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CONTRAINDICATIONS

JARDIANCE: Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE, reactions such as angioedema have occurred.

SYNJARDY and SYNJARDY XR: Severe renal impairment (eGFR <30 mL/min/ 1.73 m²), end-stage renal disease, or dialysis; acute or chronic metabolic acidosis, including diabetic ketoacidosis; hypersensitivity to empagliflozin, metformin, or any of the excipients in SYNJARDY or SYNJARDY XR, reactions such as angioedema have occurred.

WARNINGS AND PRECAUTIONS

Lactic Acidosis: SYNJARDY, SYNJARDY XR

There have been cases of metformin-associated lactic acidosis, including fatal cases. These cases had a 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. Additional findings included 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.

If lactic acidosis is suspected, immediately discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures promptly in a hospital setting. Prompt hemodialysis is recommended to correct the acidosis.

Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue SYNJARDY or SYNJARDY XR and promptly notify their healthcare provider.

Recommendations to reduce the risk include:

• Renal Impairment: Obtain eGFR prior to initiating and annually, or more frequently, in patients at increased risk of developing renal impairment
• Drug Interactions: More frequent monitoring is recommended when administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation
• Age 65 or Greater: Assess renal function more frequently
• Radiological Studies with Contrast: Stop SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of <60 mL/min/1.73 m²; patients with a history of hepatic impairment, alcoholism or heart failure; or patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the procedure and restart SYNJARDY or SYNJARDY XR if renal function is stable
• Surgery and Other Procedures: Discontinue while patients have restricted food and fluid intake
• Hypoxic States: Discontinue in conditions associated with hypoxemia
• Excessive Alcohol Intake: Warn patients against excessive alcohol intake
• Hepatic Impairment: Avoid use in patients with hepatic disease

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: JARDIANCE, SYNJARDY, SYNJARDY XR

Empagliflozin increases the risk of life-threatening ketoacidosis in patients with type 1 diabetes and fatal ketoacidosis has occurred with empagliflozin. Type 2 diabetes and pancreatic disorders are also risk factors for ketoacidosis and fatal events of ketoacidosis have been reported in patients with type 2 diabetes using JARDIANCE, SYNJARDY, or SYNJARDY XR. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms of diabetic ketoacidosis are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Assess patients who present with signs and symptoms of metabolic ketoacidosis, regardless of blood glucose levels. If suspected, discontinue JARDIANCE, SYNJARDY, or SYNJARDY XR, treat promptly and monitor for resolution before restarting. Consider ketone monitoring in patients with type 1 diabetes mellitus as well as in others at risk for ketoacidosis. Withhold JARDIANCE, SYNJARDY, or SYNJARDY XR in clinical situations known to predispose to ketoacidosis and resume when clinically stable. Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue JARDIANCE, SYNJARDY, or SYNJARDY XR and seek medical attention immediately if signs and symptoms occur.

Volume Depletion: JARDIANCE, SYNJARDY, SYNJARDY XR

Empagliflozin can cause intravascular volume depletion which may manifest as symptomatic hypotension or acute transient changes in creatinine. Acute kidney injury requiring hospitalization and dialysis has been reported in patients with type 2 diabetes receiving SGLT2 inhibitors, including empagliflozin. Before initiating, assess volume status and renal function in patients with impaired renal function (eGFR <60 mL/min/1.73 m²), elderly patients or patients on loop diuretics. In patients with volume depletion, correct this condition before initiating JARDIANCE, SYNJARDY, or SYNJARDY XR. After initiating, monitor for signs and symptoms of volume depletion and renal function.

Urosepsis and Pyelonephritis: JARDIANCE, SYNJARDY, SYNJARDY XR

Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been identified in patients receiving empagliflozin. Treatment with empagliflozin increases the risk of urinary tract infections. Evaluate for signs and symptoms of urinary tract infections and treat promptly.

Hypoglycemia: JARDIANCE, SYNJARDY, SYNJARDY XR

In adults, the use of JARDIANCE, SYNJARDY or SYNJARDY XR in combination with insulin or insulin secretagogues can increase the risk of hypoglycemia. In pediatric patients aged 10 years and older (JARDIANCE and SYNJARDY), the risk of hypoglycemia was higher with empagliflozin regardless of insulin use. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin.

Lower Limb Amputation: JARDIANCE, SYNJARDY, SYNJARDY XR

Lower limb amputations have been observed in patients with chronic kidney disease taking JARDIANCE, SYNJARDY and SYNJARDY XR are not indicated for the treatment of chronic kidney disease. Peripheral artery disease, and diabetic foot infection (including osteomyelitis), were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of diabetic foot, peripheral artery disease (including previous amputation) or diabetes. Counsel patients receiving JARDIANCE, SYNJARDY, or SYNJARDY XR about the importance of routine preventative foot care and monitor for signs and symptoms of diabetic foot infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and institute appropriate treatment.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): JARDIANCE, SYNJARDY, SYNJARDY XR

Serious, life-threatening cases requiring urgent surgical intervention have occurred in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. 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 and discontinue JARDIANCE, SYNJARDY or SYNJARDY XR.

Genital Mycotic Infections: JARDIANCE, SYNJARDY, SYNJARDY XR

Empagliflozin increases the risk of genital mycotic infections, especially in patients with prior infections. Monitor and treat as appropriate.

Hypersensitivity Reactions: JARDIANCE, SYNJARDY, SYNJARDY XR

Serious hypersensitivity reactions have occurred with empagliflozin (angioedema). If hypersensitivity reactions occur, discontinue JARDIANCE, SYNJARDY or SYNJARDY XR, treat promptly, and monitor until signs and symptoms resolve.

Vitamin B₁₂ Deficiency: SYNJARDY, SYNJARDY XR

Metformin may lower vitamin B₁₂ levels. Measure hematologic parameters annually and vitamin B₁₂ at 2- to 3-year intervals and manage any abnormalities.

MOST COMMON ADVERSE REACTIONS (≥5%)

JARDIANCE: urinary tract infections and female genital mycotic infections.

SYNJARDY and SYNJARDY XR: urinary tract infections and female genital mycotic infections, diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors: The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may increase the risk of lactic acidosis. Consider more frequent monitoring.

Drugs that reduce metformin clearance such as ranolazine, vandetanib, dolutegravir, or cimetidine may increase the accumulation of metformin and increase the risk of lactic acidosis. Consider the benefits and risks of concomitant use.

Alcohol: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while taking SYNJARDY orSYNJARDY XR.

Diuretics: Coadministration of empagliflozin with diuretics may enhance the potential for volume depletion. Monitor for signs and symptoms.

Lithium: Concomitant use of empagliflozin with lithium may decrease serum lithium concentrations. Monitor more frequently during JARDIANCE, SYNJARDY orSYNJARDY XR initiation and dosage changes.

USE IN SPECIAL POPULATIONS

Pregnancy: JARDIANCE, SYNJARDY, and SYNJARDY XR are not recommended during the second and third trimesters. With SYNJARDY or SYNJARDY XR, discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

Lactation: JARDIANCE, SYNJARDY, and SYNJARDY XR are not recommended while breastfeeding.

Geriatric Use: Empagliflozin is expected to have diminished glycemic efficacy in elderly patients with renal impairment. Assess renal function more frequently in elderly patients. For SYNJARDY and SYNJARDY XR, dose selection should be cautious, starting at the lowest dose. The incidence of volume depletion-related adverse reactions and urinary tract infections increased in T2D patients ≥75 years treated with empagliflozin.

CL-JAR-100189 10.30.2023