Dosing & Uses
Dosage Forms & Strengths
extended-release tablet (Jentadueto XR)
Diabetes Mellitus Type 2
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
- Initial dose (not currently taking metformin): 2.5 mg/500 mg PO BID
- Initial dose (already taking metformin): Base dose on current metformin dose (eg, if taking metformin 1000 mg BID, initiate with 2.5 mg/1000 mg PO BID)
- Not to exceed 2.5 mg/1,000 mg BID
- Individualize dose on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended total daily dose of linagliptin/metformin 5 mg/2000 mg
- Initial dose (not currently taking metformin): 5 mg/1000 mg PO qDay
- Initial dose (already taking metformin): 5 mg of linagliptin total daily dose and a similar total daily dose of metformin qDay
- Switch from prompt-release linagliptin/metformin: 5 mg of linagliptin total daily dose and a similar total daily dose of metformin qDay
Hepatic impairment: Not recommended because of increased risk of lactic acidosis
- Obtain eGFR before starting metformin
- eGFR <30 mL/min/1.73 m²: Contraindicated
- eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment
- Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
- If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated
- If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug
Not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings
Has not been studied in patients with a history of pancreatitis; unknown whether patients with a history of pancreatitis are at an increased risk of developing pancreatitis when taking linagliptin
Has not been studied in combination with insulin
<18 years: Safety and efficacy not established
Should not be initiated in patients aged ≥80 years unless CrCl measurement demonstrates that renal function is not reduced
Serious - Use Alternative
Significant - Monitor Closely
Hypoglycemia (with sulfonylurea) (22.9%)
Hypoglycemia (without sulfonylurea) (1.4%)
Frequency Not Defined
Hypersensitivity (eg, urticaria, angioedema, or bronchial hyperactivity)
Acute pancreatitis, including fatal pancreatitis
Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
Mouth ulceration, stomatitis
Severe and disabling arthralgia
Black Box Warnings
Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
- Lactic acidosis can occur due to metformin accumulation
- Risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute CHF
- Symptoms include 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, discontinue linagliptin/metformin and hospitalize the patient immediately
Renal impairment (eg, eGFR <30 ml/min/1.73 m²) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
Acute or chronic metabolic acidosis, including diabetic ketoacidosis; diabetic ketoacidosis should be treated with insulin
History of hypersensitivity reaction to linagliptin (eg, urticaria, angioedema, bronchial hyperreactivity) or metformin
Rare reports of lactic acidosis (see Black Box Warnings)
Monitor hepatic and renal function; risk of metformin accumulation and lactic acidosis increases with renal impairment; hepatic impairment limits ability to clear lactate
Avoid excessive alcohol intake; alcohol is known to potentiate effect of metformin on lactate metabolism
Use of concomitant medications that may affect renal function or metformin disposition
Use in combination with an insulin secretagogue (eg, sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial
May lead to decreases levels of vitamin B12 without clinical manifestations (occurred in approximately 7% of patients)
Cardiovascular collapse (shock) from whatever cause (eg, 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; discontinue drug promptly
Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate
No conclusive evidence of macrovascular risk reduction reported with antidiabetic drugs
Serious hypersensitivity reactions reported including anaphylaxis, angioedema, and exfoliative skin conditions; discontinue therapy promptly, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes
Iodinated contrast imaging procedures
- Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
- Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable
- Postmarketing reports of acute pancreatitis, including fatal pancreatitis; monitor for signs and symptoms of pancreatitis, and discontinue if suspected
- Unknown if patients with history of pancreatitis are at increased risk for the development of pancreatitis while using linagliptin
Pregnancy & Lactation
Pregnancy Category: B
Lactation: Metformin excreted in human milk in low concentrations; unknown if linagliptin excreted in human milk
No studies in lactating animals have been conducted with the combined components of Jentadueto; because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Mechanism of Action
Linagliptin: Dipeptidyl peptidase 4 (DPP-4) inhibitor; increases and prolongs incretin hormone activity from glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) which are inactivated by the DPP-4 enzyme; incretins increase insulin release and reduce glucagon secretion
Metformin: Decreases hepatic glucose production; decreases GI intestinal glucose absorption; increases target cell insulin sensitivity; lowers both basal and postprandial plasma glucose and unlike sulfonylureas, does not typically produce hypoglycemia or hyperinsulinemia
Bioavailability: 30% (linagliptin); 50-60% (metformin)
Protein Bound: 70-80% (linagliptin); >90% (metformin)
Vd: ~1,110 L (linagliptin); ~654 L (metformin)
- Metabolites: Has pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin
- CYP3A4 substrate
- Weak-to-moderate CYP3A4 inhibitor
- P-gp substrate; inhibits P-gp transport at high concentrations
- Metformin is excreted 100% in the urine therefore does not undergo metabolism in the body the following information is for linagliptin
Half-life: 12 hr (linagliptin); 6.2 hr (metformin)
Dialyzable: Removal of linagliptin by dialysis is unlikely and metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions)
Renal clearance: 70 mL/min (linagliptin)
Excretion: Linagliptin enterohepatic system (80%) or urine (5%); metformin urine (90%)
Take with a meal
Dosing should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dose for either prompt-release or extended-release tablets
Prompt-release: When initiating, dose escalation should be gradual to reduce the GI side effects associated with metformin
- Swallow tablet whole; do not split, crush, dissolve, or chew before swallowing
- Extended-release tablet should be taken as a single tablet once daily; if dose is 5 mg/2000 mg, use 2.5 mg linagliptin/1000 mg metformin extended-release tablets and take two tablets together once daily
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|1||This drug is available at the lowest co-pay. Most commonly, these are generic drugs.|
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