WARNING: LACTIC ACIDOSIS WITH TRIJARDY 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 TRIJARDY XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

INDICATIONS

JARDIANCE is indicated to reduce the risk of cardiovascular (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.

Limitations of Use

JARDIANCE, TRADJENTA and TRIJARDY XR are not recommended for patients with type 1 diabetes or for the treatment 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.

CONTRAINDICATIONS

JARDIANCE: History of serious hypersensitivity to empagliflozin or any of the excipients in JARDIANCE; severe renal impairment, end-stage renal disease, or 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.

WARNINGS AND PRECAUTIONS

Lactic Acidosis: TRIJARDY 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 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:

• 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 TRIJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of <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 TRIJARDY 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.

Pancreatitis: TRADJENTA, TRIJARDY XR
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.

Heart Failure: TRADJENTA, TRIJARDY XR
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.

Hypotension: JARDIANCE, TRIJARDY XR
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, 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.

Acute Kidney Injury: JARDIANCE, TRIJARDY XR
Empagliflozin causes intravascular volume contraction and can cause renal impairment. Acute kidney injury requiring hospitalization and dialysis has 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, TRIJARDY 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 for urinary tract infections. Evaluate for signs and symptoms of urinary tract infections and treat promptly.

Hypoglycemia: JARDIANCE, TRADJENTA, TRIJARDY 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.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): JARDIANCE, TRIJARDY 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 or TRIJARDY XR.

Genital Mycotic Infections: JARDIANCE, TRIJARDY XR
Empagliflozin increases the risk for genital mycotic infections, especially in patients with prior infections. Monitor and treat as appropriate.

Hypersensitivity Reactions

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.

Vitamin B₁₂ Deficiency: TRIJARDY XR
Metformin may lower vitamin B₁₂ levels. Monitor hematologic parameters annually and routine serum vitamin B₁₂ measurement at 2- to 3-year intervals.

Increased Low-Density Lipoprotein Cholesterol (LDL-C): JARDIANCE,
Monitor and treat as appropriate.

Severe and Disabling Arthralgia: TRADJENTA, TRIJARDY XR
Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider linagliptin as a possible cause for severe joint pain and discontinue, if appropriate.

Bullous Pemphigoid: TRADJENTA, TRIJARDY XR
There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue.

MOST COMMON ADVERSE REACTIONS (≥5%)

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.

DRUG INTERACTIONS

JARDIANCE, TRIJARDY XR:

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

TRIJARDY XR:

• 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 TRIJARDY XR.

TRADJENTA and TRIJARDY XR:

• Inducers of P-glycoprotein or CYP3A4 Enzymes: The efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Alternative treatments should be used.

USE IN SPECIAL POPULATIONS

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: With JARDIANCE or TRIJARDY XR, empagliflozin is expected to have diminished efficacy in elderly patients with renal impairment. For TRIJARDY XR, assess renal function more frequently in elderly patients, and 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.

CL-JAR-100064 03.30.2020

Please see TRIJARDY XR Prescribing Information, including Boxed Warning and Medication Guide.

Please see JARDIANCE Prescribing Information and Medication Guide.

Please see TRADJENTA Prescribing Information and Medication Guide.

Copyright © 2020 Boehringer Ingelheim Pharmaceuticals, Inc.
All rights reserved. (5/20) PC-US-114769