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 TRIJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
JARDIANCE is indicated to reduce the risk of cardiovascular (CV) death and hospitalization for heart failure in adults with heart failure; and reduce the risk of CV death in adults with type 2 diabetes mellitus and established CV disease.
JARDIANCE, TRADJENTA and TRIJARDY XR are indicated as adjuncts to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
TRADJENTA is not recommended in patients with type 1 diabetes.
JARDIANCE and TRIJARDY XR are not recommended in patients with type 1 diabetes mellitus. It may increase their risk of diabetic ketoacidosis.
TRADJENTA and TRIJARDY XR have not been studied in patients with a history of pancreatitis, and it is unknown if using TRADJENTA or TRIJARDY XR increases the risk of developing pancreatitis in these patients.
JARDIANCE is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR <30 mL/min/1.73 m2. JARDIANCE is likely to be ineffective in this setting based upon its mechanism of action.
JARDIANCE: Hypersensitivity to empagliflozin or any of the excipients in JARDIANCE, reactions such as angioedema have occurred; patients on dialysis.
TRADJENTA: Hypersensitivity to linagliptin, or any of the excipients in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred.
TRIJARDY 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, linagliptin, metformin, or any of the excipients in TRIJARDY XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred.
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 TRIJARDY 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 TRIJARDY XR and promptly notify their healthcare provider.
Recommendations to reduce the risk include:
Acute pancreatitis, including fatal pancreatitis, has been reported in patients taking linagliptin, a component of TRADJENTA or TRIJARDY XR. Take careful notice of potential signs and symptoms of pancreatitis and, if suspected, promptly discontinue and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using TRADJENTA or TRIJARDY XR.
Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been identified in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (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. For patients who undergo scheduled surgery, consider temporarily discontinuing for at least 3 days prior to surgery.
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. After initiating, monitor for signs and symptoms of hypotension, and renal function.
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 for urinary tract infections. Evaluate for signs and symptoms of urinary tract infections and treat promptly.
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.
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 or TRIJARDY XR.
Empagliflozin increases the risk for genital mycotic infections, especially in patients with prior infections. Monitor and treat as appropriate.
JARDIANCE: Serious hypersensitivity reactions have occurred with empagliflozin (angioedema). If hypersensitivity reactions occur, discontinue JARDIANCE, treat promptly, and monitor until signs and symptoms resolve.
TRADJENTA, TRIJARDY XR: Serious hypersensitivity reactions have occurred with linagliptin (anaphylaxis, angioedema and exfoliative skin conditions) and empagliflozin (angioedema). If hypersensitivity reactions occur, discontinue TRADJENTA or TRIJARDY XR, treat promptly, and monitor until signs and symptoms resolve. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with TRADJENTA or TRIJARDY XR.
Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually and vitamin B12 at 2- to 3-year intervals.
Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue, if appropriate.
There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue.
Heart failure has been observed with two other members of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Consider risks and benefits of TRADJENTA or TRIJARDY XR in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment. Monitor patients for signs and symptoms. Advise patients of the symptoms of heart failure and to immediately report such symptoms. If heart failure develops, consider discontinuation of TRADJENTA or TRIJARDY XR.
JARDIANCE: urinary tract infections and female genital mycotic infections.
TRADJENTA: nasopharyngitis, hypoglycemia (when used in combination with sulfonylurea).
TRIJARDY XR: upper respiratory tract infections, urinary tract infection, nasopharyngitis, diarrhea, constipation, headache, gastroenteritis.
Pregnancy: JARDIANCE and TRIJARDY XR are not recommended during the second and third trimesters. With TRIJARDY XR, discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.
Lactation: JARDIANCE or TRIJARDY 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 TRIJARDY XR, dose selection should be cautious, starting at the lower end of the dosage range for the metformin component. The incidence of volume depletion-related adverse reactions and urinary tract infections increased in T2D patients ≥75 years treated with empagliflozin.
CL-JAR-100132 10.17.2022
Please see TRIJARDY XR Prescribing Information, including Boxed Warning and Medication Guide.
Please see JARDIANCE Prescribing Information, including Medication Guide.
Please see TRADJENTA Prescribing Information, including Medication Guide.
*3-in-1 pill is a fixed-dose combination treatment
†TRIJARDY
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