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.
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.
Use with Medications Known to Cause Hypoglycemia: The use in combination with
insulin or insulin secretagogues increases the risk of hypoglycemia. A lower dose 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. 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 Levels: Metformin may lower Vitamin B12 levels.
Monitor hematologic parameters annually and routine serum Vitamin B12 measurement at 2- to 3-
year intervals.
Severe and Disabling Arthralgia: Severe and disabling arthralgia has been
reported in patients taking DPP-4 inhibitors. 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.
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
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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.
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Lactation: Exercise caution when administering JENTADUETO or JENTADUETO XR to a nursing
woman.
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Geriatric Use: JENTADUETO or JENTADUETO XR should be used with caution as age
increases, as aging can be associated with reduced renal function.
