HIGHLIGHTS OF PRESCRIBING INFORMATION -------------------------------CONTRAINDICATIONS-----------------------------­ These highlights do not include all the information needed to use • Severe renal impairment (eGFR below 30 mL/min/1.73 m2), end stage SYNJARDY XR safely and effectively. See full prescribing information renal disease, or on dialysis (4, 5.1) for SYNJARDY XR. • Metabolic acidosis, including diabetic ketoacidosis (1, 4, 5.1) • Hypersensitivity to empagliflozin, metformin or any of the excipients in ® SYNJARDY XR (empagliflozin and metformin hydrochloride extended- SYNJARDY XR (4) release tablets), for oral use Initial U.S. Approval: 2015 -----------------------WARNINGS AND PRECAUTIONS-----------------------­ • Lactic Acidosis: See boxed warning (5.1) WARNING: LACTIC ACIDOSIS • Ketoacidosis: Assess patients who present with signs and symptoms of See full prescribing information for complete boxed warning. metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue SYNJARDY XR, evaluate and treat promptly. • Postmarketing cases of metformin-associated lactic acidosis Before initiating SYNJARDY XR, consider risk factors for ketoacidosis. have resulted in death, hypothermia, hypotension, and Patients on SYNJARDY XR may require monitoring and temporary resistant bradyarrhythmias. Symptoms included malaise, discontinuation of therapy in clinical situations known to predispose to myalgias, respiratory distress, somnolence, and abdominal ketoacidosis. (5.2) pain. Laboratory abnormalities included elevated blood • Volume Depletion: Before initiating SYNJARDY XR, assess volume lactate levels, anion gap acidosis, increased lactate/pyruvate status and renal function in patients with impaired renal function, elderly ratio; and metformin plasma levels generally >5 mcg/mL. (5.1) patients, or patients on loop diuretics. Monitor for signs and symptoms • Risk factors include renal impairment, concomitant use of during therapy. (5.3, 6.1) certain drugs, age ≥65 years old, radiological studies with • Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms contrast, surgery and other procedures, hypoxic states, of urinary tract infections and treat promptly, if indicated (5.4) excessive alcohol intake, and hepatic impairment. Steps to • Hypoglycemia: Consider lowering the dose of insulin secretagogue or reduce the risk of and manage metformin-associated lactic insulin to reduce the risk of hypoglycemia when initiating SYNJARDY acidosis in these high risk groups are provided in the Full XR (5.5) Prescribing Information. (5.1) • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, • If lactic acidosis is suspected, discontinue SYNJARDY XR and life-threatening cases have occurred in both females and males. Assess institute general supportive measures in a hospital setting. patients presenting with pain or tenderness, erythema, or swelling in the Prompt hemodialysis is recommended. (5.1) genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. (5.6) ----------------------------RECENT MAJOR CHANGES-------------------------­ • Genital Mycotic Infections: Monitor and treat as appropriate (5.7) Indications and Usage (1) 6/2021 • Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g., Dosage and Administration (2.1, 2.3, 2.4) 6/2021 angioedema) have occurred with empagliflozin. If hypersensitivity Contraindications (4) 6/2021 reactions occur, discontinue SYNJARDY XR, treat promptly, and Warnings and Precautions (5.1, 5.2, 5.3) 6/2021 monitor until signs and symptoms resolve (5.8) Warnings and Precautions (5.11, 5.12) – Removed 6/2021 • Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. ----------------------------INDICATIONS AND USAGE--------------------------­ Monitor hematologic parameters annually. (5.9) SYNJARDY XR is a combination of empagliflozin, a sodium-glucose ------------------------------ADVERSE REACTIONS------------------------------­ co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl), a • Most common adverse reactions associated with empagliflozin (5% or biguanide, indicated as an adjunct to diet and exercise to improve glycemic greater incidence) were urinary tract infection and female genital control in adults with type 2 diabetes mellitus. mycotic infections. (6.1) • Most common adverse reactions associated with metformin (>5%) are Empagliflozin is indicated to reduce the risk of cardiovascular death in adults diarrhea, nausea/vomiting, flatulence, abdominal discomfort, with type 2 diabetes mellitus and established cardiovascular disease. (1) indigestion, asthenia, and headache. (6.1) Limitation of Use: To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Not recommended in patients with type 1 diabetes mellitus. It may increase Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or FDA at 1-800-FDA­ the risk of diabetic ketoacidosis in these patients (1) 1088 or www.fda.gov/medwatch. ----------------------DOSAGE AND ADMINISTRATION----------------------­ ------------------------------DRUG INTERACTIONS------------------------------­ • Assess renal function before initiating and as clinically indicated (2.1). • Carbonic anhydrase inhibitors may increase risk of lactic acidosis. • Individualize the starting dose based on the patient’s current regimen Consider more frequent monitoring. (7) and renal function (2.2, 2.3) • Drugs that reduce metformin clearance (such as ranolazine, vandetanib, • Initiation of SYNJARDY XR is not recommended in patients with an dolutegravir, and cimetidine) may increase the accumulation of eGFR less than 45 mL/min/1.73 m2, due to the metformin component metformin. Consider the benefits and risks of concomitant use. (7) (2.3) • Alcohol can potentiate the effect of metformin on lactate metabolism. • The maximum recommended total daily dose is 25 mg empagliflozin Warn patients against excessive alcohol intake. (7) and 2000 mg metformin HCl (2.2) -----------------------USE IN SPECIFIC POPULATIONS-----------------------­ • Take once daily with a meal in the morning, with gradual dose • Pregnancy: Advise females of the potential risk to a fetus especially escalation to reduce the gastrointestinal side effects due to metformin during the second and third trimesters. (8.1) (2.2) • Lactation: SYNJARDY XR is not recommended when breastfeeding. • Swallow whole; do not split, crush, dissolve, or chew (2.2) (8.2) • SYNJARDY XR may need to be discontinued at time of, or prior to, • Females and Males of Reproductive Potential: Advise premenopausal iodinated contrast imaging procedures (2.4) females of the potential for an unintended pregnancy. (8.3). ---------------------DOSAGE FORMS AND STRENGTHS---------------------­ • Geriatric Patients: Higher incidence of adverse reactions related to Tablets: volume depletion and reduced renal function. (5.1, 5.3, 8.5, 8.6) 5 mg empagliflozin/1000 mg metformin HCl extended-release • Renal Impairment: Higher incidence of adverse reactions related to 10 mg empagliflozin/1000 mg metformin HCl extended-release reduced renal function (2.1, 5.1, 5.3, 8.6) 12.5 mg empagliflozin/1000 mg metformin HCl extended-release • Hepatic Impairment: Avoid use in patients with hepatic impairment. 25 mg empagliflozin/1000 mg metformin HCl extended-release (3) (8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 6/2021 1 Reference ID: 4810096 _______________________________________________________________________________________________________________________________________ FULL PRESCRIBING INFORMATION: CONTENTS* 7 DRUG INTERACTIONS WARNING: LACTIC ACIDOSIS 8 USE IN SPECIFIC POPULATIONS 1 INDICATIONS AND USAGE 8.1 Pregnancy 2 DOSAGE AND ADMINISTRATION 8.2 Lactation 2.1 Prior to Initiation of SYNJARDY XR 8.3 Females and Males of Reproductive Potential 2.2 Recommended Dosage and Administration 8.4 Pediatric Use 2.3 Dosage Recommendations in Patients with Renal Impairment 8.5 Geriatric Use 2.4 Discontinuation for Iodinated Contrast Imaging Procedures 8.6 Renal Impairment 3 DOSAGE FORMS AND STRENGTHS 8.7 Hepatic Impairment 4 CONTRAINDICATIONS 10 OVERDOSAGE 5 WARNINGS AND PRECAUTIONS 11 DESCRIPTION 5.1 Lactic Acidosis 12 CLINICAL PHARMACOLOGY 5.2 Ketoacidosis 12.1 Mechanism of Action 5.3 Volume Depletion 12.2 Pharmacodynamics 5.4 Urosepsis and Pyelonephritis 12.3 Pharmacokinetics 5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin 13 NONCLINICAL TOXICOLOGY Secretagogues 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) 14 CLINICAL STUDIES 5.7 Genital Mycotic Infections 16 HOW SUPPLIED/STORAGE AND HANDLING 5.8 Hypersensitivity Reactions 17 PATIENT COUNSELING INFORMATION 5.9 Vitamin B12 Deficiency 6 ADVERSE REACTIONS *Sections or subsections omitted from the full prescribing information are not 6.1 Clinical Trials Experience listed. 6.2 Postmarketing Experience 2 Reference ID: 4810096 FULL PRESCRIBING INFORMATION 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/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased