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:
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 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.
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: 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
Hypoglycemia: The use in combination with insulin or insulin secretagogues may increase 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 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 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.
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,
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.