WARNING: LACTIC ACIDOSIS
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 JENTADUETO or JENTADUETO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
CONTRAINDICATIONS: 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: 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 and promptly notify their healthcare provider.
Recommendations to reduce the risk include:
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Renal Impairment: Obtain eGFR prior to initiating and annually or more frequently in patients at increased risk of developing renal impairment.
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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.
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Age 65 or Greater: Assess renal function more frequently.
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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 of
30‑60 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 imaging procedure, and restart JENTADUETO or JENTADUETO XR if renal function is stable.
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Surgery and Other Procedures: Discontinue while patients have restricted food and fluid intake.
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Hypoxic States: Discontinue in conditions associated with hypoxemia.
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Excessive Alcohol Intake: Warn patients against excessive alcohol intake.
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Hepatic Impairment: Avoid use in patients with hepatic disease.
Pancreatitis: 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 JENTADUETO or JENTADUETO XR.
Hypoglycemia: The use in combination with insulin or insulin secretagogues may increase the risk of hypoglycemia. A lower dosage of insulin or insulin secretagogue may be required.
Hypersensitivity Reactions: Discontinue JENTADUETO or JENTADUETO XR, 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 JENTADUETO or JENTADUETO XR.
Vitamin B12 Deficiency: 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: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider linagliptin 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 JENTADUETO or JENTADUETO XR.
Heart Failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider the risks and benefits of JENTADUETO or JENTADUETO 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 JENTADUETO or JENTADUETO XR.
MOST COMMON ADVERSE REACTIONS (≥5%): 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 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.
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: JENTADUETO or JENTADUETO XR should be used during pregnancy only if clearly needed. 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 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-100041 06.16.2023
