HIGHLIGHTS OF PRESCRIBING INFORMATION 5 mg dapagliflozin/1000 mg metformin HCl extended-release (3) These highlights do not include all the information needed to use 10 mg dapagliflozin/500 mg metformin HCl extended-release (3) XIGDUO XR safely and effectively. See full prescribing information for 10 mg dapagliflozin/1000 mg metformin HCl extended-release (3) XIGDUO XR. ------------------------------ CONTRAINDICATIONS ----------------------------- ® XIGDUO XR (dapagliflozin and metformin HCl extended-release) Severe renal impairment: (eGFR below 30 mL/min/1.73 m2), end-stage tablets, for oral use renal disease or dialysis. (4, 5.1) Initial U.S. Approval: 2014 History of serious hypersensitivity to dapagliflozin or hypersensitivity to metformin HCl. (4, 6.1) WARNING: LACTIC ACIDOSIS Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1) See full prescribing information for complete boxed warning. ----------------------- WARNINGS AND PRECAUTIONS ---------------------- Postmarketing cases of metformin-associated lactic acidosis have Lactic Acidosis: See boxed warning (2.3, 4, 5.1) resulted in death, hypothermia, hypotension, and resistant Hypotension: Before initiating XIGDUO XR, assess and correct volume bradyarrhythmias. Symptoms included malaise, myalgias, status in the elderly, patients with renal impairment or low systolic blood respiratory distress, somnolence, and abdominal pain. Laboratory pressure, and in patients on diuretics. Monitor for signs and symptoms abnormalities included elevated blood lactate levels, anion gap during therapy. (5.2, 6.1) acidosis, increased lactate/pyruvate ratio; and metformin plasma Ketoacidosis: Assess patients who present with signs and symptoms of levels generally >5 mcg/mL. (5.1) metabolic acidosis for ketoacidosis regardless of blood glucose level. If Risk factors include renal impairment, concomitant use of certain suspected, discontinue XIGDUO XR, evaluate and treat promptly. drugs, age >65 years old, radiological studies with contrast, Before initiating XIGDUO XR, consider risk factors for ketoacidosis. surgery and other procedures, hypoxic states, excessive alcohol Patients on XIGDUO XR may require monitoring and temporary intake, and hepatic impairment. Steps to reduce the risk of and discontinuation of therapy in clinical situations known to predispose to manage metformin-associated lactic acidosis in these high-risk ketoacidosis. (5.3) groups are provided in the Full Prescribing Information. (5.1) Acute Kidney Injury: Consider temporarily discontinuing in settings of If lactic acidosis is suspected, discontinue XIGDUO XR and reduced oral intake or fluid losses. If acute kidney injury occurs, institute general supportive measures in a hospital setting. Prompt discontinue and promptly treat. Monitor renal function during therapy. hemodialysis is recommended. (5.1) (5.4) Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. (5.5) ---------------------------RECENT MAJOR CHANGES--------------------------- Hypoglycemia: In patients taking insulin or an insulin secretagogue with Indications and Usage (1) 10/2019 XIGDUO XR, consider a lower dose of insulin or the insulin Dosage and Administration (2) 10/2019 secretagogue to reduce the risk of hypoglycemia. (5.6) Contraindications (4) 02/2019 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, Warnings and Precautions (5.3) 1/2020 life-threatening cases have occurred in both females and males. Assess Warnings and Precautions (5.4, 5.6) 10/2019 patients presenting with pain or tenderness, erythema, or swelling in the Warnings and Precautions (5.1) 02/2019 genital or perineal area, along with fever or malaise. If suspected, Warnings and Precautions (5.10, 5.11, 5.12) Removed 10/2019 institute prompt treatment. (5.7) Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. --------------------------- INDICATIONS AND USAGE -------------------------- Measure hematological parameters annually. (5.8, 6.1) XIGDUO XR is a combination of dapagliflozin, a sodium-glucose Genital Mycotic Infections: Monitor and treat if indicated. (5.9) cotransporter 2 (SGLT2) inhibitor, and metformin, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type ------------------------------ ADVERSE REACTIONS ----------------------------- 2 diabetes mellitus. (1) The most common adverse reactions associated with XIGDUO XR (5% Dapagliflozin is indicated in adults with type 2 diabetes mellitus to reduce the or greater incidence) were female genital mycotic infection, risk of hospitalization for heart failure in adults with type 2 diabetes mellitus nasopharyngitis, urinary tract infection, diarrhea, and headache. (6.1) and established cardiovascular disease or multiple cardiovascular risk factors. Adverse reactions reported in >5% of patients treated with metformin (1) extended-release and more commonly than in patients treated with Limitations of use: placebo are: diarrhea and nausea/vomiting. (6.1) Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis. (1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca ---------------------- DOSAGE AND ADMINISTRATION ---------------------- at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Assess renal function before initiating. Do not initiate or continue if 2 eGFR is below 45 mL/min/1.73 m . (2.1, 4) ------------------------------ DRUG INTERACTIONS ----------------------------- Individualize the starting dose based on the patient’s current treatment. Carbonic anhydrase inhibitors may increase the risk of lactic acidosis. (2.2) Consider more frequent monitoring. (7.3) Administer once daily in the morning with food. (2.2) Drugs that reduce metformin clearance (such as ranolazine, vandetanib, Swallow whole. Never crush, cut, or chew. (2.2) dolutegravir, and cimetidine) may increase the accumulation of For patients not already taking dapagliflozin, the recommended starting metformin. Consider the benefits and risks of concomitant use. (7.4) dose for dapagliflozin is 5 mg once daily. (2.2) Alcohol can potentiate the effect of metformin on lactate metabolism. The recommended dose of dapagliflozin to reduce the risk of Warn patients against excessive alcohol intake. (7.5) hospitalization for heart failure is 10 mg once daily. (2.2) For patients requiring a dose of 5 mg dapagliflozin and 2000 mg ----------------------- USE IN SPECIFIC POPULATIONS ---------------------- metformin HCl extended-release, use two of the 2.5 mg/1000 mg Pregnancy: Advise females of the potential risk to a fetus, especially metformin HCl extended-release tablets. (2.2) during the second and third trimesters. (8.1) Do not exceed a daily dose of 10 mg dapagliflozin/2000 mg metformin Lactation: XIGDUO XR is not recommended when breastfeeding. (8.2) HCl extended-release. (2.2) Females and Males of Reproductive Potential: Advise premenopausal No dosage adjustment is indicated in patients with eGFR greater or females of the potential for an unintended pregnancy. (8.3) equal to 45 mL/min/1.73 m2. (2.3) Geriatrics: Higher incidence of adverse reactions related to reduced XIGDUO XR may need to be discontinued at time of, or prior to, intravascular volume. Assess renal function more frequently. (5.1, 8.5, 8.6) iodinated contrast imaging procedures. (2.4) Renal Impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function. (5.1, 8.6) --------------------- DOSAGE FORMS AND STRENGTHS -------------------- Hepatic Impairment: Avoid use in patients with hepatic impairment. 2.5 mg dapagliflozin/1000 mg metformin HCl extended-release (3) (8.7) 5 mg dapagliflozin/500 mg metformin HCl extended-release (3) Reference ID: 4555351 See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 1/2020 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 7.6 Drugs Affecting Glycemic Control 2 DOSAGE AND ADMINISTRATION 8 USE IN SPECIFIC POPULATIONS 2.1 Prior to Initiation of XIGDUO XR 8.1 Pregnancy 2.2 Recommended Dosage 8.2 Lactation 2.3 Patients with Renal Impairment 8.3 Females and Males of Reproductive Potential 2.4 Discontinuation for Iodinated Contrast Imaging Procedures 8.4 Pediatric Use 3 DOSAGE FORMS AND STRENGTHS 8.5 Geriatric Use 4 CONTRAINDICATIONS 8.6 Renal Impairment 5 WARNINGS AND PRECAUTIONS 8.7 Hepatic Impairment 5.1 Lactic Acidosis 10 OVERDOSAGE 5.2 Hypotension 11 DESCRIPTION 5.3 Ketoacidosis 12 CLINICAL PHARMACOLOGY 5.4 Acute Kidney Injury 12.1 Mechanism of Action 5.5 Urosepsis and Pyelonephritis 12.2 Pharmacodynamics 5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin 12.3 Pharmacokinetics Secretagogues 13 NONCLINICAL TOXICOLOGY 5.7 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.8 Vitamin B12 Concentrations 14 CLINICAL STUDIES 5.9 Genital Mycotic Infections 14.1 Glycemic Control 6 ADVERSE REACTIONS 14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus 6.1 Clinical Trials Experience 16 HOW SUPPLIED/STORAGE AND HANDLING 6.2 Postmarketing Experience 17 PATIENT COUNSELING INFORMATION 7 DRUG INTERACTIONS *Sections or subsections omitted from the full prescribing information 7.1 Positive Urine Glucose Test are not listed. 7.2 Interference with 1,5-anhydroglucitol (1,5-AG) Assay 7.3 Carbonic Anhydrase Inhibitors 7.4 Drugs that Reduce Metformin Clearance 7.5 Alcohol