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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.

CONTRAINDICATIONS

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/1.73 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 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.

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: 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 empagliflozin. 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 TRIJARDY 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 TRIJARDY 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 TRIJARDY XR and seek medical attention immediately if signs and symptoms occur.

Pancreatitis: Acute pancreatitis, including fatal pancreatitis, has been reported in patients taking linagliptin, a component of 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 TRIJARDY XR.

Volume Depletion: 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. After initiating, monitor for signs and symptoms of volume depletion and renal function.

Urosepsis and Pyelonephritis: 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: The use in combination with insulin or insulin secretagogues can increase the risk of hypoglycemia. A lower dosage of insulin or the insulin secretagogue may be required.

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

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

Lower Limb Amputation: Lower limb amputations have been observed in patients with chronic kidney disease taking empagliflozin. TRIJARDY XR is 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 TRIJARDY 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.

Hypersensitivity Reactions: Serious hypersensitivity reactions have occurred with linagliptin (anaphylaxis, angioedema and exfoliative skin conditions) and empagliflozin (angioedema). If hypersensitivity reactions occur, discontinue 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 TRIJARDY XR.

Vitamin B₁₂ Deficiency: Metformin may lower vitamin B₁₂ levels. Measure hematologic parameters annually and vitamin B₁₂ at 2- to 3-year intervals.

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

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

Heart Failure: Heart failure has been observed with two other members of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Consider the risks and benefits of 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 TRIJARDY XR.

MOST COMMON ADVERSE REACTIONS (≥5%)

Upper respiratory tract infections, urinary tract infection, nasopharyngitis, diarrhea, constipation, headache, gastroenteritis.

DRUG INTERACTIONS

Carbonic Anhydrase Inhibitors: The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and TRIJARDY XR 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.

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

Lithium: Concomitant use with lithium may decrease serum lithium concentrations. Monitor more frequently during TRIJARDY XR initiation and dosage changes.

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: TRIJARDY XR is 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: TRIJARDY XR is not recommended while breastfeeding.

Geriatric Use: Assess renal function more frequently in elderly patients. Dose selection should be cautious, starting at the lower end of the dosage range for the metformin component of TRIJARDY XR. The incidence of volume depletion-related adverse reactions and urinary tract infections increased in patients ≥75 years treated with empagliflozin.

CL-TRI-100056 10.30.2023

INDICATIONS AND LIMITATIONS OF USE FOR JARDIANCE

JARDIANCE is indicated:

• to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure
• to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression
• to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease
• as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus

JARDIANCE is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. It may increase their risk of diabetic ketoacidosis.

JARDIANCE is not recommended for use to improve glycemic control in patients 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 is not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of intravenous immunosuppressive therapy or greater than 45 mg of prednisone or equivalent for kidney disease. JARDIANCE is not expected to be effective in these populations.

IMPORTANT SAFETY INFORMATION FOR JARDIANCE

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

WARNINGS AND PRECAUTIONS

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: JARDIANCE increases the risk of life-threatening ketoacidosis in patients with type 1 diabetes and fatal ketoacidosis has occurred with JARDIANCE. 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. 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, 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 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 and seek medical attention immediately if signs and symptoms occur.

Volume Depletion: JARDIANCE 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 JARDIANCE. 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. After initiating, monitor for signs and symptoms of volume depletion and renal function.

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

Hypoglycemia: In adult patients, the use of JARDIANCE in combination with insulin or insulin secretagogues can increase the risk of hypoglycemia. In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher with JARDIANCE 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.

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases requiring urgent surgical intervention have occurred in both females and males receiving JARDIANCE. 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.

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

Lower Limb Amputation: Lower limb amputations have been observed in patients with chronic kidney disease taking JARDIANCE. 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 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.

Hypersensitivity Reactions: Serious hypersensitivity reactions have occurred with JARDIANCE (angioedema). If hypersensitivity reactions occur, discontinue JARDIANCE, treat promptly, and monitor until signs and symptoms resolve.

MOST COMMON ADVERSE REACTIONS (≥5%): Urinary tract infections and female genital mycotic infections.

DRUG INTERACTIONS:

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

Lithium: Concomitant use with lithium may decrease serum lithium concentrations. Monitor more frequently during JARDIANCE initiation and dosage changes.

USE IN SPECIAL POPULATIONS

Pregnancy: JARDIANCE is not recommended during the second and third trimesters.


Lactation: JARDIANCE is not recommended while breastfeeding.


Geriatric Use: JARDIANCE is expected to have diminished glycemic efficacy in elderly patients with renal impairment. Assess renal function more frequently in elderly patients. The incidence of volume depletion-related adverse reactions and urinary tract infections increased in T2D patients ≥75 years treated with empagliflozin.

CL-JAR-100162 09.21.2023

INDICATION AND LIMITATIONS OF USE FOR TRADJENTA

TRADJENTA is indicated as an adjunct 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 mellitus.

TRADJENTA has not been studied in patients with a history of pancreatitis, and it is unknown if using TRADJENTA increases the risk of developing pancreatitis in these patients.

IMPORTANT SAFETY INFORMATION FOR TRADJENTA

CONTRAINDICATIONS: Hypersensitivity to linagliptin or any of the excipients in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred.

WARNINGS AND PRECAUTIONS

Pancreatitis: Acute pancreatitis, including fatal pancreatitis, has been reported in patients taking TRADJENTA. 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.

Hypoglycemia: The use in combination with insulin or insulin secretagogues increases the risk of hypoglycemia. A lower dosage of insulin or insulin secretagogue may be required.

Hypersensitivity Reactions: Discontinue TRADJENTA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes mellitus. 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.

Severe and Disabling Arthralgia: Severe and disabling arthralgia has been reported in patients taking TRADJENTA. Consider TRADJENTA as a possible cause for severe joint pain and/or disabling arthralgia and discontinue, if appropriate.

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

Heart Failure: Heart failure has been observed with two other members of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Consider the risks and benefits of TRADJENTA 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.

MOST COMMON ADVERSE REACTIONS (≥5%): Nasopharyngitis, hypoglycemia (when used in combination with sulfonylurea).

DRUG INTERACTIONS: The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Alternative treatments should be used.

USE IN SPECIFIC POPULATIONS: Use during pregnancy only if clearly needed. Exercise caution when administering to a nursing woman.

CL-TJ-100060 06.16.2023