DAPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE

1 INDICATIONS AND USAGE Dapagliflozin and metformin hydrochloride extended-release tablets are combination of dapagliflozin and metformin hydrochloride (HCl) extended-release, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Dapagliflozin when used as a component of dapagliflozin and metformin hydrochloride extended-release tablets, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Sustained eGFR decline, end-stage kidney disease, cardiovascular death and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. Cardiovascular death, hospitalization for heart failure and urgent heart failure visit in patients with heart failure. Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors. Limitations of Use Dapagliflozin and metformin hydrochloride extended-release tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions ( 5.2 )] . Because of the metformin HCl component, the use of dapagliflozin and metformin hydrochloride extended-release tablet is limited to patients with type 2 diabetes mellitus for all indications. Dapagliflozin and metformin hydrochloride extended-release tablets are not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for kidney disease. Dapagliflozin and metformin hydrochloride extended-release tablets are not expected to be effective in these populations. Pediatric use information is approved for AstraZeneca AB's Xigduo ® XR (dapagliflozin and metformin hydrochloride) Extended-Release Tablets. However, due to AstraZeneca AB's marketing exclusivity rights, this drug product is not labeled with that information. Dapagliflozin and metformin hydrochloride extended-release tablets are combination of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Dapagliflozin when used as a component of dapagliflozin and metformin hydrochloride extended-release tablets, is indicated in adults with type 2 diabetes mellitus to reduce the risk of: Sustained eGFR decline, end-stage kidney disease, cardiovascular death and hospitalization for heart failure in patients with chronic kidney disease at risk of progression. (1) Cardiovascular death, hospitalization for heart failure and urgent heart failure visit in patients with heart failure. (1) Hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. ( 1 ) L i mitations of use : Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 ) Because of the metformin HCl component, the use of dapagliflozin and metformin hydrochloride extended-release tablet is limited to patients with type 2 diabetes mellitus for all indications. ( 1 ) Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for the treatment of kidney disease. Dapagliflozin and metformin hydrochloride extended-release tablet is not expected to be effective in these populations. ( 1 )

2 DOSAGE AND ADMINISTRATION Assess renal function prior to initiating and then as clinically indicated. ( 2.1 ) Assess volume status and correct volume depletion before initiating. ( 2.1 ) Individualize the starting dosage based on the patient's current treatment. ( 2.3 ) Administer orally once daily in the morning with food. ( 2.2 ) To improve glycemic control, for patients not already taking dapagliflozin, the recommended starting dosage for dapagliflozin is 5 mg once daily. ( 2.3 ) For indications in adults related to heart failure and chronic kidney disease the recommended dosage of dapagliflozin is 10 mg once daily. ( 2.3 ) Do not exceed a daily dosage of 10 mg dapagliflozin/2000 mg metformin HCl extended-release. ( 2.3 ) See Full Prescribing Information for dosage recommendations in patients with renal impairment. ( 2.4 ) Dapagliflozin and metformin hydrochloride extended-release tablet may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. ( 2.5 ) Withhold dapagliflozin and metformin hydrochloride extended-release tablets for at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. ( 2.6 ) 2.1 Testing Prior to Initiation of Dapagliflozin and Metformin Hydrochloride Extended-Release Tablets Assess renal function prior to initiating dapagliflozin and metformin hydrochloride extended-release tablets and then as clinically indicated [see Warnings and Precautions ( 5.1 , 5.3 )]. Assess volume status. In patients with volume depletion, correct this condition before initiating dapagliflozin and metformin hydrochloride extended-release tablets [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.5 , 8.6 )] . 2.2 Recommended Administration Take dapagliflozin and metformin hydrochloride extended-release tablets orally once daily in the morning with food. Swallow dapagliflozin and metformin hydrochloride extended-release tablets whole and never crush, cut, or chew. 2.3 Recommended Dosage Individualize the starting dosage of dapagliflozin and metformin hydrochloride extended-release tablets based upon the patient's current regimen. Patients taking an evening dosage of metformin HCl extended-release should skip their last dose before starting dapagliflozin and metformin hydrochloride extended-release tablets. To improve glycemic control in patients not already taking: Dapagliflozin: the recommended starting dosage of dapagliflozin in dapagliflozin and metformin hydrochloride extended-release tablets is 5 mg orally once daily. Metformin HCl extended-release is dapagliflozin and metformin hydrochloride extended-release tablets are 500 mg orally once daily. For dapagliflozin and metformin hydrochloride extended-release tablets indications in adults related to heart failure and chronic kidney disease, the recommended dosage of dapagliflozin in dapagliflozin and metformin hydrochloride extended-release tablets are 10 mg orally once daily. For all dapagliflozin and metformin hydrochloride extended-release tablets indications, the dosage may be adjusted based on effectiveness and tolerability. The maximum recommended daily dosage of dapagliflozin is 10 mg and 2,000 mg of metformin HCl extended-release, with gradual dosage escalation to reduce gastrointestinal adverse reactions with metformin HCl [See Adverse Reactions ( 6.1 )] . Pediatric use information is approved for AstraZeneca AB's Xigduo ® XR (dapagliflozin and metformin hydrochloride) Extended-Release Tablets. However, due to AstraZeneca AB's marketing exclusivity rights, this drug product is not labeled with that information. 2.4 Recommended Dosage in Patients with Renal Impairment The recommended dosage of dapagliflozin and metformin hydrochloride extended-release tablets in patients with an estimated glomerular filtration rate (eGFR) greater than or equal to 45 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function. Initiation of dapagliflozin and…

5 WARNINGS AND PRECAUTIONS Lactic Acidosis: See boxed warning. ( 5.1 ) Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue dapagliflozin and metformin hydrochloride extended-release tablets if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.2 ) Volume Depletion: Before initiating dapagliflozin and metformin hydrochloride extended-release tablets, 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. ( 5.3 ) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. ( 5.4 ) Hypoglycemia: consider a lower dosage of insulin or an insulin secretagogue to reduce the risk of hypoglycemia when used concomitantly with dapagliflozin and metformin hydrochloride extended-release tablets. ( 5.5 ) Necrotizing Fasciitis of the Perineum (Fournier's 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 ) Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels. Measure hematological parameters annually. ( 5.7 ) Genital 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 a subtle onset and were accompanied by non-specific 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 a hospital setting, along with immediate discontinuation of dapagliflozin and metformin hydrochloride extended-release tablets. In dapagliflozin and metformin hydrochloride extended-release tablets-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a 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 dapagliflozin and metformin hydrochloride extended-release tablets 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 patient's renal function include [see Dosage and Administration (…

4 CONTRAINDICATIONS Dapagliflozin and metformin hydrochloride extended-release tablets are contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) or end-stage renal disease [see Warnings and Precautions ( 5.1 )]. History of a serious hypersensitivity reaction to dapagliflozin, metformin HCl, or any of the excipients in dapagliflozin and metformin hydrochloride extended-release tablets. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin [see Adverse Reactions ( 6.1 )] . Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions ( 5.1 ) and Warnings and Precautions ( 5.2 )] . Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ), end-stage renal disease. ( 4 ) History of serious hypersensitivity to dapagliflozin, metformin HCl, or any of the excipients in dapagliflozin and metformin hydrochloride extended-release tablets. ( 4 ) Metabolic acidosis, including diabetic ketoacidosis. ( 4 )

7 DRUG INTERACTIONS Table 6: Clinically Relevant Interactions with Dapagliflozin and Metformin Hydrochloride Extended-Release Tablets Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with dapagliflozin and metformin hydrochloride extended-release tablets may increase the risk for lactic acidosis. Intervention Consider more frequent monitoring of these patients. Drugs that Reduce Metformin Clearance Clinical Impact Concomitant 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 )] . Intervention Consider the benefits and risks of concomitant use. Alcohol Clinical Impact Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention Warn patients against excessive alcohol intake while receiving dapagliflozin and metformin hydrochloride extended-release tablets. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when dapagliflozin and metformin hydrochloride extended-release tablet is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions ( 5.5 )] . Intervention Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact Certain 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. Intervention When such drugs are administered to a patient receiving dapagliflozin and metformin hydrochloride extended-release tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving dapagliflozin and metformin hydrochloride extended-release tablets, observe the patient closely for hypoglycemia. Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during dapagliflozin and metformin hydrochloride extended-release tablets initiation and dosage changes. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. Ca r b o n i c anhydrase inhibitor s: May increase risk of lactic acidosis. Consider more frequent monitoring. ( 7 ) Dr u g s that reduce metformin clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use. ( 7 ) See full prescribing information for additional drug interactions and information on interference of dapagliflozin and metformin hydrochloride extended-release tablets with laboratory tests. ( 7 )

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, dapagliflozin and metformin hydrochloride extended-release tablets are not recommended during the second and third trimesters of pregnancy. Limited data with dapagliflozin and metformin hydrochloride extended-release tablets 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 a 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 a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data) . The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk: Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data: Published data from post-marketing studies have not reported a 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 Data: Dapagliflozin Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation. Increased incidence or severity of renal pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development. In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin w…

8.2 Lactation Risk Summary There is no information regarding the presence of dapagliflozin and metformin hydrochloride extended-release tablets 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 is not clear. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in breastfed infants, advise women that use of dapagliflozin and metformin hydrochloride extended-release tablets are not recommended while breastfeeding. Data Dapagliflozin: Dapagliflozin was present in rat milk at a milk/plasma ratio of 0.49, indicating that dapagliflozin and its metabolites are transferred into milk at a concentration that is approximately 50% of that in maternal plasma. Juvenile rats directly exposed to dapagliflozin showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Metformin HCl: Published 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 a 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.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Lactic Acidosis [see Boxed Warning and Warnings and Precautions ( 5.1 )] Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions ( 5.2 )] Volume Depletion [see Warnings and Precautions ( 5.3 )] Urosepsis and Pyelonephritis [see Warnings and Precautions ( 5.4 )] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.5 )] Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) [see Warnings and Precautions ( 5.6 )] Vitamin B 12 Concentrations [see Warnings and Precautions ( 5.7 )] Genital Mycotic Infections [see Warnings and Precautions ( 5.8 )] Adverse reactions reported in >5% of patients treated with dapagliflozin and metformin hydrochloride extended-release tablets were female genital mycotic infection, nasopharyngitis, urinary tract infection, diarrhea, and headache. ( 6.1 ) Adverse reactions reported in >5% of patients treated with metformin extended-release are: diarrhea and nausea/vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus In placebo-controlled monotherapy trials of metformin HCl extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin HCl extended-release. Clinical Trials with Dapagliflozin in Adults Dapagliflozin Dapagliflozin has been evaluated in clinical trials in adult patients with type 2 diabetes mellitus, in adult patients with heart failure, and in adult patients with chronic kidney disease. The overall safety profile of dapagliflozin was consistent across the studied indications. No new adverse reactions were identified in the DAPA-HF, DELIVER and DAPA-CKD trials. Pools of Placebo-Controlled Clinical Trials for Glycemic Control in Adults Pool of 8 Placebo-Controlled Adult Trials for Dapagliflozin and Metformin HCl for Glycemic Control Data from a prespecified pool of adult patients from 8 short-term, placebo-controlled trials of dapagliflozin coadministered with metformin HCl immediate- or extended-release was used to evaluate safety. . This pool included several add-on trials (metformin HCl alone and in combination with a dipeptidyl peptidase-4 [DPP4] inhibitor and metformin HCl, or insulin and metformin HCl, 2 initial combination with metformin HCl trials, and 2 trials of patients with CVD and type 2 diabetes mellitus who received their usual treatment [with metformin HCl as background therapy]). For trials that included background therapy with and without metformin HCl, only patients who received metformin HCl were included in the 8-trial placebo-controlled pool. Across these 8 trials, 983 patients were treated once daily with dapagliflozin 10 mg and metformin HCl, and 1185 were treated with placebo and metformin HCl. These 8 trials provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 9…