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mechanism of action is Dipeptidyl Peptidase 4 Inhibitors [MoA]

Jentadueto

(Linagliptin And Metformin Hydrochloride)

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Dosage & Administration

* Individualize the starting dosage of JENTADUETO based on the patient's current regimen (

2.1 Recommended Dosage and Administration

The dosage of JENTADUETO should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dosage of 2.5 mg linagliptin/1,000 mg metformin hydrochloride (HCl), taken orally twice daily. JENTADUETO should be given twice daily with meals. 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 treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily.
* In patients already treated with metformin HCl, start with 2.5 mg linagliptin and the current dosage of metformin HCl taken at each of the two daily meals (e.g., a patient on metformin HCl 1,000 mg twice daily would be started on 2.5 mg linagliptin/1,000 mg metformin HCl twice daily with meals).
* Patients already treated with linagliptin and metformin HCl individual components may be switched to JENTADUETO containing the same dosages of each component.

)
* The maximum recommended dosage is 2.5 mg linagliptin/1,000 mg metformin HCl twice daily (

2.1 Recommended Dosage and Administration

Recommended starting dosage:

)
* Take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal effects due to metformin (

2.1 Recommended Dosage and Administration

Recommended starting dosage:

)
* Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (

2.2 Recommended Dosing in Renal Impairment

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

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

Initiation of JENTADUETO in patients with an eGFR between 30-45 mL/min/1.73 m²is not recommended.

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

Discontinue JENTADUETO if the patient's eGFR later falls below 30 mL/min/1.73 m²

[see Contraindications (4)and Warnings and Precautions (5.1)].

)
* 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 may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (

2.3 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue JENTADUETO 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 if renal function is stable

[see Warnings and Precautions (5.1)].

)

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Jentadueto Prescribing Information

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

5.1 Lactic Acidosis

Metformin

There have been postmarketing 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. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of JENTADUETO. In JENTADUETO-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue JENTADUETO and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment:

The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include

[see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]:

Before initiating JENTADUETO, obtain an estimated glomerular filtration rate (eGFR).
JENTADUETO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
[see Contraindications (4)].
Initiation of JENTADUETO is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m².
Obtain an eGFR at least annually in all patients taking JENTADUETO. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
In patients taking JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m², assess the benefit and risk of continuing therapy.

Drug Interactions:

The concomitant use of JENTADUETO with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation

[see Drug Interactions (7)]

. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:

The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients

[see Use in Specific Populations (8.5)].

Radiological Studies with Contrast:

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop JENTADUETO 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 hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JENTADUETO if renal function is stable.

Surgery and Other Procedures:

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. JENTADUETO should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States:

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue JENTADUETO.

Excessive Alcohol Intake:

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving JENTADUETO.

Hepatic Impairment:

Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of JENTADUETO in patients with clinical or laboratory evidence of hepatic disease.

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

2.2 Recommended Dosing in Renal Impairment

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

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

Initiation of JENTADUETO in patients with an eGFR between 30-45 mL/min/1.73 m²is not recommended.

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

Discontinue JENTADUETO if the patient's eGFR later falls below 30 mL/min/1.73 m²

[see Contraindications (4)and Warnings and Precautions (5.1)].

4 CONTRAINDICATIONS

JENTADUETO 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, 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)].

Severe renal impairment (eGFR below 30 mL/min/1.73 m²)
Metabolic acidosis, including diabetic ketoacidosis
Hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO

5.1 Lactic Acidosis

Metformin

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue JENTADUETO and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment:

[see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]:

Before initiating JENTADUETO, obtain an estimated glomerular filtration rate (eGFR).
JENTADUETO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
[see Contraindications (4)].
Initiation of JENTADUETO is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m².
Obtain an eGFR at least annually in all patients taking JENTADUETO. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
In patients taking JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m², assess the benefit and risk of continuing therapy.

Drug Interactions:

[see Drug Interactions (7)]

. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:

[see Use in Specific Populations (8.5)].

Radiological Studies with Contrast:

Surgery and Other Procedures:

Hypoxic States:

Excessive Alcohol Intake:

Hepatic Impairment:

7 DRUG INTERACTIONS

Table 2 describes clinically relevant interactions with JENTADUETO.

Table 2 Clinically Relevant Interactions with JENTADUETO
Carbonic Anhydrase Inhibitors
Clinical Impact	Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with JENTADUETO may increase the risk of lactic acidosis.
Intervention	Consider more frequent monitoring of these patients.
Drugs that Reduce Metformin Clearance
Clinical Impact	Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)] .
Intervention	Consider the benefits and risks of concomitant use.
Alcohol
Clinical Impact	Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Intervention	Warn patients against excessive alcohol intake while receiving JENTADUETO.
Insulin or Insulin Secretagogues
Clinical Impact	The risk of hypoglycemia is increased when JENTADUETO is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin.
Intervention	Coadministration of JENTADUETO with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Drugs Affecting Glycemic Control
Clinical Impact	Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.
Intervention	When such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia.
Inducers of P-glycoprotein or CYP3A4 Enzymes
Clinical Impact	Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer.
Intervention	Use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer.

Carbonic Anhydrase Inhibitors:
May increase risk of lactic acidosis. Consider more frequent monitoring.
Drugs that Reduce Metformin Clearance:
May increase risk of lactic acidosis. Consider benefits and risks of concomitant use.
Alcohol:
Can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake.
Strong P-glycoprotein/CYP3A4 Inducer:
Efficacy may be reduced when administered in combination (e.g., rifampin). Use of alternative treatments is strongly recommended.

, and

8.6 Renal Impairment

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

JENTADUETO 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/1.73 m²). 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 m²and 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.

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. JENTADUETO is not recommended in patients with hepatic impairment

[see Warnings and Precautions (5.1)].

If metformin-associated lactic acidosis is suspected, immediately discontinue JENTADUETO and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended

[see

5.1 Lactic Acidosis

Metformin

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue JENTADUETO and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment:

[see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]:

Before initiating JENTADUETO, obtain an estimated glomerular filtration rate (eGFR).
JENTADUETO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
[see Contraindications (4)].
Initiation of JENTADUETO is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m².
Obtain an eGFR at least annually in all patients taking JENTADUETO. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
In patients taking JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m², assess the benefit and risk of continuing therapy.

Drug Interactions:

[see Drug Interactions (7)]

. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater:

[see Use in Specific Populations (8.5)].

Radiological Studies with Contrast:

Surgery and Other Procedures:

Hypoxic States:

Excessive Alcohol Intake:

Hepatic Impairment:

Individualize the starting dosage of JENTADUETO based on the patient's current regimen (
2.1 Recommended Dosage and Administration
The dosage of JENTADUETO should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dosage of 2.5 mg linagliptin/1,000 mg metformin hydrochloride (HCl), taken orally twice daily. JENTADUETO should be given twice daily with meals. 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 treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily.
- In patients already treated with metformin HCl, start with 2.5 mg linagliptin and the current dosage of metformin HCl taken at each of the two daily meals (e.g., a patient on metformin HCl 1,000 mg twice daily would be started on 2.5 mg linagliptin/1,000 mg metformin HCl twice daily with meals).
- Patients already treated with linagliptin and metformin HCl individual components may be switched to JENTADUETO containing the same dosages of each component.
)
The maximum recommended dosage is 2.5 mg linagliptin/1,000 mg metformin HCl twice daily (
2.1 Recommended Dosage and Administration
The dosage of JENTADUETO should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dosage of 2.5 mg linagliptin/1,000 mg metformin hydrochloride (HCl), taken orally twice daily. JENTADUETO should be given twice daily with meals. 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 treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily.
- In patients already treated with metformin HCl, start with 2.5 mg linagliptin and the current dosage of metformin HCl taken at each of the two daily meals (e.g., a patient on metformin HCl 1,000 mg twice daily would be started on 2.5 mg linagliptin/1,000 mg metformin HCl twice daily with meals).
- Patients already treated with linagliptin and metformin HCl individual components may be switched to JENTADUETO containing the same dosages of each component.
)
Take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal effects due to metformin (
2.1 Recommended Dosage and Administration
The dosage of JENTADUETO should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dosage of 2.5 mg linagliptin/1,000 mg metformin hydrochloride (HCl), taken orally twice daily. JENTADUETO should be given twice daily with meals. 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 treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily.
- In patients already treated with metformin HCl, start with 2.5 mg linagliptin and the current dosage of metformin HCl taken at each of the two daily meals (e.g., a patient on metformin HCl 1,000 mg twice daily would be started on 2.5 mg linagliptin/1,000 mg metformin HCl twice daily with meals).
- Patients already treated with linagliptin and metformin HCl individual components may be switched to JENTADUETO containing the same dosages of each component.
)
Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (
2.2 Recommended Dosing in Renal Impairment
Assess renal function prior to initiation of JENTADUETO and periodically thereafter.
JENTADUETO is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².
Initiation of JENTADUETO in patients with an eGFR between 30-45 mL/min/1.73 m²is not recommended.
In patients taking JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m², assess benefit/risk of continuing therapy.
Discontinue JENTADUETO if the patient's eGFR later falls below 30 mL/min/1.73 m²
[see Contraindications (4)and Warnings and Precautions (5.1)].
)
- 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 may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (
2.3 Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue JENTADUETO 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 if renal function is stable
[see Warnings and Precautions (5.1)].
)

JENTADUETO tablets are a combination of linagliptin and metformin HCl available as:

2.5 mg linagliptin/500 mg metformin HCl tablets are light yellow, oval, biconvex tablets debossed with "D2/500" on one side and the Boehringer Ingelheim symbol on the other side
2.5 mg linagliptin/850 mg metformin HCl tablets are light orange, oval, biconvex tablets debossed with "D2/850" on one side and the Boehringer Ingelheim symbol on the other side
2.5 mg linagliptin/1,000 mg metformin HCl tablets are light pink, oval, biconvex tablets debossed with "D2/1000" on one side and the Boehringer Ingelheim symbol on the other side

Females and Males of Reproductive Potential:
Advise premenopausal females of the potential for an unintended pregnancy (
8.3 Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as therapy with metformin may result in ovulation in some anovulatory women.
)
Geriatric Use:
Assess renal function more frequently (
8.5 Geriatric Use
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)].
Linagliptin
In linagliptin studies, 1,085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.
Metformin
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients
[see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
)
Hepatic Impairment:
Avoid use in patients with hepatic impairment (
8.7 Hepatic Impairment
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. JENTADUETO is not recommended in patients with hepatic impairment
[see Warnings and Precautions (5.1)].
)

JENTADUETO is contraindicated in patients with:

severe renal impairment (eGFR below 30 mL/min/1.73 m²)
[see
5.1 Lactic Acidosis
Metformin
There have been postmarketing 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. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of JENTADUETO. In JENTADUETO-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery
.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue JENTADUETO and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal Impairment:
The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include
[see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]:
Before initiating JENTADUETO, obtain an estimated glomerular filtration rate (eGFR).
JENTADUETO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
[see Contraindications (4)].
Initiation of JENTADUETO is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m².
Obtain an eGFR at least annually in all patients taking JENTADUETO. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
In patients taking JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m², assess the benefit and risk of continuing therapy.
Drug Interactions:
The concomitant use of JENTADUETO with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation
[see Drug Interactions (7)]
. Therefore, consider more frequent monitoring of patients.
Age 65 or Greater:
The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients
[see Use in Specific Populations (8.5)].
Radiological Studies with Contrast:
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop JENTADUETO 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 hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JENTADUETO if renal function is stable.
Surgery and Other Procedures:
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. JENTADUETO should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States:
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue JENTADUETO.
Excessive Alcohol Intake:
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving JENTADUETO.
Hepatic Impairment:
Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of JENTADUETO in patients with clinical or laboratory evidence of hepatic disease.
].
acute or chronic metabolic acidosis, including diabetic ketoacidosis
[see
5.1 Lactic Acidosis
Metformin
There have been postmarketing 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. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of JENTADUETO. In JENTADUETO-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery
.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue JENTADUETO and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal Impairment:
The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include
[see Dosage and Administration (2.2)and Clinical Pharmacology (12.3)]:
Before initiating JENTADUETO, obtain an estimated glomerular filtration rate (eGFR).
JENTADUETO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m²
[see Contraindications (4)].
Initiation of JENTADUETO is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m².
Obtain an eGFR at least annually in all patients taking JENTADUETO. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
In patients taking JENTADUETO whose eGFR later falls below 45 mL/min/1.73 m², assess the benefit and risk of continuing therapy.
Drug Interactions:
The concomitant use of JENTADUETO with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation
[see Drug Interactions (7)]
. Therefore, consider more frequent monitoring of patients.
Age 65 or Greater:
The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients
[see Use in Specific Populations (8.5)].
Radiological Studies with Contrast:
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop JENTADUETO 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 hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart JENTADUETO if renal function is stable.
Surgery and Other Procedures:
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. JENTADUETO should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States:
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue JENTADUETO.
Excessive Alcohol Intake:
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving JENTADUETO.
Hepatic Impairment:
Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of JENTADUETO in patients with clinical or laboratory evidence of hepatic disease.
].

hypersensitivity to linagliptin, metformin, or any of the excipients in JENTADUETO, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin

[see

5.4 Hypersensitivity Reactions

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, 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.

and

6.1 Clinical Trials Experience

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.

Linagliptin/Metformin

The safety of concomitantly administered linagliptin (daily dosage 5 mg) and metformin (mean daily dosage of approximately 1,800 mg) has been evaluated in 2,816 patients with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials.

Three placebo-controlled trials with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 trial was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse reactions which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%).

In a 24-week factorial design trial, adverse reactions reported in ≥5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.

Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Trial
Adverse Reactions	Placebo (%) n=72	Linagliptin Monotherapy (%) n=142	Metformin Monotherapy (%) n=291	Combination of Linagliptin with Metformin (%) n=286
Nasopharyngitis	1.4	5.6	2.7	6.3
Diarrhea	2.8	3.5	3.8	6.3

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

Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%).

Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin therapy.

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. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year 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 (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.

Other Adverse Reactions

Hypoglycemia

Linagliptin/Metformin

In a 24-week factorial design trial, 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. The incidence of hypoglycemia with plasma glucose <54 mg/dL was 8.1% in the linagliptin group (N=792) compared to 5.3% in the placebo group (N=263) when administered in combination with metformin and sulfonylurea in a 24-week trial.

Linagliptin

The incidence of severe hypoglycemia (requiring assistance) was 1.7% in the linagliptin group (N=631) compared to 1.1% in the placebo group (N=630) when administered in combination with basal insulin in a 52-week trial.

Laboratory Test Abnormalities in Clinical Trials of Linagliptin or Metformin

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.

Increase in Amylase:

In a cardiovascular safety trial comparing linagliptin versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the linagliptin and glimepiride arms, respectively.

The clinical significance of elevations in lipase and amylase with linagliptin is unknown in the absence of potential signs and symptoms of pancreatitis

[see Warnings and Precautions (5.2)].

Metformin

Decrease in Vitamin B₁₂:

In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂levels was observed in approximately 7% of patients.

Jentadueto

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