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CONTRAINDICATIONS

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.

JENTADUETO and JENTADUETO XR: Severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²); acute or chronic metabolic acidosis, including diabetic ketoacidosis; hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO or JENTADUETO XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin.

WARNINGS AND PRECAUTIONS

Lactic Acidosis: JENTADUETO and JENTADUETO 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 JENTADUETO or JENTADUETO 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 JENTADUETO or JENTADUETO 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 JENTADUETO or JENTADUETO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JENTADUETO or JENTADUETO XR if renal function is stable.
• Surgery and Other Procedures: Discontinue while patients have restricted food and fluid intake during surgical or other procedures.
• 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, JENTADUETO and JENTADUETO XR
Acute pancreatitis, including fatal pancreatitis, has been reported in patients taking linagliptin. 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, JENTADUETO or JENTADUETO XR.

Hypoglycemia: TRADJENTA, JENTADUETO and JENTADUETO XR
The use in combination with insulin or insulin secretagogues increases the risk of hypoglycemia. A lower dosage of the insulin or insulin secretagogue may be required to reduce the risk of hypoglycemia.

Hypersensitivity Reactions: TRADJENTA, JENTADUETO and JENTADUETO XR
Discontinue, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes mellitus. Use caution in a patient with history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with TRADJENTA, JENTADUETO or JENTADUETO XR.

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

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

Bullous Pemphigoid: TRADJENTA, JENTADUETO and JENTADUETO XR
There have been reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue TRADJENTA, JENTADUETO or JENTADUETO XR.

Heart Failure: TRADJENTA, JENTADUETO and JENTADUETO XR
Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider the risks and benefits 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.

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

JENTADUETO and JENTADUETO XR: Nasopharyngitis, diarrhea, hypoglycemia (when used in combination with sulfonylurea), nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

DRUG INTERACTIONS

Metformin:
Carbonic Anhydrase Inhibitors (e.g., topiramate): The concomitant use with 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 for 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.

Linagliptin: 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 SPECIFIC POPULATIONS

Pregnancy:
TRADJENTA, JENTADUETO or JENTADUETO XR should be used during pregnancy only if clearly needed. For JENTADUETO and JENTADUETO XR, discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

Lactation:
Exercise caution when administering TRADJENTA, JENTADUETO or JENTADUETO XR to a nursing woman.

Geriatric Use:
JENTADUETO or JENTADUETO XR should be used with caution as age increases, as aging can be associated with reduced renal function.

CL-JD-100043 06.16.2023