These Highlights Do Not Include All The Information Needed To Use Jentadueto Xr Safely And Effectively. See Full Prescribing Information For Jentadueto Xr.

Limitations of Use

JENTADUETO XR is not recommended in patients with type 1 diabetes mellitus.

JENTADUETO XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using JENTADUETO XR [see Warnings and Precautions (5.2)].

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity.

In the event of an overdose with JENTADUETO XR, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

JENTADUETO XR tablets for oral use contain: linagliptin and metformin HCl.

In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ at 2 to 3 year intervals in patients on JENTADUETO XR and manage any abnormalities [see Adverse Reactions (6.1)].

Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical Studies (14.2)], acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with linagliptin.

Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO XR 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 XR.

An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

Consider the risks and benefits of JENTADUETO XR prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of JENTADUETO XR.

Safety and effectiveness of JENTADUETO XR have not been established in pediatric patients.

Effectiveness of linagliptin was not demonstrated in a 26-week randomized, double-blind, placebo-controlled trial (NCT03429543) in 157 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.

Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

JENTADUETO XR is contraindicated in patients with:

• severe renal impairment (eGFR below 30 mL/min/1.73 m²) [see Warnings and Precautions (5.1)].
• acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
• hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Lactic Acidosis [see Warnings and Precautions (5.1)]
• Pancreatitis [see Warnings and Precautions (5.2)]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
• Vitamin B₁₂ Deficiency [see Warnings and Precautions (5.5)]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)]
• Bullous Pemphigoid [see Warnings and Precautions (5.7)]
• Heart Failure [see Warnings and Precautions (5.8)]

Table 2 describes clinically relevant interactions with JENTADUETO XR.

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.

JENTADUETO XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

In the linagliptin treatment arm of the CARMELINA trial [see Clinical Studies (14.2)], 2,200 (63%) patients had renal impairment (eGFR <60 mL/min/1.73m²). Approximately 20% of the population had eGFR ≥45 to <60 mL/min/1.73 m², 28% of the population had eGFR ≥30 to <45 mL/min/1.73 m² and 15% had eGFR <30 mL/min/1.73 m². The overall incidence of adverse reactions were generally similar between the linagliptin and placebo treatment arms.

Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical Studies (14.2)], and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JENTADUETO XR. If bullous pemphigoid is suspected, JENTADUETO XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. JENTADUETO XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

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

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), 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 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue JENTADUETO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

• Lactic acidosis: See boxed warning (5.1)
• Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO XR. (5.2)
• Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating JENTADUETO XR. (5.3)
• Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with JENTADUETO XR. If hypersensitivity reactions occur discontinue JENTADUETO XR, treat promptly, and monitor until signs and symptoms resolve. (5.4)
• 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. (5.5)
• Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (5.6)
• 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 XR. (5.7)
• Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of JENTADUETO XR in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (5.8)

• Individualize the starting dosage of JENTADUETO XR based on the patient's current regimen (2.1)
• The maximum recommended dosage is 5 mg linagliptin/2,000 mg metformin HCl once daily (2.1)
• Take orally once daily with a meal, with gradual dose escalation to reduce the gastrointestinal effects due to metformin (2.1)
• Swallow whole; do not split, crush, dissolve, or chew (2.1)
• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.2)
  • Do not use in patients with eGFR below 30 mL/min/1.73 m²
  • Initiation is not recommended in patients with eGFR between 30 - 45 mL/min/1.73 m²
  • Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m²
  • Discontinue if eGFR falls below 30 mL/min/1.73 m²
• JENTADUETO XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.3)

JENTADUETO XR tablets are a combination of linagliptin and extended-release metformin HCl available as:

• 5 mg/1,000 mg are white, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim symbol and "D5" on the top line and "1000 M" on the bottom line.
• 2.5 mg/1,000 mg are yellow, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim symbol and "D2" on the top line and "1000 M" on the bottom line.

The following adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3)
• Geriatric Use: Assess renal function more frequently (8.5)
• Hepatic Impairment: Avoid use in patients with hepatic impairment (8.7)

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly 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 XR, assess for other potential causes for the event, and institute alternative treatment for diabetes mellitus.

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 XR.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

JENTADUETO XR (linagliptin and metformin HCl extended-release) tablets 5 mg/1,000 mg, white, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim symbol and "D5" on the top line and "1000 M" on the bottom line, are supplied as follows:

Bottles of 30 (NDC 0597-0275-33)

Bottles of 90 (NDC 0597-0275-81)

JENTADUETO XR (linagliptin and metformin HCl extended-release) tablets 2.5 mg/1,000 mg, yellow, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim symbol and "D2" on the top line and "1000 M" on the bottom line, are supplied as follows:

Bottles of 60 (NDC 0597-0270-73)

Bottles of 180 (NDC 0597-0270-94)

The dosage of JENTADUETO XR should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended total daily dosage of linagliptin 5 mg and metformin hydrochloride (HCl) 2,000 mg. JENTADUETO XR should be given orally once daily with a meal. Dosage escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with metformin use.

Recommended starting dosage:

• In patients currently not treated with metformin HCl, initiate JENTADUETO XR treatment with 5 mg linagliptin/1,000 mg metformin HCl extended-release once daily with a meal.
• In patients already treated with metformin HCl, start JENTADUETO XR with 5 mg of linagliptin total daily dosage and a similar total daily dosage of metformin HCl once daily with a meal.
• In patients already treated with linagliptin and metformin HCl or JENTADUETO, switch to JENTADUETO XR containing 5 mg of linagliptin total daily dosage and a similar total daily dosage of metformin HCl once daily with a meal.

JENTADUETO XR should be swallowed whole. The tablets must not be split, crushed, dissolved, or chewed.

JENTADUETO XR 5 mg linagliptin/1,000 mg metformin HCl extended-release tablet should be taken as a single tablet once daily. Patients using 2.5 mg linagliptin/1,000 mg metformin HCl extended-release tablets should take two tablets together once daily.

Assess renal function prior to initiation of JENTADUETO XR and periodically thereafter.

JENTADUETO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².

Initiation of JENTADUETO XR in patients with an eGFR between 30-45 mL/min/1.73 m² is not recommended.

In patients taking JENTADUETO XR whose eGFR later falls below 45 mL/min/1.73 m², assess benefit/risk of continuing therapy.

Discontinue JENTADUETO XR if the patient's eGFR later falls below 30 mL/min/1.73 m² [see Contraindications (4) and Warnings and Precautions (5.1)].

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

NDC 0597-0275-33

DISPENSE WITH ACCOMPANYING

MEDICATION GUIDE

Jentadueto^® XR

(linagliptin and metformin

hydrochloride extended-release

tablets)

5 mg/1,000 mg*

Rx only

30 tablets

Boehringer

Ingelheim

Discontinue JENTADUETO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart JENTADUETO XR if renal function is stable [see Warnings and Precautions (5.1)].

NDC 0597-0270-73

DISPENSE WITH ACCOMPANYING MEDICATION GUIDE

Jentadueto^® XR

(linagliptin and metformin

hydrochloride extended-release tablets)

2.5 mg/1,000 mg*

Rx only

60 tablets

Boehringer

Ingelheim

Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when JENTADUETO XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1)]. Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO XR.

Limitations of Use

JENTADUETO XR is not recommended in patients with type 1 diabetes mellitus.

JENTADUETO XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using JENTADUETO XR [see Warnings and Precautions (5.2)].

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity.

In the event of an overdose with JENTADUETO XR, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

JENTADUETO XR tablets for oral use contain: linagliptin and metformin HCl.

In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ at 2 to 3 year intervals in patients on JENTADUETO XR and manage any abnormalities [see Adverse Reactions (6.1)].

Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial [see Clinical Studies (14.2)], acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with linagliptin.

Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO XR 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 XR.

An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.

Consider the risks and benefits of JENTADUETO XR prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of JENTADUETO XR.

Safety and effectiveness of JENTADUETO XR have not been established in pediatric patients.

Effectiveness of linagliptin was not demonstrated in a 26-week randomized, double-blind, placebo-controlled trial (NCT03429543) in 157 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.

Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

JENTADUETO XR is contraindicated in patients with:

• severe renal impairment (eGFR below 30 mL/min/1.73 m²) [see Warnings and Precautions (5.1)].
• acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
• hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO XR, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Lactic Acidosis [see Warnings and Precautions (5.1)]
• Pancreatitis [see Warnings and Precautions (5.2)]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.3)]
• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
• Vitamin B₁₂ Deficiency [see Warnings and Precautions (5.5)]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)]
• Bullous Pemphigoid [see Warnings and Precautions (5.7)]
• Heart Failure [see Warnings and Precautions (5.8)]

Table 2 describes clinically relevant interactions with JENTADUETO XR.

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.

JENTADUETO XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

In the linagliptin treatment arm of the CARMELINA trial [see Clinical Studies (14.2)], 2,200 (63%) patients had renal impairment (eGFR <60 mL/min/1.73m²). Approximately 20% of the population had eGFR ≥45 to <60 mL/min/1.73 m², 28% of the population had eGFR ≥30 to <45 mL/min/1.73 m² and 15% had eGFR <30 mL/min/1.73 m². The overall incidence of adverse reactions were generally similar between the linagliptin and placebo treatment arms.

Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial [see Clinical Studies (14.2)], and 3 of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving JENTADUETO XR. If bullous pemphigoid is suspected, JENTADUETO XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. JENTADUETO XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].

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

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), 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 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue JENTADUETO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

• Lactic acidosis: See boxed warning (5.1)
• Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO XR. (5.2)
• Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating JENTADUETO XR. (5.3)
• Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with JENTADUETO XR. If hypersensitivity reactions occur discontinue JENTADUETO XR, treat promptly, and monitor until signs and symptoms resolve. (5.4)
• 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. (5.5)
• Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (5.6)
• 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 XR. (5.7)
• Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of JENTADUETO XR in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (5.8)

• Individualize the starting dosage of JENTADUETO XR based on the patient's current regimen (2.1)
• The maximum recommended dosage is 5 mg linagliptin/2,000 mg metformin HCl once daily (2.1)
• Take orally once daily with a meal, with gradual dose escalation to reduce the gastrointestinal effects due to metformin (2.1)
• Swallow whole; do not split, crush, dissolve, or chew (2.1)
• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.2)
  • Do not use in patients with eGFR below 30 mL/min/1.73 m²
  • Initiation is not recommended in patients with eGFR between 30 - 45 mL/min/1.73 m²
  • Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m²
  • Discontinue if eGFR falls below 30 mL/min/1.73 m²
• JENTADUETO XR may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.3)

JENTADUETO XR tablets are a combination of linagliptin and extended-release metformin HCl available as:

• 5 mg/1,000 mg are white, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim symbol and "D5" on the top line and "1000 M" on the bottom line.
• 2.5 mg/1,000 mg are yellow, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim symbol and "D2" on the top line and "1000 M" on the bottom line.

The following adverse reactions have been identified during postapproval use. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3)
• Geriatric Use: Assess renal function more frequently (8.5)
• Hepatic Impairment: Avoid use in patients with hepatic impairment (8.7)

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly 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 XR, assess for other potential causes for the event, and institute alternative treatment for diabetes mellitus.

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 XR.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

JENTADUETO XR (linagliptin and metformin HCl extended-release) tablets 5 mg/1,000 mg, white, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim symbol and "D5" on the top line and "1000 M" on the bottom line, are supplied as follows:

Bottles of 30 (NDC 0597-0275-33)

Bottles of 90 (NDC 0597-0275-81)

JENTADUETO XR (linagliptin and metformin HCl extended-release) tablets 2.5 mg/1,000 mg, yellow, oval-shaped coated tablets with one side printed in black ink with the Boehringer Ingelheim symbol and "D2" on the top line and "1000 M" on the bottom line, are supplied as follows:

Bottles of 60 (NDC 0597-0270-73)

Bottles of 180 (NDC 0597-0270-94)

The dosage of JENTADUETO XR should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended total daily dosage of linagliptin 5 mg and metformin hydrochloride (HCl) 2,000 mg. JENTADUETO XR should be given orally once daily with a meal. Dosage escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with metformin use.

Recommended starting dosage:

• In patients currently not treated with metformin HCl, initiate JENTADUETO XR treatment with 5 mg linagliptin/1,000 mg metformin HCl extended-release once daily with a meal.
• In patients already treated with metformin HCl, start JENTADUETO XR with 5 mg of linagliptin total daily dosage and a similar total daily dosage of metformin HCl once daily with a meal.
• In patients already treated with linagliptin and metformin HCl or JENTADUETO, switch to JENTADUETO XR containing 5 mg of linagliptin total daily dosage and a similar total daily dosage of metformin HCl once daily with a meal.

JENTADUETO XR should be swallowed whole. The tablets must not be split, crushed, dissolved, or chewed.

JENTADUETO XR 5 mg linagliptin/1,000 mg metformin HCl extended-release tablet should be taken as a single tablet once daily. Patients using 2.5 mg linagliptin/1,000 mg metformin HCl extended-release tablets should take two tablets together once daily.

Assess renal function prior to initiation of JENTADUETO XR and periodically thereafter.

JENTADUETO XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².

Initiation of JENTADUETO XR in patients with an eGFR between 30-45 mL/min/1.73 m² is not recommended.

In patients taking JENTADUETO XR whose eGFR later falls below 45 mL/min/1.73 m², assess benefit/risk of continuing therapy.

Discontinue JENTADUETO XR if the patient's eGFR later falls below 30 mL/min/1.73 m² [see Contraindications (4) and Warnings and Precautions (5.1)].

Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.

NDC 0597-0275-33

DISPENSE WITH ACCOMPANYING

MEDICATION GUIDE

Jentadueto^® XR

(linagliptin and metformin

hydrochloride extended-release

tablets)

5 mg/1,000 mg*

Rx only

30 tablets

Boehringer

Ingelheim

Discontinue JENTADUETO XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart JENTADUETO XR if renal function is stable [see Warnings and Precautions (5.1)].

NDC 0597-0270-73

DISPENSE WITH ACCOMPANYING MEDICATION GUIDE

Jentadueto^® XR

(linagliptin and metformin

hydrochloride extended-release tablets)

2.5 mg/1,000 mg*

Rx only

60 tablets

Boehringer

Ingelheim

Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when JENTADUETO XR is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin [see Adverse Reactions (6.1)]. Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO XR.