linagliptin/metformin (Rx)

Brand and Other Names:Jentadueto, Jentadueto XR
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

linagliptin/metformin

tablet (Jentadueto)

  • 2.5mg/500mg
  • 2.5mg/850mg
  • 2.5mg/1000mg

extended-release tablet (Jentadueto XR)

  • 2.5mg/1000mg
  • 5mg/1000mg
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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

Prompt-release tablets

  • 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

Extended-release tablets

  • 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

Dosage Modifications

Hepatic impairment: Not recommended because of increased risk of lactic acidosis

Renal impairment

  • 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

Dosing Considerations

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

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Interactions

Interaction Checker

and linagliptin/metformin

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Hypoglycemia (with sulfonylurea) (22.9%)

            1-10%

            Nasopharyngitis (6.3%)

            Diarrhea (6.3%)

            Hypoglycemia (without sulfonylurea) (1.4%)

            Frequency Not Defined

            Hypersensitivity (eg, urticaria, angioedema, or bronchial hyperactivity)

            Cough

            Decreased appetite

            Nausea

            Vomiting

            Pruritus

            Pancreatitis

            Postmarketing Reports

            Acute pancreatitis, including fatal pancreatitis

            Rash

            Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions

            Mouth ulceration, stomatitis

            Severe and disabling arthralgia

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            Warnings

            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

            • 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

            Contraindications

            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

            Cautions

            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

            Pancreatitis

            • 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
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            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

            Pregnancy Categories

            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.

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            Pharmacology

            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

            Absorption

            Bioavailability: 30% (linagliptin); 50-60% (metformin)

            Distribution

            Protein Bound: 70-80% (linagliptin); >90% (metformin)

            Vd: ~1,110 L (linagliptin); ~654 L (metformin)

            Metabolism

            Linagliptin

            • 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

            • Metformin is excreted 100% in the urine therefore does not undergo metabolism in the body the following information is for linagliptin

            Elimination

            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%)

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            Administration

            Oral Administration

            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

            Extended-release

            • 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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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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