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 mg, and 4.8% on dapagliflozin 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study 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 2). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with history of genital mycotic infections were more likely to have genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin mg, and dapagliflozin 10 mg, respectively). In the DECLARE study [see Clinical Studies (14.2)], 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 study 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 studies, 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 study [see Clinical Studies (14.2)], events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 patients in the dapagliflozin-treated group and in 12 out of 8569 patients in the placebo group. The events were evenly distributed over the study period.. Laboratory Tests. Increases in Serum Creatinine and Decreases in eGFR. DapagliflozinInitiation of SGLT2 inhibitors, including dapagliflozin, causes small increase in serum creatinine and decrease in eGFR. In patients with normal or mildly impaired renal function at baseline, these changes in serum creatinine and eGFR generally occur within weeks of starting therapy and then stabilize. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions (5.2)]. The acute effect on eGFR reverses after treatment discontinuation, suggesting acute hemodynamic changes may play role in the renal function changes observed with dapagliflozin.. Increase in Hematocrit. DapagliflozinIn the pool of 13 placebo-controlled studies of glycemic control, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 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. DapagliflozinIn the pool of 13 placebo-controlled studies of glycemic control, changes from baseline in mean lipid values were reported in dapagliflozin-treated 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 study [see Clinical Studies (14.2)], mean changes from baseline after 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.. Vitamin B12 Concentrations. Metformin HClIn metformin clinical trials of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.. 6.2 Postmarketing Experience DapagliflozinAdditional adverse reactions have been identified during postapproval use of dapagliflozin. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.oKetoacidosis oAcute Kidney InjuryoUrosepsis and Pyelonephritis oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene)oRashMetformin HCloCholestatic, hepatocellular, and mixed hepatocellular liver injury. oKetoacidosis oAcute Kidney Injury. oUrosepsis and Pyelonephritis oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene). oRash. oCholestatic, hepatocellular, and mixed hepatocellular liver injury.

BOXED WARNING SECTION.

WARNING: LACTIC ACIDOSIS. Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].o Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information [see Dosage and Administration 2.1 and 2.4), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].o If metformin-associated lactic acidosis is suspected, immediately discontinue XIGDUO XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.oPostmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1) oRisk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information. (5.1) oIf lactic acidosis is suspected, discontinue XIGDUO XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.1) oPostmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. (5.1) oRisk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information. (5.1) oIf lactic acidosis is suspected, discontinue XIGDUO XR and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. XIGDUO XRNo animal studies have been conducted with XIGDUO XR to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with dapagliflozin and metformin individually.. DapagliflozinDapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10 and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72-times (males) and 105-times (females) the clinical dose of 10 mg per day, based on AUC exposure. In rats, the highest dose was approximately 131-times (males) and 186-times (females) the clinical dose of 10 mg per day, based on AUC exposure.Dapagliflozin was negative in the Ames mutagenicity assay and was positive in series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations greater than or equal to 100 ug/mL. Dapagliflozin was negative for clastogenicity in series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples greater than 2100-times the clinical dose.Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples less than or equal to 1708-times and 998-times the maximum recommended human dose in males and females, respectively.. Metformin HClLong-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 and 1500 mg/kg/day, respectively. These doses are both approximately times the maximum recommended human dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately times the maximum recommended human dose based on body surface area comparisons.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. DapagliflozinSodium-glucose cotransporter (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 lowers the renal threshold for glucose, and thereby increases 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.. Metformin HClMetformin is an antihyperglycemic agent which improves glucose tolerance in patients with type diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.. 12.2 Pharmacodynamics. General. DapagliflozinIncreases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of or 10 mg per day in patients with type diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day. near maximum glucose excretion was observed at the dapagliflozin daily dose 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 days for the 10 mg dose.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 Diabetes Mellitus (T2DM) (Semi-Log Plot). Figure 1. 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 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. XIGDUO XRThe administration of XIGDUO XR in healthy subjects after 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 delay of to 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. AbsorptionDapagliflozinFollowing oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within hours under fasting state. The Cmax 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 10 mg dose is 78%. Administration of dapagliflozin with high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately 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 HClFollowing single oral dose of metformin extended-release, Cmax is achieved with median value of hours and range of to hours. The extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food. There was no effect of food on Cmax and Tmax of metformin.DistributionDapagliflozinDapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.Metformin HClDistribution 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. DapagliflozinThe metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is 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 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.. Metformin HClIntravenous 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. DapagliflozinDapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following single 50 mg dose of [14C]-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 single oral dose of dapagliflozin 10 mg.. Metformin HClRenal 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 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 compartment of distribution.. Specific Populations. Renal Impairment. DapagliflozinAt steady-state (20 mg once daily dapagliflozin for days), patients with type 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 diabetes mellitus with normal renal function. Higher systemic exposure of dapagliflozin in patients with type diabetes mellitus with renal impairment did not result in correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 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 (5.2) and Use in Specific Populations (8.6)].. Metformin HClIn 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)].. Hepatic Impairment. DapagliflozinIn patients with mild and moderate hepatic impairment (Child-Pugh classes and B), mean Cmax 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 patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls. Metformin HClNo pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions (5.1)].. Geriatric. DapagliflozinBased on population pharmacokinetic analysis, age does not have clinically meaningful effect on systemic exposures of dapagliflozin.. Metformin HClLimited 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 Cmax 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 change in renal function. Gender. DapagliflozinBased on population pharmacokinetic analysis, gender does not have clinically meaningful effect on systemic exposures of dapagliflozin.. Metformin HClMetformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type diabetes, the antihyperglycemic effect of metformin was comparable in males and females.. Race. DapagliflozinBased on population pharmacokinetic analysis, race (White, Black, or Asian) does not have clinically meaningful effect on systemic exposures of dapagliflozin.. Metformin HClNo studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).. Body Weight. DapagliflozinBased on population pharmacokinetic analysis, body weight does not have 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. DapagliflozinIn 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 weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is 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 shows the effect of other coadministered drugs on metformin.Table 6: Effect of Coadministered Drug on Plasma Metformin Systemic ExposureCoadministered Drug(Dose Regimen)All metformin and coadministered drugs were given as single doses. Metformin(Dose Regimen) MetforminChangePercent change (with/without coadministered drug and no change 0%); and indicate the exposure increase and decrease, respectively. in AUCAUC AUC(INF). Change in Cmax No dosing adjustments required for the following:Glyburide (5 mg)850 mg9%Ratio of arithmetic means. 7% Furosemide (40 mg)850 mg15% 22% Nifedipine (10 mg)850 mg9%20%Propranolol (40 mg)850 mg10%6%Ibuprofen (400 mg)850 mg5% 7% Drugs eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7) ].Cimetidine (400 mg)850 mg40%60%. Effects of Metformin on Other Drugs. Table shows the effect of metformin on other coadministered drugs.Table 7: Effect of Metformin on Coadministered Drug Systemic ExposureCoadministered Drug(Dose Regimen)All metformin and coadministered drugs were given as single doses. Metformin(Dose Regimen) Coadministered DrugChangePercent change (with/without coadministered drug and no change 0%); and indicate the exposure increase and decrease, respectively. in AUCAUC AUC(INF) unless otherwise noted. Change in Cmax No dosing adjustments required for the following:Glyburide (5 mg)850 mg22%Ratio of arithmetic means, p-value of difference <0.05. 37% Furosemide (40 mg)850 mg12% 31% Nifedipine (10 mg)850 mg10%AUC(0-24 hr) reported. 8%Propranolol (40 mg)850 mg1% 2%Ibuprofen (400 mg)850 mg3%Ratio of arithmetic means. 1% Cimetidine (400 mg)850 mg5% 1%. Effects of Other Drugs on Dapagliflozin. Table shows the effect of coadministered drugs on dapagliflozin. No dose adjustments are recommended for dapagliflozin.Table 8: Effects of Coadministered Drugs on Dapagliflozin Systemic ExposureCoadministered Drug(Dose Regimen)Single dose unless otherwise noted. Dapagliflozin(Dose Regimen)DapagliflozinChangePercent change (with/without coadministered drug and no change 0%); and indicate the exposure increase and decrease, respectively. in AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses. Change in Cmax No dosing adjustments required for the following:Oral Antidiabetic Agents Metformin (1000 mg)20 mg1%7% Pioglitazone (45 mg)50 mg0%9% Sitagliptin (100 mg)20 mg8%4% Glimepiride (4 mg)20 mg1%1% Voglibose (0.2 mg three times daily)10 mg1%4%Other Medications Hydrochlorothiazide (25 mg)50 mg7%1% Bumetanide (1 mg)10 mg once daily for days5%8% Valsartan (320 mg)20 mg2%12% Simvastatin (40 mg)20 mg1%2%Anti-infective Agent Rifampin (600 mg once daily for days)10 mg22%7%Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every hours)10 mg51%13%. Effects of Dapagliflozin on Other Drugs. Table shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.Table 9: Effects of Dapagliflozin on the Systemic Exposures of Coadministered DrugsCoadministered Drug(Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)Coadministered DrugChangePercent change (with/without coadministered drug and no change 0%); and indicate the exposure increase and decrease, respectively. in AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.Change in Cmax No dosing adjustments required for the following:Oral Antidiabetic Agents Metformin (1000 mg)20 mg0%5% Pioglitazone (45 mg)50 mg0%7% Sitagliptin (100 mg)20 mg1%11% Glimepiride (4 mg)20 mg13%4%Other Medications Hydrochlorothiazide (25 mg)50 mg1%5% Bumetanide (1 mg)10 mg once daily for days13%13% Valsartan (320 mg)20 mg5%6% Simvastatin (40 mg)20 mg19%6% Digoxin (0.25 mg)20 mg loading dose then 10 mg once daily for days0%1% Warfarin (25 mg) S-warfarin R-warfarin20 mg loading dose then 10 mg once daily for days3%6%7%8%.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. There have been no clinical efficacy studies conducted with XIGDUO XR combination tablets to characterize its effect on HbA1c reduction. XIGDUO XR is considered to be bioequivalent to coadministered dapagliflozin and metformin HCl extended-release (XR) tablets [see Clinical Pharmacology (12.3)]. Relative bioavailability studies between XIGDUO XR and coadministered dapagliflozin and metformin HCl immediate-release (IR) tablets have not been conducted. The metformin HCl XR tablets and metformin HCl IR tablets have similar extent of absorption (as measured by AUC), while peak plasma levels of XR tablets are approximately 20% lower than those of IR tablets at the same dose.. 14.1 Glycemic Control The coadministration of dapagliflozin and metformin XR tablets has been studied in treatment-naive patients inadequately controlled on diet and exercise alone. The coadministration of dapagliflozin and metformin IR or XR tablets has been studied in patients with type diabetes mellitus inadequately controlled on metformin and compared with sulfonylurea (glipizide) in combination with metformin. Treatment with dapagliflozin plus metformin at all doses produced clinically relevant and statistically significant improvements in HbA1c and fasting plasma glucose (FPG) compared to placebo in combination with metformin (initial or add-on therapy). HbA1c reductions were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).. Initial Combination Therapy with Metformin Extended-Release. total of 1236 treatment-naive patients with inadequately controlled type diabetes mellitus (HbA1c >=7.5% and <=12%) participated in active-controlled studies of 24-week duration to evaluate initial therapy with dapagliflozin mg (NCT00643851) or 10 mg (NCT00859898) in combination with metformin extended-release (XR) formulation.In one study, 638 patients randomized to of treatment arms following 1-week lead-in period received: dapagliflozin 10 mg plus metformin XR (up to 2000 mg/day), dapagliflozin 10 mg plus placebo, or metformin XR (up to 2000 mg/day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with median dose achieved of 2000 mg.The combination treatment of dapagliflozin 10 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 10 and Figure 2). Dapagliflozin 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin alone and was noninferior to metformin XR monotherapy in lowering HbA1c.Table 10: Results at Week 24 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) in an Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XREfficacy ParameterDapagliflozin10 mg+Metformin XRDapagliflozin10 mgMetformin XRN=211All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period. N=219N=208HbA1c (%) Baseline (mean)9.19.09.0 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) -2.0-1.5-1.4 Difference from dapagliflozin (adjusted mean) (95% CI)-0.5p-value <0.0001. (-0.7, -0.3) Difference from metformin XR (adjusted mean) (95% CI)-0.5 (-0.8, -0.3)0.0Noninferior versus metformin XR. (-0.2, 0.2) Percent of patients achieving HbA1c <7% adjusted for baseline46.6%31.7%35.2%FPG (mg/dL) Baseline (mean)189.6197.5189.9 Change from baseline (adjusted mean) -60.4-46.4-34.8 Difference from dapagliflozin (adjusted mean) (95% CI)-13.9 (-20.9, -7.0) Difference from metformin XR (adjusted mean) (95% CI)-25.5 (-32.6, -18.5)-11.6p-value <0.05. (-18.6, -4.6)Body Weight (kg) Baseline (mean)88.688.587.2 Change from baseline (adjusted mean) -3.3-2.7-1.4 Difference from metformin XR (adjusted mean) (95% CI)-2.0 (-2.6, -1.3)-1.4 (-2.0, -0.7)Figure 2: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in 24-Week Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XRIn the second study, 603 patients were randomized to of treatment arms following 1-week lead-in period: dapagliflozin mg plus metformin XR (up to 2000 mg/day), dapagliflozin mg plus placebo, or metformin XR (up to 2000 mg/day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with median dose achieved of 2000 mg.The combination treatment of dapagliflozin mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 11). Table 11: Results at Week 24 (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) in an Active-Controlled Study of Dapagliflozin Initial Combination Therapy with Metformin XREfficacy ParameterDapagliflozin5 mg+Metformin XRDapagliflozin5 mgMetformin XRN=194All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.N=203N=201HbA1c (%) Baseline (mean)9.29.19.1 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) -2.1-1.2-1.4 Difference from dapagliflozin (adjusted mean) (95% CI)-0.9p-value <0.0001. (-1.1, -0.6) Difference from metformin XR (adjusted mean) (95% CI)-0.7 (-0.9, -0.5) Percent of patients achieving HbA1c <7% adjusted for baseline52.4%p-value <0.05. 22.5%34.6%FPG (mg/dL) Baseline (mean)193.4190.8196.7 Change from baseline (adjusted mean) -61.0-42.0-33.6 Difference from dapagliflozin (adjusted mean) (95% CI)-19.1 (-26.7, -11.4) Difference from metformin XR (adjusted mean) (95% CI)-27.5 (-35.1, -19.8)Body Weight (kg) Baseline (mean)84.286.285.8 Change from baseline (adjusted mean) -2.7-2.6-1.3 Difference from metformin XR (adjusted mean) (95% CI)-1.4 (-2.0, -0.7). Figure 2. Add-On to Metformin Immediate-Release. total of 546 patients with type diabetes mellitus with inadequate glycemic control (HbA1c >=7% and <=10%) participated in 24-week, placebo-controlled study to evaluate dapagliflozin in combination with metformin (NCT00528879). Patients on metformin at dose of at least 1500 mg/day were randomized after completing 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin mg, dapagliflozin 10 mg, or placebo in addition to their current dose of metformin.As add-on treatment to metformin, dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 12 and Figure 3). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus metformin were -4.5 mmHg and -5.3 mmHg with dapagliflozin mg and 10 mg plus metformin, respectively.Table 12: Results of 24-Week (LOCFLOCF: last observation (prior to rescue for rescued patients) carried forward.) Placebo-Controlled Study of Dapagliflozin in Add-On Combination with MetforminEfficacy ParameterDapagliflozin10 mg+MetforminN=135All randomized patients who took at least one dose of double-blind study medication during the short-term double-blind period.Dapagliflozin5 mg+MetforminN=137Placebo +Metformin N=137HbA1c (%) Baseline (mean)7.98.28.1 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) -0.8 -0.7-0.3 Difference from placebo (adjusted mean) (95% CI)-0.5p-value <0.0001 versus placebo metformin. (-0.7, -0.3)-0.4 (-0.6, -0.2) Percent of patients achieving HbA1c <7% adjusted for baseline40.6%p-value <0.05 versus placebo metformin. 37.5% 25.9%FPG (mg/dL) Baseline (mean)156.0 169.2165.6 Change from baseline at Week 24 (adjusted mean) -23.5-21.5-6.0 Difference from placebo (adjusted mean) (95% CI)-17.5 (-25.0, -10.0)-15.5 (-22.9, -8.1) Change from baseline at Week (adjusted mean)-16.5 (N=115)-12.0 (N=121)1.2(N=126)Body Weight (kg) Baseline (mean)86.3 84.787.7 Change from baseline (adjusted mean) -2.9 -3.0-0.9 Difference from placebo (adjusted mean) (95% CI)-2.0 (-2.6, -1.3)-2.2 (-2.8, -1.5)Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in 24-Week Placebo-Controlled Study of Dapagliflozin in Combination with Metformin. Figure 3: Graph. Active Glipizide-Controlled Study Add-On to Metformin Immediate-Release. total of 816 patients with type diabetes mellitus with inadequate glycemic control (HbA1c >6.5% and <=10%) were randomized in 52-week, glipizide-controlled, noninferiority study to evaluate dapagliflozin as add-on therapy to metformin (NCT00660907). Patients on metformin at dose of at least 1500 mg/day were randomized following 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin treatment led to similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating noninferiority (see Table 13). Dapagliflozin treatment led to statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was -5.0 mmHg with dapagliflozin plus metformin.Table 13: Results at Week 52 (LOCFLOCF: last observation carried forward.) in an Active-Controlled Study Comparing Dapagliflozin to Glipizide as Add-On to MetforminEfficacy ParameterDapagliflozin+MetforminN=400Randomized and treated patients with baseline and at least postbaseline efficacy measurement.Glipizide+MetforminN=401HbA1c (%) Baseline (mean)7.77.7 Change from baseline (adjusted meanLeast squares mean adjusted for baseline value.) -0.5-0.5 Difference from glipizide metformin (adjusted mean) (95% CI)0.0Noninferior to glipizide metformin. (-0.1, 0.1)Body Weight (kg) Baseline (mean)88.487.6 Change from baseline (adjusted mean) -3.21.4 Difference from glipizide metformin (adjusted mean) (95% CI)-4.7p-value <0.0001. (-5.1, -4.2). Use in Patients with Type Diabetes Mellitus and Moderate Renal Impairment. Dapagliflozin was assessed in two placebo-controlled studies of patients with type diabetes mellitus and moderate renal impairment. Patients with type diabetes mellitus and an eGFR between 45 to less than 60 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in 24-week, double-blind, placebo-controlled clinical study (NCT02413398). Patients were randomized to either dapagliflozin 10 mg or placebo, administered orally once daily. At Week 24, dapagliflozin provided statistically significant reductions in HbA1c compared with placebo (Table 14).Table 14: Results at Week 24 of Placebo-Controlled Study for Dapagliflozin in Patients with Type Diabetes Mellitus and Renal Impairment (eGFR 45 to less than 60 mL/min/1.73 m2)Dapagliflozin 10 mgPlaceboNumber of patients:N=160N=161HbA1c (%)Baseline (mean)8.38.0Change from baseline (adjusted meanLeast squares mean adjusted for baseline value; at Week 24, HbA1c was missing for 5.6% and 6.8% of individuals treated with dapagliflozin and placebo, respectively. Retrieved dropouts, i.e. observed HbA1c at Week 24 from subjects who discontinued treatment, were used to impute missing values in HbA1c. )-0.4-0.1Difference from placebo (adjusted mean) (95% CI)-0.3p-value =0.008 versus placebo. (-0.5, -0.1). 14.2 Cardiovascular Outcomes in Patients with Type Diabetes Mellitus Dapagliflozin Effect on Cardiovascular Events (DECLARE, NCT01730534) was an international, multicenter, randomized, double-blind, placebo-controlled, clinical study conducted to determine the effect of dapagliflozin 10 mg relative to placebo on cardiovascular (CV) outcomes when added to current background therapy. All patients had type diabetes mellitus and either established CV disease or two or more additional CV risk factors (age >=55 years in men or >=60 years in women and one or more of dyslipidemia, hypertension, or current tobacco use). Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186 (59.4%) did not have established CV disease. total of 8582 patients were randomized to dapagliflozin 10 mg, 8578 to placebo, and patients were followed for median of 4.2 years. Approximately 80% of the trial population was White, 4% Black or African American, and 13% Asian. The mean age was 64 years, and approximately 63% were male.Mean duration of diabetes was 11.9 years and 22.4% of patients had diabetes for less than years. Mean eGFR was 85.2 mL/min/1.73 m2. At baseline, 23.5% of patients had microalbuminuria (UACR >=30 to <=300 mg/g) and 6.8% had macroalbuminuria (UACR >300 mg/g). Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m2. At baseline, 10% of patients had history of heart failure. Most patients (98.1%) used one or more antihyperglycemic medications at baseline. 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with sulfonylurea, 16.8% with DPP4 inhibitor, and 4.4% with GLP-1 receptor agonist.Approximately 81.3% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics, and 10.5% with loop diuretics.A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio (HR) of the composite of CV death, myocardial infarction (MI), or ischemic stroke (MACE) and if non-inferiority was demonstrated, to test for superiority on the two primary endpoints: 1) the composite of hospitalization for heart failure or CV death, and 2) MACE.The incidence rate of MACE was similar in both treatment arms: 2.30 MACE events per 100 patient-years on dapagliflozin vs 2.46 MACE events per 100 patient-years on placebo. The estimated hazard ratio of MACE associated with dapagliflozin relative to placebo was 0.93 with 95% CI of (0.84,1.03). The upper bound of this confidence interval, 1.03, excluded the pre-specified non-inferiority margin of 1.3. Dapagliflozin 10 mg was superior to placebo in reducing the incidence of the primary composite endpoint of hospitalization for heart failure or CV death (HR 0.83 [95% CI 0.73, 0.95]).The treatment effect was due to significant reduction in the risk of hospitalization for heart failure in subjects randomized to dapagliflozin 10 mg (HR 0.73 [95% CI 0.61, 0.88]), with no change in the risk of CV death (Table 15 and Figures and 5). Table 15: Treatment Effects for the Primary Endpoints and their ComponentsFull analysis set. in the DECLARE StudyPatients with events n(%)Efficacy Variable(time to first occurrence)Dapagliflozin10 mgN=8582PlaceboN=8578Hazard Ratio(95% CI)Primary EndpointsComposite of Hospitalization for Heart Failure, CV Deathp-value =0.005 versus placebo. 417 (4.9)496 (5.8)0.83 (0.73, 0.95)Composite Endpoint of CV Death, MI, Ischemic Stroke756 (8.8)803 (9.4)0.93 (0.84, 1.03)Components of the composite endpointstotal number of events presented for each component of the composite endpoints. Hospitalization for Heart Failure212 (2.5)286 (3.3)0.73 (0.61, 0.88) CV Death245 (2.9)249 (2.9)0.98 (0.82, 1.17) Myocardial Infarction393 (4.6)441 (5.1)0.89 (0.77, 1.01) Ischemic Stroke235 (2.7)231 (2.7)1.01 (0.84, 1.21)N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction, eGFR=estimated glomerular filtration rate, ESRD=End stage renal diseaseFigure 4: Time to First Occurrence of Hospitalization for Heart Failure or CV Death in the DECLARE StudyFigure 5: Time to First Occurrence of Hospitalization for Heart Failure in the DECLARE Study. Figure 4. Figure 5. 14.3 Heart Failure with Reduced Ejection Fraction Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF, NCT03036124) was an international, multicenter, randomized, double-blind, placebo-controlled study in patients with heart failure (New York Heart Association [NYHA] functional class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] 40% or less) to determine whether dapagliflozin reduces the risk of cardiovascular death and hospitalization for heart failure. Of 4744 patients, 2373 were randomized to dapagliflozin 10 mg and 2371 to placebo and were followed for median of 18 months. The study included patients with type diabetes mellitus (n=2139) and patients without diabetes (n=2605). The mean age of the study population was 66 years, 77% were male and 70% were White, 5% Black or African American, and 24% Asian. At baseline, 68% patients were classified as NYHA class II, 32% class III, and 1% class IV; median LVEF was 32%. At baseline, 94% of patients were treated with ACEi, ARB or angiotensin receptor-neprilysin inhibitor (ARNI, including sacubitril/valsartan 11%), 96% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 93% with diuretic, and 26% had an implantable device (with defibrillator function). Patients with eGFR 30 mL/min/1.73 m2 or greater at enrollment were included in the study.History of type diabetes mellitus was present in 42%, and an additional 3% had type diabetes mellitus based on HbA1c >=6.5% at both enrollment and randomization, totaling to 1075 patients in the dapagliflozin group and 1064 in the placebo group. At baseline of the patients with type diabetes mellitus, 48% were treated with metformin (505 patients on dapagliflozin 10 mg and 515 on placebo) and 25% were treated with insulin.The mean age of the type diabetes mellitus population was 67 years, 78% were male, 70% White, 6% Black or African American and 23% Asian. At baseline, 64% patients were classified as NYHA class II, 35% class III and 1% class IV, median LVEF was 32%. Patients were on standard of care therapy; 93% of type diabetes mellitus patients were treated with ACEi, ARB, or angiotensin receptor-neprilysin inhibitor (ARNI, 11%), 97% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 95% with diuretic and 27% had an implantable device (with defibrillator function). In these patients, mean eGFR was 63 mL/min/1.73 m2.Dapagliflozin 10 mg reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit in overall population (HR 0.74 [95% CI 0.65, 0.85]; p<0.0001). All three components of the primary composite endpoint individually contributed to the treatment effect. There were few urgent heart failure visits. The Kaplan-Meier curves for dapagliflozin 10 mg and placebo separated early and continued to diverge over the study period (Table 16 and Figure 6).The treatment benefit of dapagliflozin 10 mg in reducing the incidence of the primary composite endpoint was consistent in patients with type diabetes mellitus (HR 0.75 [95% CI 0.63, 0.90]), and in patients with type diabetes mellitus and metformin as background therapy (HR 0.67 [95% CI 0.51, 0.88]).Table 16: Treatment Effects for the Primary Composite EndpointFull analyses set., its Components, and Secondary Endpoints in the DAPA-HF StudyPatients with events (event rateEvent rates are presented as the number of subjects with event per 100 patient years of follow-up. )Efficacy Variable(time to first occurrence)Dapagliflozin10 mgN=2373PlaceboN=2371Hazard ratio(95% CI)p-valueTwo-sided p-values. Composite of hHF, CV Death or Urgent Heart Failure Visit Urgent heart failure visit was defined as an urgent, unplanned, assessment by physician, e.g., in an Emergency Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics). 386 (11.6)502 (15.6)0.74 (0.65, 0.85)<0.0001Composite of CV Death or hHF382 (11.4)495 (15.3)0.75(0.65, 0.85)<0.0001Components of the Composite Endpoints CV Death227 (6.5)273 (7.9)0.82(0.69, 0.98)hHF or Urgent Heart Failure Visit 237 (7.1)326 (10.1)0.70(0.59, 0.83)hHF231 (6.9)318 (9.8)0.70(0.59, 0.83)Urgent Heart Failure Visit 10 (0.3)23 (0.7)0.43(0.20, 0.90)All-Cause Mortality276 (7.9)329 (9.5)0.83(0.71, 0.97)N=Number of patients, CI=Confidence interval, CV=Cardiovascular, hHF=hospitalization for heart failureNOTE: Hazard Ratio based on Cox proportional hazards model with treatment as factor, stratified by T2DM status at randomization, and adjusted for history of hHF (except for the analysis of all-cause mortality). The number of first events for the single components are the actual number of first events for each component and does not add up to the number of events in the composite endpoint.Figure 6: Time to the First Occurrence of the Composite of Cardiovascular Death, Hospitalization for Heart Failure or Urgent Heart Failure Visit in the DAPA-HF Study. Figure6.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. XIGDUO XR is contraindicated in patients with: oSevere renal impairment (eGFR below 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis [see Warnings and Precautions (5.1)]. oHistory of serious hypersensitivity reaction to dapagliflozin, such as anaphylactic reactions or angioedema, or hypersensitivity to metformin HCl [see Adverse Reactions (6.1)].oAcute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.. oSevere renal impairment (eGFR below 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis [see Warnings and Precautions (5.1)]. oHistory of serious hypersensitivity reaction to dapagliflozin, such as anaphylactic reactions or angioedema, or hypersensitivity to metformin HCl [see Adverse Reactions (6.1)].. oAcute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.. oSevere renal impairment: (eGFR below 30 mL/min/1.73 m2), end-stage renal disease or dialysis. (4, 5.1)oHistory of serious hypersensitivity to dapagliflozin or hypersensitivity to metformin HCl. (4, 6.1)oMetabolic acidosis, including diabetic ketoacidosis. (4, 5.1). oSevere renal impairment: (eGFR below 30 mL/min/1.73 m2), end-stage renal disease or dialysis. (4, 5.1). oHistory of serious hypersensitivity to dapagliflozin or hypersensitivity to metformin HCl. (4, 6.1). oMetabolic acidosis, including diabetic ketoacidosis. (4, 5.1).

DESCRIPTION SECTION.

11 DESCRIPTION. XIGDUO XR tablets contain: dapagliflozin, SGLT2 inhibitor, and metformin HCl, biguanide.. DapagliflozinDapagliflozin is described chemically as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1). The empirical formula is C21H25ClO6oC3H8O2oH2O and the formula weight is 502.98. The structural formula is:. Dapagliflozin chemical structure. Metformin hydrochlorideMetformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is white to off-white crystalline compound with molecular formula of C4H11N5oHCl and molecular weight of 165.63. Metformin hydrochloride is freely soluble in water, slightly soluble in alcohol, and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is:. Metformin hydrochloride chemical structure. XIGDUO XRXIGDUO XR is available for oral administration as tablets containing the equivalent of 2.5 mg dapagliflozin as dapagliflozin propanediol and 1000 mg metformin hydrochloride which is equivalent to 779.86 mg metformin base (XIGDUO XR 2.5 mg/1,000 mg), mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin hydrochloride which is equivalent to 389.9 mg metformin base (XIGDUO XR mg/500 mg), the equivalent of mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin hydrochloride which is equivalent to 779.86 mg metformin base (XIGDUO XR mg/1,000 mg), the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 500 mg metformin hydrochloride which is equivalent to 389.9 mg metformin base (XIGDUO XR 10 mg/500 mg), or the equivalent of 10 mg dapagliflozin as dapagliflozin propanediol and 1,000 mg metformin hydrochloride which is equivalent to 779.86 mg metformin base (XIGDUO XR 10 mg/1,000 mg).Each film-coated tablet of XIGDUO XR contains the following inactive ingredients: microcrystalline cellulose, lactose anhydrous, crospovidone, silicon dioxide, magnesium stearate, carboxymethylcellulose sodium, and hypromellose.The film coatings contain the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Additionally, the film coating for the XIGDUO XR mg/500 mg tablets contains FD&C Yellow No. 6/Sunset Yellow FCF aluminum lake. The film coating for the XIGDUO XR 2.5 mg/1,000 mg, mg/1,000 mg, 10 mg/500 mg, and 10 mg/1000 mg tablets contains iron oxides.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oAssess renal function before initiating. Do not initiate or continue if eGFR is below 45 mL/min/1.73 m2. (2.1, 4)oIndividualize the starting dose based on the patients current treatment. (2.2) oAdminister once daily in the morning with food. (2.2)oSwallow whole. Never crush, cut, or chew. (2.2)oTo improve glycemic control, for patients not already taking dapagliflozin, the recommended starting dose for dapagliflozin is mg once daily. (2.3)oFor indications related to heart failure the recommended dose of dapagliflozin is 10 mg once daily. (2.3)oDo not exceed daily dose of 10 mg dapagliflozin/2,000 mg metformin HCl extended-release. (2.3)oNo dosage adjustment is indicated in patients with eGFR greater or equal to 45 mL/min/1.73 m2. (2.4)oXIGDUO XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.5). oAssess renal function before initiating. Do not initiate or continue if eGFR is below 45 mL/min/1.73 m2. (2.1, 4). oIndividualize the starting dose based on the patients current treatment. (2.2) oAdminister once daily in the morning with food. (2.2). oSwallow whole. Never crush, cut, or chew. (2.2). oTo improve glycemic control, for patients not already taking dapagliflozin, the recommended starting dose for dapagliflozin is mg once daily. (2.3). oFor indications related to heart failure the recommended dose of dapagliflozin is 10 mg once daily. (2.3). oDo not exceed daily dose of 10 mg dapagliflozin/2,000 mg metformin HCl extended-release. (2.3). oNo dosage adjustment is indicated in patients with eGFR greater or equal to 45 mL/min/1.73 m2. (2.4). oXIGDUO XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.5). 2.1 Prior to Initiation of XIGDUO XR. oAssess renal function before initiating XIGDUO XR therapy and periodically thereafter [see Warnings and Precautions (5.1, 5.2)].oAssess volume status and, if necessary, correct volume depletion prior to initiation of XIGDUO XR [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)]. oAssess renal function before initiating XIGDUO XR therapy and periodically thereafter [see Warnings and Precautions (5.1, 5.2)].. oAssess volume status and, if necessary, correct volume depletion prior to initiation of XIGDUO XR [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)]. 2.2 Recommended Administration. oTake XIGDUO XR orally once daily in the morning with food.oSwallow XIGDUO XR tablets whole and never crush, cut, or chew.. oTake XIGDUO XR orally once daily in the morning with food.. oSwallow XIGDUO XR tablets whole and never crush, cut, or chew.. 2.3 Recommended Dosage oIndividualize the starting dose of XIGDUO XR based upon the patients current regimen. Patients taking an evening dose of metformin extended-release should skip their last dose before starting XIGDUO XR.oTo improve glycemic control in patients not already taking dapagliflozin, the recommended starting dose for dapagliflozin is mg once daily.oFor indications related to heart failure, the recommended dose for dapagliflozin is 10 mg once daily.oDosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 10 mg dapagliflozin and 2,000 mg metformin hydrochloride (HCl) extended-release.. oIndividualize the starting dose of XIGDUO XR based upon the patients current regimen. Patients taking an evening dose of metformin extended-release should skip their last dose before starting XIGDUO XR.. oTo improve glycemic control in patients not already taking dapagliflozin, the recommended starting dose for dapagliflozin is mg once daily.. oFor indications related to heart failure, the recommended dose for dapagliflozin is 10 mg once daily.. oDosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 10 mg dapagliflozin and 2,000 mg metformin hydrochloride (HCl) extended-release.. 2.4 Patients with Renal Impairment oNo dose adjustment for XIGDUO XR is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.oXIGDUO XR is not recommended in patients with an eGFR below 45 mL/min/1.73 m2.oXIGDUO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Contraindications (4), Warnings and Precautions (5.1, 5.2), and Use in Specific Populations (8.6)].. oNo dose adjustment for XIGDUO XR is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.. oXIGDUO XR is not recommended in patients with an eGFR below 45 mL/min/1.73 m2.. oXIGDUO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [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 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. XIGDUO XR (dapagliflozin and metformin HCl) extended-release tablets are available as follows:Dapagliflozin strengthMetformin HCl StrengthColor/ShapeTablet Markings2.5 mg1,000 mglight brown to brown, biconvex, oval-shaped, and film-coated tablet1074 and 2.5/1000 debossed on one side and plain on the reverse side5 mg500 mgorange, biconvex, capsule-shaped, and film-coated tablet1070 and 5/500 debossed on one side and plain on the reverse side5 mg1,000 mgpink to dark pink, biconvex, oval-shaped, and film-coated tablet1071 and 5/1000 debossed on one side and plain on the reverse side10 mg500 mgpink, biconvex, capsule-shaped, and film-coated tablet1072 and 10/500 debossed on one side and plain on the reverse side10 mg1,000 mgyellow to dark yellow, biconvex, oval-shaped, and film-coated tablet1073 and 10/1000 debossed on one side and plain on the reverse side. o2.5 mg dapagliflozin/1,000 mg metformin HCl extended-release (3)o5 mg dapagliflozin/500 mg metformin HCl extended-release (3)o5 mg dapagliflozin/1,000 mg metformin HCl extended-release (3)o10 mg dapagliflozin/500 mg metformin HCl extended-release (3)o10 mg dapagliflozin/1,000 mg metformin HCl extended-release (3). o2.5 mg dapagliflozin/1,000 mg metformin HCl extended-release (3). o5 mg dapagliflozin/500 mg metformin HCl extended-release (3). o5 mg dapagliflozin/1,000 mg metformin HCl extended-release (3). o10 mg dapagliflozin/500 mg metformin HCl extended-release (3). o10 mg dapagliflozin/1,000 mg metformin HCl extended-release (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 5: Clinically Relevant Interactions with XIGDUO XRCarbonic Anhydrase InhibitorsClinical ImpactTopiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with XIGDUO XR may increase the risk for lactic acidosis.InterventionConsider more frequent monitoring of these patients.Drugs that Reduce Metformin ClearanceClinical ImpactConcomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors, such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)].InterventionConsider the benefits and risks of concomitant use.AlcoholClinical ImpactAlcohol is known to potentiate the effect of metformin on lactate metabolism.InterventionWarn patients against excessive alcohol intake while receiving XIGDUO XR.Drugs Affecting Glycemic ControlClinical ImpactCertain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These medications include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.InterventionWhen such drugs are administered to patient receiving XIGDUO XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from patient receiving XIGDUO XR, observe the patient closely for hypoglycemia.Positive Urine Glucose TestClinical ImpactSGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests.InterventionMonitoring 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) AssayClinical ImpactMeasurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors.InterventionMonitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.. oCarbonic anhydrase inhibitors may increase the risk of lactic acidosis. Consider more frequent monitoring. (7)oDrugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. (7)oAlcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7). oCarbonic anhydrase inhibitors may increase the risk of lactic acidosis. Consider more frequent monitoring. (7). oDrugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. (7). oAlcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. XIGDUO XRNo XIGDUO XR dosage change is recommended based on age. More frequent assessment of renal function is recommended in elderly patients.DapagliflozinA 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 pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. 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, higher proportion of patients treated with dapagliflozin had adverse reactions of hypotension [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].In the overall population of the DAPA-HF study, 2714 (57%) out of 4744 patients with heart failure with reduced ejection fraction (HFrEF) were older than 65 years. Out of 2139 patients with HFrEF and type diabetes mellitus, 1211 (56.6%) were older than 65 years. Safety and efficacy were similar for patients age 65 years and younger and those older than 65 in both the overall population and the patients with type diabetes mellitus.Metformin HClControlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.1)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How Supplied. XIGDUO(R) XR (dapagliflozin and metformin HCl extended-release) tablets have markings on one side, are plain on the reverse side, and are available in the strengths and packages listed in Table 17.Table 17: XIGDUO XR Tablet PresentationsTablet StrengthFilm-Coated TabletColor/ShapeTabletMarkingsPack SizeNDC Code2.5 mg/1,000 mgLight brown to brown, biconvex, oval-shaped1074 and 2.5/1000 debossed on one side and plain on the reverse sideBottle of 600310-6225-605 mg/500 mgorange, biconvex, capsule-shaped1070 and 5/500 debossed on one side and plain on the reverse sideBottle of 30Bottle of 5000310-6250-300310-6250-505 mg/1,000 mgpink to dark pink, biconvex, oval-shaped1071 and 5/1000 debossed on one side and plain on the reverse sideBottle of 30Bottle of 60Bottle of 90Bottle of 4000310-6260-300310-6260-600310-6260-900310-6260-4010 mg/500 mgpink, biconvex, capsule-shaped1072 and 10/500 debossed on one side and plain on the reverse sideBottle of 30Bottle of 5000310-6270-300310-6270-5010 mg/1,000 mgyellow to dark yellow, biconvex, oval-shaped1073 and 10/1000 debossed on one side and plain on the reverse sideBottle of 30Bottle of 90Bottle of 4000310-6280-300310-6280-900310-6280-40. Storage and Handling. Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. XIGDUO XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.Dapagliflozin is indicated to reduceothe risk of hospitalization for heart failure in adults with type diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.othe risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction.Limitations of UseoXIGDUO XR is not recommended for patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.oBecause of the metformin component, the use of XIGDUO XR is limited to adults with type diabetes mellitus for all indications.. othe risk of hospitalization for heart failure in adults with type diabetes mellitus and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.. othe risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction.. oXIGDUO XR is not recommended for patients with type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients.. oBecause of the metformin component, the use of XIGDUO XR is limited to adults with type diabetes mellitus for all indications.. XIGDUO XR is combination of dapagliflozin, sodium-glucose cotransporter (SGLT2) inhibitor, and metformin, biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus. (1) Dapagliflozin is indicated to reduce:othe risk of hospitalization for heart failure in adults with type diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors. (1)othe risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction. (1)Limitations of use:oNot for treatment of type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1)oBecause of the metformin component, the use of XIGDUO XR is limited to adults with type diabetes mellitus for all indications. (1). othe risk of hospitalization for heart failure in adults with type diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors. (1). othe risk of cardiovascular death and hospitalization for heart failure in adults with heart failure (NYHA class II-IV) with reduced ejection fraction. (1). oNot for treatment of type diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients. (1). oBecause of the metformin component, the use of XIGDUO XR is limited to adults with type diabetes mellitus for all indications. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Lactic AcidosisInform patients of the risks of lactic acidosis due to the metformin component and its symptoms and conditions that predispose to its development [see Warnings and Precautions (5.1)]. Advise patients to discontinue XIGDUO XR immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, dizziness, slow or irregular heartbeat, sensation of feeling cold (especially in the extremities), or other nonspecific symptoms occur. Gastrointestinal symptoms are common during initiation of metformin treatment and may occur during initiation of XIGDUO XR therapy; however, inform patients to consult their physician if they develop unexplained symptoms. Although gastrointestinal symptoms that occur after stabilization are unlikely to be drug related, such an occurrence of symptoms should be evaluated to determine if it may be due to lactic acidosis or other serious disease.Counsel patients against excessive alcohol intake while receiving XIGDUO XR [see Warnings and Precautions (5.1)].Inform patients about the importance of regular testing of renal function and hematological parameters when receiving treatment with XIGDUO XR [see Contraindications (4) and Warnings and Precautions (5.1)]. Instruct patients to inform their healthcare provider that they are taking XIGDUO XR prior to any surgical or radiological procedure, as temporary discontinuation of XIGDUO XR may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1)].Volume DepletionInform patients that symptomatic hypotension may occur with XIGDUO XR and advise them to contact their healthcare provider if they experience such symptoms [see Warnings and Precautions (5.2)]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.KetoacidosisInform patients that ketoacidosis is serious life-threatening condition and that cases of ketoacidosis have been reported during use of dapagliflozin, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue XIGDUO XR and seek medical attention immediately [see Warnings and Precautions (5.3)].Serious Urinary Tract InfectionsInform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.4) ].HypoglycemiaInform patients that the incidence of hypoglycemia may be increased when XIGDUO XR is added to an insulin secretagogue (e.g., sulfonylurea) or insulin [see Warnings and Precautions (5.5) ].Necrotizing Fasciitis of the Perineum (Fourniers Gangrene)Inform patients that necrotizing infections of the perineum (Fourniers Gangrene) have occurred with dapagliflozin, component of XIGDUO XR. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with fever above 100.4F or malaise [see Warnings and Precautions (5.6) ].Genital Mycotic Infections in Females (e.g., Vulvovaginitis)Inform female patients that vaginal yeast infections may occur and provide them with information on the signs and symptoms of vaginal yeast infections. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8) ].Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis) Inform male patients that yeast infections of the penis (e.g., balanitis or balanoposthitis) may occur, especially in patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.8) ].Hypersensitivity ReactionsInform patients that serious hypersensitivity reactions (e.g., urticaria, anaphylactic reactions, and angioedema) have been reported with the components of XIGDUO XR. Advise patients to immediately report any signs or symptoms suggesting allergic reaction or angioedema, and to take no more of the drug until they have consulted prescribing physicians.PregnancyAdvise pregnant patients of the potential risk to fetus with treatment with XIGDUO XR. Instruct patients to immediately inform their healthcare provider if pregnant or planning to become pregnant [see Use in Specific Populations (8.1)].LactationAdvise patients that use of XIGDUO XR is not recommended while breastfeeding [see Use in Specific Populations (8.2)].Females and Males of Reproductive PotentialInform female patients that treatment with metformin may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].AdministrationInstruct patients that XIGDUO XR must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as soft mass that may resemble the original tablet.Laboratory TestsDue to the mechanism of action of dapagliflozin, patients taking XIGDUO XR will test positive for glucose in their urine.Missed DoseIf dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of XIGDUO XR at the same time. GLUCOPHAGE(R) is registered trademark of Merck Sante S.A.S., subsidiary of Merck KGaA of Darmstadt, Germany, licensed to Bristol-Myers Squibb Company.FARXIGA(R) is registered trademark of the AstraZeneca group of companies.Distributed by:AstraZeneca Pharmaceuticals LPWilmington, DE 19850.

LABORATORY TESTS SECTION.

Laboratory Tests. Increases in Serum Creatinine and Decreases in eGFR. DapagliflozinInitiation of SGLT2 inhibitors, including dapagliflozin, causes small increase in serum creatinine and decrease in eGFR. In patients with normal or mildly impaired renal function at baseline, these changes in serum creatinine and eGFR generally occur within weeks of starting therapy and then stabilize. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions (5.2)]. The acute effect on eGFR reverses after treatment discontinuation, suggesting acute hemodynamic changes may play role in the renal function changes observed with dapagliflozin.. Increase in Hematocrit. DapagliflozinIn the pool of 13 placebo-controlled studies of glycemic control, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 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.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere is no information regarding the presence of XIGDUO XR or dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk (see Data). However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin 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 are not clear. Since human kidney maturation occurs in utero and during the first 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 XIGDUO XR is not recommended while breastfeeding. DataDapagliflozinDapagliflozin was present in rat milk at milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at 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.Metformin HClPublished clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. DapagliflozinSodium-glucose cotransporter (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 lowers the renal threshold for glucose, and thereby increases 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.. Metformin HClMetformin is an antihyperglycemic agent which improves glucose tolerance in patients with type diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. XIGDUO XRNo animal studies have been conducted with XIGDUO XR to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on the findings in the studies with dapagliflozin and metformin individually.. DapagliflozinDapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year carcinogenicity studies. Oral doses in mice consisted of 5, 15, and 40 mg/kg/day in males and 2, 10 and 20 mg/kg/day in females, and oral doses in rats were 0.5, 2, and 10 mg/kg/day for both males and females. The highest doses evaluated in mice were approximately 72-times (males) and 105-times (females) the clinical dose of 10 mg per day, based on AUC exposure. In rats, the highest dose was approximately 131-times (males) and 186-times (females) the clinical dose of 10 mg per day, based on AUC exposure.Dapagliflozin was negative in the Ames mutagenicity assay and was positive in series of in vitro clastogenicity assays in the presence of S9 activation and at concentrations greater than or equal to 100 ug/mL. Dapagliflozin was negative for clastogenicity in series of in vivo studies evaluating micronuclei or DNA repair in rats at exposure multiples greater than 2100-times the clinical dose.Dapagliflozin had no effects on mating, fertility, or early embryonic development in treated male or female rats at exposure multiples less than or equal to 1708-times and 998-times the maximum recommended human dose in males and females, respectively.. Metformin HClLong-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 and 1500 mg/kg/day, respectively. These doses are both approximately times the maximum recommended human dose of 2000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately times the maximum recommended human dose based on body surface area comparisons.

OVERDOSAGE SECTION.

10 OVERDOSAGE. DapagliflozinIn the event of an overdose, contact the Poison Control Center. The removal of dapagliflozin by hemodialysis has not been studied.. Metformin HClOverdose of metformin HCl has occurred, including ingestion of amounts >50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 2.5 mg/1000 mg 60 Tablets NDC 0310-6225-60xigduo(R) XR(dapagliflozin/metformin HClextended-release) tablets2.5 mg/1000 mgDispense with Medication GuideRx onlyDo not crush, cut, or chew tablets.Tablets must be swallowed whole.AstraZeneca. 3941801.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of XIGDUO XR in pediatric patients under 18 years of age have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. General. DapagliflozinIncreases in the amount of glucose excreted in the urine were observed in healthy subjects and in patients with type diabetes mellitus following the administration of dapagliflozin (see Figure 1). Dapagliflozin doses of or 10 mg per day in patients with type diabetes mellitus for 12 weeks resulted in excretion of approximately 70 grams of glucose in the urine per day. near maximum glucose excretion was observed at the dapagliflozin daily dose 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 days for the 10 mg dose.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 Diabetes Mellitus (T2DM) (Semi-Log Plot). Figure 1. 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 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. XIGDUO XRThe administration of XIGDUO XR in healthy subjects after 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 delay of to 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. AbsorptionDapagliflozinFollowing oral administration of dapagliflozin, the maximum plasma concentration (Cmax) is usually attained within hours under fasting state. The Cmax 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 10 mg dose is 78%. Administration of dapagliflozin with high-fat meal decreases its Cmax by up to 50% and prolongs Tmax by approximately 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 HClFollowing single oral dose of metformin extended-release, Cmax is achieved with median value of hours and range of to hours. The extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food. There was no effect of food on Cmax and Tmax of metformin.DistributionDapagliflozinDapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment.Metformin HClDistribution 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. DapagliflozinThe metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is 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 50 mg [14C]-dapagliflozin dose and is the predominant drug-related component in human plasma.. Metformin HClIntravenous 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. DapagliflozinDapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following single 50 mg dose of [14C]-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 single oral dose of dapagliflozin 10 mg.. Metformin HClRenal 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 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 compartment of distribution.. Specific Populations. Renal Impairment. DapagliflozinAt steady-state (20 mg once daily dapagliflozin for days), patients with type 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 diabetes mellitus with normal renal function. Higher systemic exposure of dapagliflozin in patients with type diabetes mellitus with renal impairment did not result in correspondingly higher 24-hour urinary glucose excretion. The steady-state 24-hour urinary glucose excretion in patients with type diabetes mellitus and mild, moderate, and severe renal impairment was 42%, 80%, and 90% lower, respectively, than in patients with type 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 (5.2) and Use in Specific Populations (8.6)].. Metformin HClIn 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)].. Hepatic Impairment. DapagliflozinIn patients with mild and moderate hepatic impairment (Child-Pugh classes and B), mean Cmax 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 patients with severe hepatic impairment (Child-Pugh class C), mean Cmax and AUC of dapagliflozin were up to 40% and 67% higher, respectively, as compared to healthy matched controls. Metformin HClNo pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions (5.1)].. Geriatric. DapagliflozinBased on population pharmacokinetic analysis, age does not have clinically meaningful effect on systemic exposures of dapagliflozin.. Metformin HClLimited 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 Cmax 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 change in renal function. Gender. DapagliflozinBased on population pharmacokinetic analysis, gender does not have clinically meaningful effect on systemic exposures of dapagliflozin.. Metformin HClMetformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type diabetes, the antihyperglycemic effect of metformin was comparable in males and females.. Race. DapagliflozinBased on population pharmacokinetic analysis, race (White, Black, or Asian) does not have clinically meaningful effect on systemic exposures of dapagliflozin.. Metformin HClNo studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).. Body Weight. DapagliflozinBased on population pharmacokinetic analysis, body weight does not have 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. DapagliflozinIn 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 weak substrate of the P-glycoprotein (P-gp) active transporter, and dapagliflozin 3-O-glucuronide is 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 shows the effect of other coadministered drugs on metformin.Table 6: Effect of Coadministered Drug on Plasma Metformin Systemic ExposureCoadministered Drug(Dose Regimen)All metformin and coadministered drugs were given as single doses. Metformin(Dose Regimen) MetforminChangePercent change (with/without coadministered drug and no change 0%); and indicate the exposure increase and decrease, respectively. in AUCAUC AUC(INF). Change in Cmax No dosing adjustments required for the following:Glyburide (5 mg)850 mg9%Ratio of arithmetic means. 7% Furosemide (40 mg)850 mg15% 22% Nifedipine (10 mg)850 mg9%20%Propranolol (40 mg)850 mg10%6%Ibuprofen (400 mg)850 mg5% 7% Drugs eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7) ].Cimetidine (400 mg)850 mg40%60%. Effects of Metformin on Other Drugs. Table shows the effect of metformin on other coadministered drugs.Table 7: Effect of Metformin on Coadministered Drug Systemic ExposureCoadministered Drug(Dose Regimen)All metformin and coadministered drugs were given as single doses. Metformin(Dose Regimen) Coadministered DrugChangePercent change (with/without coadministered drug and no change 0%); and indicate the exposure increase and decrease, respectively. in AUCAUC AUC(INF) unless otherwise noted. Change in Cmax No dosing adjustments required for the following:Glyburide (5 mg)850 mg22%Ratio of arithmetic means, p-value of difference <0.05. 37% Furosemide (40 mg)850 mg12% 31% Nifedipine (10 mg)850 mg10%AUC(0-24 hr) reported. 8%Propranolol (40 mg)850 mg1% 2%Ibuprofen (400 mg)850 mg3%Ratio of arithmetic means. 1% Cimetidine (400 mg)850 mg5% 1%. Effects of Other Drugs on Dapagliflozin. Table shows the effect of coadministered drugs on dapagliflozin. No dose adjustments are recommended for dapagliflozin.Table 8: Effects of Coadministered Drugs on Dapagliflozin Systemic ExposureCoadministered Drug(Dose Regimen)Single dose unless otherwise noted. Dapagliflozin(Dose Regimen)DapagliflozinChangePercent change (with/without coadministered drug and no change 0%); and indicate the exposure increase and decrease, respectively. in AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses. Change in Cmax No dosing adjustments required for the following:Oral Antidiabetic Agents Metformin (1000 mg)20 mg1%7% Pioglitazone (45 mg)50 mg0%9% Sitagliptin (100 mg)20 mg8%4% Glimepiride (4 mg)20 mg1%1% Voglibose (0.2 mg three times daily)10 mg1%4%Other Medications Hydrochlorothiazide (25 mg)50 mg7%1% Bumetanide (1 mg)10 mg once daily for days5%8% Valsartan (320 mg)20 mg2%12% Simvastatin (40 mg)20 mg1%2%Anti-infective Agent Rifampin (600 mg once daily for days)10 mg22%7%Nonsteroidal Anti-inflammatory Agent Mefenamic Acid (loading dose of 500 mg followed by 14 doses of 250 mg every hours)10 mg51%13%. Effects of Dapagliflozin on Other Drugs. Table shows the effect of dapagliflozin on other coadministered drugs. Dapagliflozin did not meaningfully affect the pharmacokinetics of the coadministered drugs.Table 9: Effects of Dapagliflozin on the Systemic Exposures of Coadministered DrugsCoadministered Drug(Dose Regimen)Single dose unless otherwise noted.Dapagliflozin(Dose Regimen)Coadministered DrugChangePercent change (with/without coadministered drug and no change 0%); and indicate the exposure increase and decrease, respectively. in AUCAUC AUC(INF) for drugs given as single dose and AUC AUC(TAU) for drugs given in multiple doses.Change in Cmax No dosing adjustments required for the following:Oral Antidiabetic Agents Metformin (1000 mg)20 mg0%5% Pioglitazone (45 mg)50 mg0%7% Sitagliptin (100 mg)20 mg1%11% Glimepiride (4 mg)20 mg13%4%Other Medications Hydrochlorothiazide (25 mg)50 mg1%5% Bumetanide (1 mg)10 mg once daily for days13%13% Valsartan (320 mg)20 mg5%6% Simvastatin (40 mg)20 mg19%6% Digoxin (0.25 mg)20 mg loading dose then 10 mg once daily for days0%1% Warfarin (25 mg) S-warfarin R-warfarin20 mg loading dose then 10 mg once daily for days3%6%7%8%.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on animal data showing adverse renal effects, XIGDUO XR is not recommended during the second and third trimesters of pregnancy.Limited data with XIGDUO XR or dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported clear association with metformin and major birth defect or miscarriage risk (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes 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 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 to 10% in women with pre-gestational diabetes with 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 to 4% and 15 to 20%, respectively. Clinical ConsiderationsDisease-associated maternal and/or embryofetal riskPoorly 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. DataHuman Data Published data from post-marketing studies have not reported clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal DataDapagliflozinDapagliflozin 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 1-month recovery period.In prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 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 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).Metformin HClMetformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively. Determination of fetal concentrations demonstrated partial placental barrier to metformin.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1) 02/2022Dosage and Administration (2) 02/2022Warnings and Precautions (5.2) 02/2022Warnings and Precautions (5.4) Removed 02/2022.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEXIGDUO(R) XR (ZIG-DO-OH X-R)(dapagliflozin and metformin hydrochloride extended-release)tablets, for oral useWhat is the most important information should know about XIGDUO XRXIGDUO XR can cause serious side effects, including:oLactic Acidosis. Metformin, one of the medicines in XIGDUO XR, can cause rare but serious condition called lactic acidosis (a build-up of an acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital.Call your healthcare provider right away if you have any of the following symptoms, which could be signs of lactic acidosis: oyou feel cold in your hands or feetoyou feel dizzy or lightheadedoyou have slow or irregular heartbeatoyou feel very weak or tiredoyou have unusual (not normal) muscle painoyou have trouble breathingoyou feel unusual sleepiness or sleep longer than usualoyou have stomach pains, nausea or vomitingMost people who have had lactic acidosis with metformin have other things that, combined with the metformin use, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have higher chance for getting lactic acidosis with XIGDUO XR if you: ohave severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.ohave liver problems.odrink alcohol very often, or drink lot of alcohol in the short-term (binge drinking).oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids.ohave surgery.ohave heart attack, severe infection, or stroke.The best way to keep from having problem with lactic acidosis from metformin is to tell your healthcare provider if you have any of the problems in the list above. Your healthcare provider may decide to stop your XIGDUO XR for while if you have any of these things.XIGDUO XR can have other serious side effects. See What are the possible side effects of XIGDUO XR What is XIGDUO XRoXIGDUO XR contains prescription medicines called dapagliflozin (FARXIGA) and metformin HCl (GLUCOPHAGE). XIGDUO XR is used in adults with type diabetes mellitus:oto improve blood sugar (glucose) control along with diet and exerciseowho have known cardiovascular disease or multiple cardiovascular risk factors and dapagliflozin is needed to reduce the risk of hospitalization for heart failureowho have heart failure (when the heart is weak and cannot pump enough blood to the rest of your body) and dapagliflozin is needed to reduce the risk of cardiovascular death and hospitalization for heart failure.oXIGDUO XR is not for people with type diabetes. XIGDUO XR may increase the risk of diabetic ketoacidosis (increased ketones in your blood or urine) in people with type diabetes.oXIGDUO XR is only for use in adults with type diabetes mellitus, because it contains the prescription medicine metformin HCl.oIt is not known if XIGDUO XR is safe and effective in children younger than 18 years of age.Who should not take XIGDUO XRDo not take XIGDUO XR if you:ohave severe kidney problems or are on dialysis.oare allergic to dapagliflozin, metformin HCl, or any of the ingredients in XIGDUO XR. See the end of this Medication Guide for complete list of ingredients in XIGDUO XR. Symptoms of serious allergic reaction to XIGDUO XR may include:oskin rashoraised red patches on your skin (hives)oswelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing If you have any of these symptoms, stop taking XIGDUO XR and contact your healthcare provider or go to the nearest hospital emergency room right away.ohave condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine).What should tell my healthcare provider before taking XIGDUO XRBefore you take XIGDUO XR, tell your healthcare provider if you:ohave type diabetes or have had diabetic ketoacidosis.ohave kidney problems.ohave liver problems.ohave history of urinary tract infections or problems urinating.ohave heart problems, including congestive heart failure.oare going to have surgery and will not be able to eat or drink much. Your healthcare provider may stop XIGDUO XR before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking XIGDUO XR and when to start it again. See What is the most important information should know about XIGDUO XRoare eating less, or there is change in your diet.ohave or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.odrink alcohol very often, or drink lot of alcohol in the short-term (binge drinking).oare going to get an injection of dye or contrast agents for an x-ray procedure. XIGDUO XR may need to be stopped for short time. Talk to your healthcare provider about when you should stop XIGDUO XR and when you should start XIGDUO XR again. See What is the most important information should know about XIGDUO XRoare pregnant or plan to become pregnant. XIGDUO XR may harm your unborn baby. If you are pregnant or plan to become pregnant, talk to your healthcare provider about the best way to control your blood sugar.oare breastfeeding or plan to breastfeed. It is not known if XIGDUO XR passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you are taking XIGDUO XR.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. XIGDUO XR may affect the way other medicines work and other medicines may affect the way XIGDUO XR works.Especially tell your healthcare provider if you take:owater pills (diuretics)orifampin (used to treat or prevent tuberculosis)ophenytoin (used to control seizures)odigoxin (used to treat heart problems)Ask your healthcare provider for list of these medicines if you are not sure if your medicine is listed above.Know the medicines you take. Keep list of them and show it to your healthcare provider and pharmacist when you get new medicine.How should take XIGDUO XRoTake XIGDUO XR exactly as your healthcare provider tells you to take it.oDo not change your dose of XIGDUO XR without talking to your healthcare provider.oTake XIGDUO XR by mouth time each day with meals to lower your chance of an upset stomach. Talk to your healthcare provider about the best time of day for you.oSwallow XIGDUO XR whole. Do not crush, cut, or chew XIGDUO XR.oYou may sometimes pass soft mass in your stools (bowel movement) that looks like XIGDUO XR tablets.oWhen your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare providers instructions.oStay on your prescribed diet and exercise program while taking XIGDUO XR.oXIGDUO XR will cause your urine to test positive for glucose.oYour healthcare provider may do certain blood tests before you start XIGDUO XR and during your treatment.oYour healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your A1c.oFollow your healthcare providers instructions for treating low blood sugar (hypoglycemia). Talk to your healthcare provider if low blood sugar is problem for you.oIf you miss dose of XIGDUO XR, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time.oIf you take too much XIGDUO XR, call your healthcare provider or go to the nearest hospital emergency room right away.What should avoid while taking XIGDUO XRoAvoid drinking alcohol very often, or drinking lot of alcohol in short period of time (binge drinking). It can increase your chances of getting serious side effects.What are the possible side effects of XIGDUO XRXIGDUO XR may cause serious side effects including:See What is the most important information should know about XIGDUO XR oDehydration. XIGDUO XR can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden kidney injury in people with type diabetes mellitus who are taking dapagliflozin, medicine in XIGDUO XR. You may be at higher risk of dehydration if you:otake medicines to lower your blood pressure, including water pills (diuretics)oare 65 years of age or olderoare on low salt dietohave kidney problems Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on daily basis.oKetoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetes or type diabetes, during treatment with dapagliflozin, one of the medicines in XIGDUO XR. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with XIGDUO XR. Ketoacidosis is serious condition, which may need to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with XIGDUO XR even if your blood sugar is less than 250 mg/dL. Stop taking XIGDUO XR and call your healthcare provider right away if you get any of the following symptoms: onauseaovomitingostomach area (abdominal) painotirednessotrouble breathing If you get any of these symptoms during treatment with XIGDUO XR, if possible check for ketones in your urine, even if your blood sugar is less than 250 mg/dL.oSerious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking dapagliflozin, one of the medicines in XIGDUO XR. Tell your healthcare provider if you have any signs or symptoms of urinary tract infection, such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting. oLow blood sugar (hypoglycemia). If you take XIGDUO XR with another medicine that can cause low blood sugar, such as sulfonylureas or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take XIGDUO XR. Signs and symptoms of low blood sugar may include:oheadacheoshaking or feelingjitteryodizzinessoweaknessosweatingofast heartbeatoconfusionodrowsinessoirritabilityohungeroA rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take dapagliflozin, one of the medicines in XIGDUO XR. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals: opain or tendernessoswellingoredness of skin (erythema)oLow vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels.oVaginal yeast infection. Women who take XIGDUO XR may get vaginal yeast infections. Symptoms of vaginal yeast infection include:ovaginal odorowhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)ovaginal itching oYeast infection of the penis (balanitis or balanoposthitis). Men who take XIGDUO XR may get yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:oredness, itching, or swelling of the penisorash of the penisofoul smelling discharge from the penisopain in the skin around the penis Talk to your healthcare provider about what to do if you get symptoms of yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medicine and your symptoms do not go away.The most common side effects of XIGDUO XR include: ovaginal yeast infectionsodiarrheaoheadacheostuffy or runny nose and sore throatourinary tract infectionTell your healthcare provider or pharmacist if you have any side effect that bothers you or does not go away.These are not all of the possible side effects of XIGDUO XR. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store XIGDUO XRStore XIGDUO XR at room temperature between 68F and 77F (20C and 25C).Keep XIGDUO XR and all medicines out of the reach of children.General information about the safe and effective use of XIGDUO XRMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use XIGDUO XR for condition for which it is not prescribed. Do not give XIGDUO XR to other people, even if they have the same symptoms you have. It may harm them.This Medication Guide summarizes the most important information about XIGDUO XR. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about XIGDUO XR that is written for health professionals.For more information, go to www.xigduoxr.com or call 1-800-236-9933What are the ingredients in XIGDUO XRActive ingredients: dapagliflozin and metformin hydrochlorideInactive ingredients: microcrystalline cellulose, lactose anhydrous, crospovidone, silicon dioxide, magnesium stearate, carboxymethylcellulose sodium, and hypromellose.The film coatings contain the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, and talc. Additionally, the film coating for the XIGDUO XR mg/500 mg tablets contains FD&C Yellow No. 6/Sunset Yellow FCF Aluminum Lake and the film coating for the XIGDUO XR 2.5 mg/1000 mg, mg/1000 mg, 10 mg/500 mg, and 10 mg/1000 mg tablets contains iron oxides.Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 2/2022. oLactic Acidosis. Metformin, one of the medicines in XIGDUO XR, can cause rare but serious condition called lactic acidosis (a build-up of an acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital.. oyou feel cold in your hands or feetoyou feel dizzy or lightheadedoyou have slow or irregular heartbeatoyou feel very weak or tiredoyou have unusual (not normal) muscle painoyou have trouble breathingoyou feel unusual sleepiness or sleep longer than usualoyou have stomach pains, nausea or vomiting. oyou feel cold in your hands or feet. oyou feel dizzy or lightheaded. oyou have slow or irregular heartbeat. oyou feel very weak or tired. oyou have unusual (not normal) muscle pain. oyou have trouble breathing. oyou feel unusual sleepiness or sleep longer than usual. oyou have stomach pains, nausea or vomiting. ohave severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.ohave liver problems.odrink alcohol very often, or drink lot of alcohol in the short-term (binge drinking).oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids.ohave surgery.ohave heart attack, severe infection, or stroke.. ohave severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.. ohave liver problems.. odrink alcohol very often, or drink lot of alcohol in the short-term (binge drinking).. oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids.. ohave surgery.. ohave heart attack, severe infection, or stroke.. oXIGDUO XR contains prescription medicines called dapagliflozin (FARXIGA) and metformin HCl (GLUCOPHAGE). XIGDUO XR is used in adults with type diabetes mellitus:oto improve blood sugar (glucose) control along with diet and exerciseowho have known cardiovascular disease or multiple cardiovascular risk factors and dapagliflozin is needed to reduce the risk of hospitalization for heart failureowho have heart failure (when the heart is weak and cannot pump enough blood to the rest of your body) and dapagliflozin is needed to reduce the risk of cardiovascular death and hospitalization for heart failure.. oto improve blood sugar (glucose) control along with diet and exercise. owho have known cardiovascular disease or multiple cardiovascular risk factors and dapagliflozin is needed to reduce the risk of hospitalization for heart failure. owho have heart failure (when the heart is weak and cannot pump enough blood to the rest of your body) and dapagliflozin is needed to reduce the risk of cardiovascular death and hospitalization for heart failure.. oXIGDUO XR is not for people with type diabetes. XIGDUO XR may increase the risk of diabetic ketoacidosis (increased ketones in your blood or urine) in people with type diabetes.. oXIGDUO XR is only for use in adults with type diabetes mellitus, because it contains the prescription medicine metformin HCl.. oIt is not known if XIGDUO XR is safe and effective in children younger than 18 years of age.. ohave severe kidney problems or are on dialysis.. oare allergic to dapagliflozin, metformin HCl, or any of the ingredients in XIGDUO XR. See the end of this Medication Guide for complete list of ingredients in XIGDUO XR. Symptoms of serious allergic reaction to XIGDUO XR may include:oskin rashoraised red patches on your skin (hives)oswelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing. oskin rash. oraised red patches on your skin (hives). oswelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing. If you have any of these symptoms, stop taking XIGDUO XR and contact your healthcare provider or go to the nearest hospital emergency room right away.. ohave condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in your blood or urine).. ohave type diabetes or have had diabetic ketoacidosis.. ohave kidney problems.. ohave liver problems.. ohave history of urinary tract infections or problems urinating.. ohave heart problems, including congestive heart failure.. oare going to have surgery and will not be able to eat or drink much. Your healthcare provider may stop XIGDUO XR before you have surgery. Talk to your healthcare provider if you are having surgery about when to stop taking XIGDUO XR and when to start it again. See What is the most important information should know about XIGDUO XR. oare eating less, or there is change in your diet.. ohave or have had problems with your pancreas, including pancreatitis or surgery on your pancreas.. odrink alcohol very often, or drink lot of alcohol in the short-term (binge drinking).. oare going to get an injection of dye or contrast agents for an x-ray procedure. XIGDUO XR may need to be stopped for short time. Talk to your healthcare provider about when you should stop XIGDUO XR and when you should start XIGDUO XR again. See What is the most important information should know about XIGDUO XR. oare pregnant or plan to become pregnant. XIGDUO XR may harm your unborn baby. If you are pregnant or plan to become pregnant, talk to your healthcare provider about the best way to control your blood sugar.. oare breastfeeding or plan to breastfeed. It is not known if XIGDUO XR passes into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you are taking XIGDUO XR.. owater pills (diuretics). orifampin (used to treat or prevent tuberculosis). ophenytoin (used to control seizures). odigoxin (used to treat heart problems). oTake XIGDUO XR exactly as your healthcare provider tells you to take it.. oDo not change your dose of XIGDUO XR without talking to your healthcare provider.. oTake XIGDUO XR by mouth time each day with meals to lower your chance of an upset stomach. Talk to your healthcare provider about the best time of day for you.. oSwallow XIGDUO XR whole. Do not crush, cut, or chew XIGDUO XR.. oYou may sometimes pass soft mass in your stools (bowel movement) that looks like XIGDUO XR tablets.. oWhen your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine you need may change. Tell your healthcare provider right away if you have any of these conditions and follow your healthcare providers instructions.. oStay on your prescribed diet and exercise program while taking XIGDUO XR.. oXIGDUO XR will cause your urine to test positive for glucose.. oYour healthcare provider may do certain blood tests before you start XIGDUO XR and during your treatment.. oYour healthcare provider will check your diabetes with regular blood tests, including your blood sugar levels and your A1c.. oFollow your healthcare providers instructions for treating low blood sugar (hypoglycemia). Talk to your healthcare provider if low blood sugar is problem for you.. oIf you miss dose of XIGDUO XR, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time.. oIf you take too much XIGDUO XR, call your healthcare provider or go to the nearest hospital emergency room right away.. oAvoid drinking alcohol very often, or drinking lot of alcohol in short period of time (binge drinking). It can increase your chances of getting serious side effects.. oDehydration. XIGDUO XR can cause some people to become dehydrated (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension). There have been reports of sudden kidney injury in people with type diabetes mellitus who are taking dapagliflozin, medicine in XIGDUO XR.. You may be at higher risk of dehydration if you:otake medicines to lower your blood pressure, including water pills (diuretics)oare 65 years of age or olderoare on low salt dietohave kidney problems. otake medicines to lower your blood pressure, including water pills (diuretics). oare 65 years of age or older. oare on low salt diet. ohave kidney problems. Talk to your healthcare provider about what you can do to prevent dehydration including how much fluid you should drink on daily basis.. oKetoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type diabetes or type diabetes, during treatment with dapagliflozin, one of the medicines in XIGDUO XR. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with XIGDUO XR. Ketoacidosis is serious condition, which may need to be treated in hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with XIGDUO XR even if your blood sugar is less than 250 mg/dL. Stop taking XIGDUO XR and call your healthcare provider right away if you get any of the following symptoms: onausea. ovomiting. ostomach area (abdominal) pain. otiredness. otrouble breathing. If you get any of these symptoms during treatment with XIGDUO XR, if possible check for ketones in your urine, even if your blood sugar is less than 250 mg/dL.. oSerious urinary tract infections. Serious urinary tract infections that may lead to hospitalization have happened in people who are taking dapagliflozin, one of the medicines in XIGDUO XR. Tell your healthcare provider if you have any signs or symptoms of urinary tract infection, such as burning feeling when passing urine, need to urinate often, the need to urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. Sometimes people also may have fever, back pain, nausea or vomiting. oLow blood sugar (hypoglycemia). If you take XIGDUO XR with another medicine that can cause low blood sugar, such as sulfonylureas or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take XIGDUO XR. Signs and symptoms of low blood sugar may include:. oheadache. oshaking or feelingjittery. odizziness. oweakness. osweating. ofast heartbeat. oconfusion. odrowsiness. oirritability. ohunger. oA rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take dapagliflozin, one of the medicines in XIGDUO XR. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals: opain or tenderness. oswelling. oredness of skin (erythema). oLow vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels.. oVaginal yeast infection. Women who take XIGDUO XR may get vaginal yeast infections. Symptoms of vaginal yeast infection include:ovaginal odorowhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese)ovaginal itching ovaginal odor. owhite or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese). ovaginal itching. oYeast infection of the penis (balanitis or balanoposthitis). Men who take XIGDUO XR may get yeast infection of the skin around the penis. Certain men who are not circumcised may have swelling of the penis that makes it difficult to pull back the skin around the tip of the penis. Other symptoms of yeast infection of the penis include:oredness, itching, or swelling of the penisorash of the penisofoul smelling discharge from the penisopain in the skin around the penis oredness, itching, or swelling of the penis. orash of the penis. ofoul smelling discharge from the penis. opain in the skin around the penis. Talk to your healthcare provider about what to do if you get symptoms of yeast infection of the vagina or penis. Your healthcare provider may suggest you use an over-the-counter antifungal medicine. Talk to your healthcare provider right away if you use an over-the-counter antifungal medicine and your symptoms do not go away.. ovaginal yeast infectionsodiarrheaoheadache. ovaginal yeast infections. odiarrhea. oheadache. ostuffy or runny nose and sore throat. ourinary tract infection.

SPL UNCLASSIFIED SECTION.

2.1 Prior to Initiation of XIGDUO XR. oAssess renal function before initiating XIGDUO XR therapy and periodically thereafter [see Warnings and Precautions (5.1, 5.2)].oAssess volume status and, if necessary, correct volume depletion prior to initiation of XIGDUO XR [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)]. oAssess renal function before initiating XIGDUO XR therapy and periodically thereafter [see Warnings and Precautions (5.1, 5.2)].. oAssess volume status and, if necessary, correct volume depletion prior to initiation of XIGDUO XR [see Warnings and Precautions (5.2) and Use in Specific Populations (8.5, 8.6)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPregnancy: Advise females of the potential risk to fetus, especially during the second and third trimesters. (8.1)oLactation: XIGDUO XR is not recommended when breastfeeding. (8.2)oFemales and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)oGeriatrics: Higher incidence of adverse reactions related to hypotension. Assess renal function more frequently. (5.1, 5.2, 8.5, 8.6)oRenal Impairment: Higher incidence of adverse reactions related to volume depletion. (5.1, 5.2, 8.6)oHepatic Impairment: Avoid use in patients with hepatic impairment. (8.7). oPregnancy: Advise females of the potential risk to fetus, especially during the second and third trimesters. (8.1). oLactation: XIGDUO XR is not recommended when breastfeeding. (8.2). oFemales and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3). oGeriatrics: Higher incidence of adverse reactions related to hypotension. Assess renal function more frequently. (5.1, 5.2, 8.5, 8.6). oRenal Impairment: Higher incidence of adverse reactions related to volume depletion. (5.1, 5.2, 8.6). oHepatic Impairment: Avoid use in patients with hepatic impairment. (8.7). 8.1 Pregnancy. Risk SummaryBased on animal data showing adverse renal effects, XIGDUO XR is not recommended during the second and third trimesters of pregnancy.Limited data with XIGDUO XR or dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported clear association with metformin and major birth defect or miscarriage risk (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes 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 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 to 10% in women with pre-gestational diabetes with 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 to 4% and 15 to 20%, respectively. Clinical ConsiderationsDisease-associated maternal and/or embryofetal riskPoorly 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. DataHuman Data Published data from post-marketing studies have not reported clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal DataDapagliflozinDapagliflozin 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 1-month recovery period.In prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 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 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).Metformin HClMetformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively. Determination of fetal concentrations demonstrated partial placental barrier to metformin.. 8.2 Lactation Risk SummaryThere is no information regarding the presence of XIGDUO XR or dapagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk (see Data). However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin 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 are not clear. Since human kidney maturation occurs in utero and during the first 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 XIGDUO XR is not recommended while breastfeeding. DataDapagliflozinDapagliflozin was present in rat milk at milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at 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.Metformin HClPublished clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.. 8.4 Pediatric Use. Safety and effectiveness of XIGDUO XR in pediatric patients under 18 years of age have not been established.. 8.5 Geriatric Use. XIGDUO XRNo XIGDUO XR dosage change is recommended based on age. More frequent assessment of renal function is recommended in elderly patients.DapagliflozinA 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 pool of 21 double-blind, controlled, clinical studies assessing the efficacy of dapagliflozin in improving glycemic control. 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, higher proportion of patients treated with dapagliflozin had adverse reactions of hypotension [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].In the overall population of the DAPA-HF study, 2714 (57%) out of 4744 patients with heart failure with reduced ejection fraction (HFrEF) were older than 65 years. Out of 2139 patients with HFrEF and type diabetes mellitus, 1211 (56.6%) were older than 65 years. Safety and efficacy were similar for patients age 65 years and younger and those older than 65 in both the overall population and the patients with type diabetes mellitus.Metformin HClControlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.1)].. 8.6 Renal Impairment. XIGDUO XR is not recommended in patients with an eGFR below 45 mL/min/1.73 m2 and is contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease or patients on dialysis [see Dosage and Administration (2.4), Contraindications (4) and Warnings and Precautions (5.1, 5.2)].DapagliflozinDapagliflozin was evaluated in two glycemic control studies that included patients with moderate renal impairment (an eGFR of 45 to less than 60 mL/min/1.73 m2, and an eGFR of 30 to less than 60 mL/min/1.73 m2) [see Clinical Studies (14.1) ]. The safety profile of dapagliflozin in the study of patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 was similar to the general population of patients with type diabetes. Although patients in the dapagliflozin arm had reduction in eGFR compared to the placebo arm, eGFR generally returned towards baseline after treatment discontinuation. Patients with diabetes and renal impairment using dapagliflozin for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury. In the study of patients with an eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients receiving dapagliflozin experienced bone fractures compared to none receiving placebo.In the DAPA-HF study [see Clinical Studies (14.3)] that included patients with eGFR equal to or above 30 mL/min/1.73 m2, there were 1926 (41%) patients with eGFR below 60 mL/min/1.73 m2 and 719 (15%) with eGFR below 45 mL/min/1.73 m2. No overall differences in safety or efficacy were seen in these patients compared to patients with normal renal function.Metformin HCl Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. XIGDUO XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Dosage and Administration (2.4) Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. XIGDUO XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oLactic Acidosis: See boxed warning. (2.3, 4, 5.1)oVolume Depletion: Before initiating XIGDUO XR, assess and correct volume status in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.2, 6.1)oKetoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis regardless of blood glucose level. If suspected, discontinue XIGDUO XR, evaluate and treat promptly. Before initiating XIGDUO XR, consider risk factors for ketoacidosis. Patients on XIGDUO XR may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. (5.3) oUrosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.4)oHypoglycemia: In patients taking insulin or an insulin secretagogue with XIGDUO XR, consider lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. (5.5)oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.6) oVitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually. (5.7, 6.1)oGenital Mycotic Infections: Monitor and treat if indicated. (5.8). oLactic Acidosis: See boxed warning. (2.3, 4, 5.1). oVolume Depletion: Before initiating XIGDUO XR, assess and correct volume status in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. (5.2, 6.1). oKetoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis regardless of blood glucose level. If suspected, discontinue XIGDUO XR, evaluate and treat promptly. Before initiating XIGDUO XR, consider risk factors for ketoacidosis. Patients on XIGDUO XR may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. (5.3) oUrosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.4). oHypoglycemia: In patients taking insulin or an insulin secretagogue with XIGDUO XR, consider lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. (5.5). oNecrotizing Fasciitis of the Perineum (Fourniers Gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.6) oVitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually. (5.7, 6.1). oGenital Mycotic Infections: Monitor and treat if indicated. (5.8). 5.1 Lactic Acidosis. There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in hospital setting, along with immediate discontinuation of XIGDUO XR. In XIGDUO XR-treated patients with diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue XIGDUO XR and report these symptoms to their healthcare provider.For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include [see Dosage and Administration (2.1 and 2.4 and Clinical Pharmacology (12.3)]:oBefore initiating XIGDUO XR, obtain an estimated glomerular filtration rate (eGFR).oXIGDUO XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].oObtain an eGFR at least annually in all patients taking XIGDUO XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.Drug Interactions: The concomitant use of XIGDUO XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patients age because elderly patients have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop XIGDUO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart XIGDUO XR if renal function is stable.Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. XIGDUO XR should be temporarily discontinued while patients have restricted food and fluid intake.Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue XIGDUO XR.Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving XIGDUO XR.Hepatic Impairment: Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of XIGDUO XR in patients with clinical or laboratory evidence of hepatic disease.. oBefore initiating XIGDUO XR, obtain an estimated glomerular filtration rate (eGFR).. oXIGDUO XR is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].. oObtain an eGFR at least annually in all patients taking XIGDUO XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.. 5.2 Volume Depletion. Dapagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type diabetes mellitus receiving sodium-glucose co-transporter (SGLT2) inhibitors, including dapagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating XIGDUO XR in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension and renal function after initiating therapy.. 5.3 Ketoacidosis Reports of ketoacidosis, serious life-threatening condition requiring urgent hospitalization have been identified in patients with type and type diabetes mellitus taking SGLT2 inhibitors, including dapagliflozin [see Adverse Reactions (6.1)]. Fatal cases of ketoacidosis have been reported in patients taking dapagliflozin. XIGDUO XR is not indicated for the treatment of patients with type diabetes mellitus [see Indications and Usage (1)]. Patients treated with XIGDUO XR who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of blood glucose levels as ketoacidosis associated with XIGDUO XR may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, XIGDUO XR should be discontinued, the patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid, and carbohydrate replacement.In many of the postmarketing reports, and particularly in patients with type diabetes, the presence of ketoacidosis was not immediately recognized, and the institution of treatment was delayed because the presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis, such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.Before initiating XIGDUO XR, consider factors in the patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction and alcohol abuse. For patients who undergo scheduled surgery, consider temporarily discontinuing XIGDUO XR for at least days prior to surgery [see Clinical Pharmacology (12.2, 12.3)]. Consider monitoring for ketoacidosis and temporarily discontinuing XIGDUO XR in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting XIGDUO XR.Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue XIGDUO XR and seek medical attention immediately if signs and symptoms occur.. 5.4 Urosepsis and Pyelonephritis Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6.2)].. 5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues. Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. XIGDUO XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with XIGDUO XR [see Drug Interactions (7) ].. 5.6 Necrotizing Fasciitis of the Perineum (Fourniers Gangrene) Reports of necrotizing fasciitis of the perineum (Fourniers Gangrene), rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.Patients treated with XIGDUO XR presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue XIGDUO XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.. 5.7 Vitamin B12 Concentrations. In controlled clinical trials of metformin of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on XIGDUO XR and manage any abnormalities [see Adverse Reactions (6.1)].. 5.8 Genital Mycotic Infections. Dapagliflozin increases the risk of genital mycotic infections. Patients with history of genital mycotic infections were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.