SELECT IMPORTANT SAFETY INFORMATION & BOXED WARNING

WARNING: RISK OF LACTIC ACIDOSIS

Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

CONTRAINDICATIONS

JENTADUETO is contraindicated in patients with:

  • Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).

  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis.

  • History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.

WARNINGS AND PRECAUTIONS

Lactic Acidosis

  • Lactic acidosis is a serious metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.

  • The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/ 1000 patient-years, with approximately 0.015 fatal cases/ 1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

  • Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.

  • The risk of lactic acidosis increases with the degree of renal impairment and the patient's age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced.

  • Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO 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.

Monitoring of Renal Function

Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.

Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.

Impaired Hepatic Function

Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment.

Use with Medications Known to Cause Hypoglycemia

Insulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO.

Vitamin B12 Levels

Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.

Alcohol Intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO.

Hypoxic States

Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug.

104-week Active-controlled Study vs Glimepiride in Combination With Metformin1,2

*Full analysis population using last observation on study.

ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline A1C as continuous covariates.

  • A1C reduction with linagliptin was demonstrated to be noninferior compared with glimepiride (1-sided noninferiority P=0.0004)
  • 0.2% A1C reduction from baseline in patients treated with linagliptin + metformin (mean baseline A1C: 7.7%) vs 0.4% A1C reduction from baseline in patients treated with glimepiride + metformin (mean baseline A1C: 7.7%)
  • A conclusion in favor of the noninferiority of linagliptin + metformin to glimepiride + metformin may be limited to patients with baseline A1C comparable to those included in the study (66% of patients had baseline A1C <8% and 91% had A1C <9%)
  • 7.5% incidence of hypoglycemia in patients receiving linagliptin + metformin vs 36.1% for glimepiride + metformin (P<0.0001 vs glimepiride)
  • Patients treated with linagliptin exhibited a mean decrease from baseline body weight compared with a weight gain in patients administered glimepiride (–1.4 kg vs 1.3 kg, P<0.0001)
  • 21.5% of patients in the glimepiride group required use of rescue therapy vs 24.7% of patients in the JENTADUETO (linagliptin + metformin) group

The safety of concomitantly administered linagliptin and metformin has been evaluated in more than 2800 patients with type 2 diabetes mellitus in clinical trials.

JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects.

Glycemic parameters at 104 weeks in study comparing linagliptin to glimepiride as
add-on therapy in patients inadequately controlled on metformin1‡

Fasting Plasma Glucose (FPG) (mg/dL)

Linagliptin 5 mg + Metformin

Glimepiride + Metformin

Number of patients

733

725

Baseline

164

166

Change from baseline (adjusted mean)§

–2

–9

 

Hypoglycemia incidence (%)

Linagliptin 5 mg + Metformin

Glimepiride + Metformin

Number of patients

776

775

Incidence

7.5#

36.1

Glimepiride dose in the study was 1 mg/day to 4 mg/day; metformin dose in the study was ≥1500 mg/day.

§ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline A1C and baseline FPG as continuous covariates.

P<0.0012 vs glimepiride.

Hypoglycemic incidence included both asymptomatic events (not accompanied by typical symptoms and plasma glucose concentration of ≤70 mg/dL) and symptomatic events with typical symptoms of hypoglycemia and plasma glucose concentration of ≤70 mg/dL.

#P<0.0001 vs glimepiride.

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Study design#

Primary endpoint—interim analysis

  • Change from prerandomization baseline in A1C (prior to 2-week placebo run-in) after 104 weeks of treatment

Secondary endpoints included

  • Change from baseline body weight after 104 weeks of treatment
  • Occurrence of hypoglycemic events up to 104 weeks
  • Change from baseline FPG after 104 weeks of treatment

#Glimepiride dose in the study was 1 mg/day to 4 mg/day; metformin dose in the study was `ge;1500 mg/day.

1. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.
2. Gallwitz B, Rosenstock J, Rauch T, Bhattacharaya S, Patel S, von Eynatten M, Dugi KA, Woerle H-J. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet. 2012;380(9840):475-483.

JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects.

Jentadueto® (linagliptin and metformin hydrochloride) tablets

INDICATION AND IMPORTANT LIMITATIONS OF USE

JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

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

JENTADUETO has not been studied in patients with a history of pancreatitis.

IMPORTANT SAFETY INFORMATION

WARNING: RISK OF LACTIC ACIDOSIS

Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

CONTRAINDICATIONS

JENTADUETO is contraindicated in patients with:

  • Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
  • History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.

WARNINGS AND PRECAUTIONS

Lactic Acidosis

  • Lactic acidosis is a serious metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.
  • The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.
  • Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.
  • The risk of lactic acidosis increases with the degree of renal impairment and the patient's age. The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced.
  • Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO 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.

Monitoring of Renal Function

Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.

Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.

Impaired Hepatic Function

Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment.

Use with Medications Known to Cause Hypoglycemia

Insulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO.

Vitamin B12 Levels

Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.

Alcohol Intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO.

Hypoxic States

Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug.

ADVERSE REACTIONS

  • In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea.
  • 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. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%).
  • In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient-years 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.

DRUG INTERACTIONS

  • Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
  • The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer or CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended.
  • The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase.

USE IN SPECIFIC POPULATIONS

  • As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed.
  • It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
  • The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established.
  • JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.

JD PROF ISI 12SEPT2013

Click here for full Prescribing Information, including Boxed Warning regarding risk of lactic acidosis, and Medication Guide.

Tradjenta® (linagliptin) tablets

Indication and Important Limitations of Use

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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

TRADJENTA has not been studied in patients with a history of pancreatitis.

Important Safety Information

CONTRAINDICATIONS

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS

Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking TRADJENTA. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA 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.

Use with Medications Known to Cause Hypoglycemia

Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

ADVERSE REACTIONS

Adverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. In patients receiving TRADJENTA as add-on therapy to a stable dose of insulin severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo.

In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA 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.

DRUG INTERACTIONS

The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS

There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman.

The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

TJ PROF ISI 19JUNE2013

Click here for full Prescribing Information, including Medication Guide.