INDICATIONS AND LIMITATIONS OF USE FOR JARDIANCE, SYNJARDY, AND SYNJARDY XR
JARDIANCE is indicated to reduce the risk of cardiovascular (CV) death in adults with type 2 diabetes mellitus and established CV disease.
JARDIANCE, SYNJARDY, and SYNJARDY XR are indicated as adjuncts to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. SYNJARDY and SYNJARDY XR are indicated when both empagliflozin and metformin hydrochloride are appropriate.
Empagliflozin, a component of SYNJARDY and SYNJARDY XR, is indicated to reduce the risk of CV death in adults with type 2 diabetes mellitus and established CV disease. However, the effectiveness of SYNJARDY and SYNJARDY XR on reducing the risk of CV death in adults with type 2 diabetes mellitus and CV disease has not been established.
Limitations of Use
JARDIANCE, SYNJARDY, and SYNJARDY XR are not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
IMPORTANT SAFETY INFORMATION
IMPORTANT SAFETY INFORMATION, INDICATIONS AND LIMITATIONS
OF USE FOR JARDIANCE, SYNJARDY, AND SYNJARDY XR
WARNING: LACTIC ACIDOSIS WITH SYNJARDY AND SYNJARDY XR
Postmarketing 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.
Risk 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.
If lactic acidosis is suspected, discontinue SYNJARDY or SYNJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
JARDIANCE: History of serious hypersensitivity to empagliflozin or any of the excipients in JARDIANCE; severe renal impairment, end-stage renal disease, or dialysis.
SYNJARDY and SYNJARDY XR: Moderate to severe renal impairment (eGFR <45 mL/min/1.73 m²), end-stage renal disease, or dialysis; acute or chronic metabolic acidosis, including diabetic ketoacidosis; history of serious hypersensitivity reaction to empagliflozin, metformin, or any of the excipients in SYNJARDY or SYNJARDY XR.
WARNINGS AND PRECAUTIONSLactic 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 45-60 mL/min/1.73m²; 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.
Empagliflozin causes intravascular volume contraction and symptomatic hypotension may occur. Before initiating, assess and correct volume status in the elderly, and in patients with renal impairment, low systolic blood pressure, or on diuretics. Monitor for hypotension.Ketoacidosis: JARDIANCE, SYNJARDY, SYNJARDY XR
Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization has been identified in patients with type 1 and type 2 diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Fatal cases of ketoacidosis have been reported in patients taking empagliflozin. Patients who present with signs and symptoms of metabolic acidosis should be assessed for ketoacidosis, even if blood glucose levels are less than 250 mg/dL. If suspected, discontinue, evaluate, and treat promptly. Before initiating, consider risk factors for ketoacidosis. Patients may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis.Acute Kidney Injury and Impairment in Renal Function: JARDIANCE, SYNJARDY, SYNJARDY XR
Empagliflozin causes intravascular volume contraction and can cause renal impairment. Acute kidney injury requiring hospitalization and dialysis have been identified in patients taking SGLT2 inhibitors, including empagliflozin; some reports involved patients younger than 65 years of age. Before initiating, consider factors that may predispose patients to acute kidney injury. Consider temporary discontinuation in settings of reduced oral intake or fluid losses. Monitor patients for signs and symptoms of acute kidney injury. If it occurs, discontinue and treat promptly.
Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Before initiating, evaluate renal function and monitor thereafter. More frequent monitoring is recommended in patients with eGFR <60 mL/min/1.73 m². Discontinue in patients with a persistent eGFR <45 mL/min/1.73 m².Urosepsis and Pyelonephritis: JARDIANCE, SYNJARDY, SYNJARDY XR
Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been identified in patients receiving SGLT2 inhibitors, including empagliflozin. Treatment with SGLT2 inhibitors increases the risk of urinary tract infections. Evaluate for signs and symptoms of urinary tract infections and treat promptly.Hypoglycemia: JARDIANCE, SYNJARDY, SYNJARDY XR
The use in combination with insulin or insulin secretagogues can increase the risk of hypoglycemia. A lower dose of insulin or the insulin secretagogue may be required.
Hypoglycemia could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation or during concomitant use of SYNJARDY or SYNJARDY XR with other glucose-lowering agents or with the use of ethanol.Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): JARDIANCE, SYNJARDY, SYNJARDY XR
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 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 and SYNJARDY XR
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. Monitor hematologic parameters annually for patients on SYNJARDY or SYNJARDY XR.Increased Low-Density Lipoprotein Cholesterol (LDL-C): JARDIANCE, SYNJARDY, SYNJARDY XR
Monitor and treat as appropriate.Macrovascular Outcomes: SYNJARDY, SYNJARDY XR
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with SYNJARDY or SYNJARDY XR.
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.
Empagliflozin: Coadministration with diuretics may enhance the potential for volume depletion.
Metformin Hydrochloride: More frequent monitoring is recommended when SYNJARDY or SYNJARDY XR is administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation.
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.
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.
Alcohol: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while taking SYNJARDY or SYNJARDY XR.
USE IN SPECIAL POPULATIONS
Pregnancy: JARDIANCE, SYNJARDY, and SYNJARDY XR are not recommended, especially 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: JARDIANCE, SYNJARDY, and SYNJARDY XR are expected to have diminished efficacy in elderly patients with renal impairment. Renal function should be assessed more frequently in elderly patients. Dose selection should be cautious, starting at the lowest dose. The incidence of volume depletion-related adverse reactions and urinary tract infections increased in patients ≥75 years treated with empagliflozin.