Adverse Reactions

The safety of concomitantly administered linagliptin and metformin has been evaluated in more than 2800 patients with type 2 diabetes mellitus treated for >12 weeks in clinical trials
Adverse Reactions Reported in ≥5% of Patients with Linagliptin/Metformin and Greater than with Placebo in a 24-week Factorial-Design Study
Adverse Reactions in Linagliptin vs. Placebo
  • Other adverse reactions reported in clinical studies with treatment of linagliptin/metformin were hypersensitivity (eg, urticaria, angioedema, or bronchial hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.

Linagliptin

  • Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (eg, urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia
  • Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients with placebo included: nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%)
  • In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient-years of exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin

Metformin

  • The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache
  • Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption, which may very rarely result in clinically significant vitamin B12 deficiency (eg, megaloblastic anemia)

Hypoglycemia

Linagliptin/Metformin

  • In a 24-week factorial-design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin/metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo
  • When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea

Linagliptin

  • In the study of patients receiving linagliptin as add-on therapy to a stable dose of insulin for up to 52 weeks, no significant difference in the incidence of investigator-reported hypoglycemia was noted compared with placebo (31.4% vs 32.9%, respectively)
  • In a study of linagliptin compared with placebo as add-on to pre-existing antidiabetic therapy in patients with severe renal impairment, the incidence of hypoglycemia was higher in patients treated with linagliptin (63%) vs in patients treated with placebo (49%). Severe hypoglycemic events were reported in 4.4% of patients treated with linagliptin vs 4.6% of patients treated with placebo in this trial

Laboratory Tests

Linagliptin

  • Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group)
  • Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively
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Important Safety Information

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.

INDICATION AND LIMITATIONS OF USE

JENTADUETO and JENTADUETO XR tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

JENTADUETO and JENTADUETO XR should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

JENTADUETO and JENTADUETO XR have not been studied in patients with a history of pancreatitis, and it is unknown if using JENTADUETO or JENTADUETO XR increases the risk of developing pancreatitis in these patients.

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 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
  • 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-JDJDX-100007 7.12.19

Please see Prescribing Information for JENTADUETO, including Boxed Warning regarding risk of lactic acidosis and Medication Guide.

Please see Prescribing Information for JENTADUETO XR, including Boxed Warning regarding risk of lactic acidosis and Medication Guide.