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Study Designs

Initial Combination Therapy with Linagliptin + Metformin

A total of 791 patients with type 2 diabetes mellitus and inadequate glycemic control on diet and exercise participated in the 24-week, randomized, double-blind portion of this placebo-controlled factorial study designed to assess the efficacy of linagliptin as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent a drug washout period of 4 weeks' duration. After the washout period and after completing a 2-week, single-blind, placebo run-in period, patients with inadequate glycemic control (A1C ≥7.0% to ≤10.5%) were randomized. Patients with inadequate glycemic control (A1C ≥7.5% to ≤11.0%) not on antihyperglycemic agents at study entry (48%) immediately entered the 2-week, single-blind, placebo run-in period and then were randomized. Randomization was stratified by baseline A1C (<8.5% vs ≥8.5%) and use of a prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in a 1:2:2:2:2:2 ratio to either placebo or 1 of 5 active-treatment arms. Approximately equal numbers of patients were randomized to receive initial therapy with 5 mg of linagliptin once daily, 500 mg or 1000 mg of metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy.

Study in Patients With High Baseline A1C

A 24-week, randomized, double-blind, parallel-group trial to assess the efficacy of linagliptin and metformin compared with linagliptin monotherapy in adult patients with type 2 diabetes diagnosed within the previous 12 months who were treatment naïve (no antidiabetic therapy for 12 weeks prior to randomization) and had inadequate glycemic control (A1C ≥8.5% to ≤12%). Patients were randomized (1:1) after a 2-week run-in period to either linagliptin 5 mg/day + placebo (n=157) or linagliptin 5 mg/day + metformin (n=159). Metformin was initiated at 1000 mg/day (500 mg BID) for 7 days. Patients were up-titrated to 1500 mg/day (500 mg qAM and 1000 mg qPM) for a subsequent 7 days based upon tolerability to the increased dose. Thereafter, metformin could be further up-titrated to a maximum daily dose of 2000 mg (1000 mg BID) up to a period of 6 weeks if the FPG was >110 mg/dL and the patient was able to tolerate the maximum dose. Titration of metformin was performed under double-blind conditions. Patients who failed to meet glycemic goals were treated with sulfonylurea, insulin, or glitazone rescue.

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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. See Important Safety Information and full Prescribing Information for complete Boxed Warning.

In addition to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes

Help your patients navigate
the Road Ahead

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, and it is unknown if using JENTADUETO increases the risk of developing pancreatitis in these patients.

In addition to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes

Efficacy

Initial Combination Therapy with Linagliptin + Metformin

A fixed-dose combination (Linagliptin + Metformin HCI)

With statistically significant A1C reductions

Placebo-adjusted mean difference in A1C at 24 weeks in patients receiving linagliptin and metformin, alone or in combination (%)1,2*†‡§

Chart: Placebo-adjusted mean difference in A1C at 24 weeks Study Designs

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

In patients receiving JENTADUETO as coadministered linagliptin 2.5 mg/metformin 1000 mg twice daily as initial therapy:1,2*

Secondary endpoint: Percent of patients who achieved A1C <7%1#

Percent of patients who achieved A1C <7% Study Designs

Study in patients with high baseline A1C

A1C Reduction with linagliptin + metformin vs linagliptin alone

Primary Endpoint: Adjusted mean difference in A1C from baseline at 24 weeks in treatment-naïve patients with high baseline A1C (≥8.5% to ≤12.0%)1

Chart: Adjusted mean difference in A1C from baseline at 24 weeks
Study Designs

The adjusted mean difference between groups in A1C change from baseline was –0.84% (P<0.0001)*†

A1C reductions over time in treatment-naïve patients with a high baseline A1C

Secondary endpoint: Adjusted mean change in A1C from baseline (≥8.5% to ≤12.0%) over 24 weeks in an FAS completers' analysis2‡

Chart: Adjusted mean change in A1C from baseline over 24 weeks Study Designs

In addition to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes

Jentadueto Dosing

A fixed dose with flexibility

Three dosing options allow you to adjust metformin dosage while keeping linagliptin at 5 mg per day.

Available in 3 Dosage Strengths Available in 3 Dosage Strengths

The dosage of JENTADUETO should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dose of 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily.

JENTADUETO should be given twice daily with meals with gradual dose escalation to reduce the gastrointestinal side effects to metformin.

No studies have been performed specifically examining the safety and efficacy of JENTADUETO in patients previously treated with other oral antihyperglycemic agents and switched to JENTADUETO. Any change in therapy should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Recommended Dosing

  • The maximum recommended dose is 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily.
  • In patients not currently treated with metformin, initiate treatment with 2.5 mg linagliptin/500 mg metformin hydrochloride twice daily.
  • In patients already treated with metformin, start with 2.5 mg linagliptin and the current dose of metformin taken at 2 of the daily meals.
  • Patients already treated with linagliptin and metformin individual components may be switched to JENTADUETO containing the same doses of each component.

Concomitant Use With an Insulin Secretagogue (e.g., Sulfonylurea) or With Insulin

When JENTADUETO is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.

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.
References:

1. JENTADUETO Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc.

2. Data on file. Boehringer Ingelheim Pharmaceuticals, Inc.

In addition to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes

Jentadueto 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 trials1

Table: Adverse Reactions
Table: Adverse Reactions
  • Other adverse reactions reported in clinical studies with treatment of linagliptin/metformin were hypersensitivity (e.g., 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 (e.g., 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 (e.g., megaloblastic anemia).
  • Hypoglycemia

  • 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.
  • 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

  • Changes in laboratory findings were similar in patients treated with linagliptin/metformin compared to patients treated with placebo plus metformin.
  • Changes in laboratory values that occurred more frequently in the linagliptin/metformin group and ≥1% more than in the placebo group were not detected.
  • No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.

In addition to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes

Resources

To help with the road ahead

PC-JD-0046-PROF-R1
Important Safety Information, Indication and Important Limitations of Use Important Safety Information, Indication
and Important Limitations of Use
+

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.
  • A history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity.
  • Hypersensitivity to 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.

Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue JENTADUETO, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. 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.

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.

Severe and Disabling Arthralgia

Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate.

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.

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, and it is unknown if using JENTADUETO increases the risk of developing pancreatitis in these patients.

JD PROF ISI 31AUG2015

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