Brand names: Jentadueto XR, Tradjenta
Drug class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
VA class: HS502
Chemical name: 8-[(3R)-3-Aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione
Molecular formula: C₂₅H₂₈N₈O₂
CAS number: 668270-12-0

Medically reviewed by Drugs.com on Jun 11, 2024. Written by ASHP.

Introduction

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.¹

Uses for Linagliptin

Type 2 Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.^{1 2 7 8}

Used in combination with metformin as initial therapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.¹

Used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a peroxisome proliferator-activated receptor_γ [PPAR_γ] agonist [thiazolidinedione]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with oral antidiabetic agent monotherapy.^{1 3 4 5 6}

Used in fixed combination with empagliflozin or in fixed combination with immediate- or extended-release metformin hydrochloride as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both drugs in the fixed combination is appropriate.^{70 72 74}

Current guidelines for the treatment of type 2 diabetes mellitus generally recommend metformin as first-line therapy in addition to lifestyle modifications in patients with recent-onset type 2 diabetes mellitus or mild hyperglycemia because of its well-established safety and efficacy (i.e., beneficial effects on glycosylated hemoglobin [hemoglobin A_1c; HbA_1c], weight, and cardiovascular mortality).^{698 704 705}

In patients with metformin contraindications or intolerance (e.g., risk of lactic acidosis, GI intolerance) or in selected other patients, some experts suggest that initial therapy with a drug from another class of antidiabetic agents (e.g., a glucagon-like peptide-1 [GLP-1] receptor agonist, sodium-glucose cotransporter 2 [SGLT2] inhibitor, DPP-4 inhibitor, sulfonylurea, thiazolidinedione, basal insulin) may be acceptable based on patient factors.^{698 704}

May need to initiate therapy with 2 agents (e.g., metformin plus another drug) in patients with high initial HbA_1c (>7.5% or ≥1.5% above target).^{698 704} In such patients with metformin intolerance, some experts suggest initiation of therapy with 2 drugs from other antidiabetic drug classes with complementary mechanisms of action.^{698 704}

Consider early initiation of combination therapy for the treatment of type 2 diabetes mellitus to extend the time to treatment failure and more rapidly attain glycemic goals.⁷⁰⁴

For patients with inadequate glycemic control on metformin monotherapy, consider patient comorbidities (e.g., atherosclerotic cardiovascular disease [ASCVD], established kidney disease, heart failure), hypoglycemia risk, impact on weight, cost, risk of adverse effects, and patient preferences when selecting additional antidiabetic agents for combination therapy.^{698 699 704 705 706} DPP-4 inhibitors recommended by some experts as one of several classes of drugs for use in combination therapy, particularly in patients with both postprandial and fasting plasma glucose elevations.^{22 698 704}

Consider early introduction of insulin for severe hyperglycemia (e.g., blood glucose of ≥300 mg/dL or HbA_1c >9–10%), especially if accompanied by catabolic manifestations (e.g., weight loss, hypertriglyceridemia, ketosis) or symptoms of hyperglycemia.^{698 704}

Should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.¹

Linagliptin Dosage and Administration

Administration

Oral Administration

Linagliptin: Administer once daily without regard to meals.¹

Fixed combination of linagliptin and empagliflozin: Administer once daily in the morning without regard to meals.⁷⁰

Fixed combination of linagliptin and immediate-release metformin hydrochloride: Administer twice daily with meals.⁷²

Fixed combination of linagliptin and extended-release metformin hydrochloride: Administer once daily with a meal.⁷⁴

If a dose of linagliptin (single entity or in fixed combination with empagliflozin or immediate- or extended-release metformin hydrochloride) is missed, do not double next dose to replace missed dose.^{1 70 72 74}

Dosage

Adults

Type 2 Diabetes Mellitus

Linagliptin Monotherapy

Oral

5 mg once daily.¹

Combination Therapy with a Sulfonylurea

Oral

5 mg once daily; dosage of the concomitant sulfonylurea may need to be reduced to decrease risk of hypoglycemia.¹

Linagliptin/Empagliflozin Fixed-combination Therapy

Oral

Initially, 5 mg of linagliptin and 10 mg of empagliflozin once daily in the morning.⁷⁰

If well tolerated, may increase dosage to 5 mg of linagliptin and 25 mg of empagliflozin once daily.⁷⁰

Linagliptin/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Oral

Individualize dosage based on effectiveness and patient tolerability.^{72 74} May increase dosage up to a maximum total daily dosage of 5 mg of linagliptin and 2 g of metformin hydrochloride (immediate- or extended-release preparation).^{72 74}

Patients not currently receiving metformin hydrochloride: Initially, 5 mg of linagliptin and 1 g of metformin hydrochloride administered in 2 divided doses daily (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).^{72 74}

Patients currently receiving metformin hydrochloride: Initially, 5 mg of linagliptin and a total daily metformin hydrochloride dosage similar to patient's existing dosage, administered in 2 divided doses (when given as the fixed combination containing immediate-release metformin hydrochloride) or once daily (when given as the fixed combination containing extended-release metformin hydrochloride).^{72 74}

Patients currently receiving linagliptin and metformin hydrochloride as individual components: Recommended initial dosage of the fixed combination containing immediate-release metformin hydrochloride is the same total daily dosage of each component administered in 2 divided doses.⁷²

Patients currently receiving linagliptin and metformin hydrochloride as individual components or the fixed combination of linagliptin and immediate-release metformin hydrochloride: Recommended initial dosage of the fixed combination containing extended-release metformin hydrochloride is 5 mg of linagliptin and a total daily metformin hydrochloride dosage similar to the patient's existing dosage, administered once daily.⁷⁴

Special Populations

Hepatic Impairment

Linagliptin Monotherapy

Dosage adjustment not routinely required.¹ (See Pharmacokinetics.)

Linagliptin/Empagliflozin Fixed-combination Therapy

May be used in patients with hepatic impairment.⁷⁰

Linagliptin/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

Use not recommended in patients with hepatic impairment.^{72 74}

Renal Impairment

Linagliptin Monotherapy

Dosage adjustment not routinely required.^{1 16} (See Pharmacokinetics.)

Linagliptin/Empagliflozin Fixed-combination Therapy

eGFR ≥45 mL/minute per 1.73 m²: No dosage adjustment necessary.⁷⁰

eGFR <45 mL/minute per 1.73 m²: Do not initiate the fixed combination.⁷⁰ Discontinue if eGFR is persistently <45 mL/minute per 1.73 m².⁷⁰

Linagliptin/Immediate- or Extended-release Metformin Hydrochloride Fixed-combination Therapy

eGFR ≥45 mL/minute per 1.73 m²: No dosage adjustment necessary.^{72 74}

eGFR of 30–45 mL/minute per 1.73 m²:^{72 74} Initiation of the fixed combination not recommended.^{72 74} Assess benefits and risks of continuing therapy the fixed combination if eGFR decreases to 30–45 mL/minute per 1.73 m² during therapy with the fixed combination.^{72 74}

eGFR <30 mL/minute per 1.73 m²: Contraindicated.^{72 74}

If fixed combination discontinued due to evidence of renal impairment, linagliptin may be continued as single-entity tablet at same total daily dosage of 5 mg.^{72 74}

Geriatric Patients

Linagliptin Monotherapy

Dosage adjustment of linagliptin not required based solely on age.¹

Cautions for Linagliptin

Contraindications

• History of hypersensitivity reaction (e.g., anaphylaxis, urticaria, angioedema, bronchial hyperreactivity) to linagliptin.¹

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal pancreatitis, reported.^{1 72 74}

FDA has been evaluating unpublished findings suggesting an increased risk of pancreatitis and precancerous pancreatic cell changes in patients with type 2 diabetes mellitus receiving incretin mimetics.^{36 37} FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when the agency has additional information to report.³⁶

FDA has recommended that clinicians continue to follow the recommendations in the prescribing information for incretin mimetics.³⁶

Monitor for manifestations of pancreatitis.¹ (See Advice to Patients.) If pancreatitis is suspected, promptly discontinue linagliptin and initiate appropriate management.¹

Safety and efficacy not established in patients with a history of pancreatitis; unknown whether such patients are at increased risk for pancreatitis.¹

Severe Arthralgia

Severe, disabling joint pain reported in patients receiving DPP-4 inhibitors (e.g., alogliptin, linagliptin, saxagliptin, sitagliptin).^{1 41} Onset of such symptoms has ranged from 1 day to years following initiation of therapy.^{1 41} Symptoms resolved upon discontinuance of the DPP-4 inhibitor; symptoms recurred in some patients when the same or another DPP-4 inhibitor was restarted.^{1 41}

Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue if appropriate.^{1 41} (See Advice to Patients.)

Heart Failure Risk

In cardiovascular outcomes studies conducted with 2 other DPP-4 inhibitors (alogliptin, saxagliptin) in patients with type 2 diabetes mellitus and ASCVD, an association between DPP-4 inhibitor treatment and heart failure was observed.^{1 42 43 44}

Consider potential risks and benefits of linagliptin therapy prior to use in patients at risk for heart failure (e.g., history of heart failure or renal impairment).¹ Monitor patients for manifestations of heart failure.¹ (See Advice to Patients.) If heart failure develops, institute appropriate evaluation and management according to current standards of care and consider discontinuance of linagliptin.¹

Concomitant Therapy with Hypoglycemic Agents

Increased risk of hypoglycemia in patients receiving linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin; reduction in sulfonylurea or insulin dosage may be necessary.^{1 27}

Dermatologic and Sensitivity Reactions

Risk of hypersensitivity reactions (e.g., anaphylaxis, angioedema, exfoliative dermatitis).¹ Onset usually within first 3 months of treatment initiation, but may occur after first dose.¹ (See Contraindications under Cautions.)

If serious hypersensitivity reaction is suspected, promptly discontinue drug, assess other potential causes for event, and initiate alternative antidiabetic therapy.¹ (See Advice to Patients.)

Use caution in patients with a history of angioedema with other DPP-4 inhibitors; unknown whether such patients will be predisposed to angioedema with linagliptin.¹

Postmarketing cases of bullous pemphigoid requiring hospitalization reported with DPP-4 inhibitor use.¹ Bullous pemphigoid reported in 7 patients (0.2%) receiving linagliptin compared with none of those receiving placebo in a clinical trial.^{72 74} Usually resolved after discontinuance of the DPP-4 inhibitor and treatment with topical or systemic immunosuppressive agents.¹ Advise patients to report the development of blisters or erosions while receiving linagliptin.¹ Discontinue drug if bullous pemphigoid is suspected and consider referral to a dermatologist for diagnosis and appropriate treatment.¹

Macrovascular Outcomes

Evidence of macrovascular risk reduction with linagliptin not conclusively demonstrated in controlled clinical trials.¹

Use of Fixed Combination

When linagliptin is used in fixed combination with empagliflozin, metformin hydrochloride, or other drugs, consider cautions, precautions, contraindications, and interactions associated with the concomitant agent(s).^{1 72 74}

Specific Populations

Pregnancy

Data regarding use of linagliptin in pregnant women insufficient to inform a drug-associated risk for major birth defects or miscarriage.¹

In animal reproduction studies, no adverse developmental effects observed when linagliptin was administered to pregnant rats during the period of organogenesis.¹

Lactation

Linagliptin distributed into milk in animals; not known whether distributed into human milk.¹ Consider benefits of breast-feeding and importance of the drug to the woman; also consider any potential adverse effects on breast-fed infant from the drug or underlying maternal condition.¹

Pediatric Use

Safety and efficacy of linagliptin alone or in fixed combination with empagliflozin or fixed combination with immediate- or extended-release metformin hydrochloride not established in patients <18 years of age.^{1 70 72 74}

Geriatric Use

No substantial differences in safety and efficacy of linagliptin relative to younger adults, but increased sensitivity cannot be ruled out.¹

Common Adverse Effects

Linagliptin monotherapy: Nasopharyngitis.¹

Linagliptin in combination with pioglitazone, a sulfonylurea, metformin, or basal insulin: Nasopharyngitis,¹ hyperlipidemia,¹ cough,¹ hypertriglyceridemia,¹ weight gain,¹ urinary tract infection,¹ constipation,¹ back pain,¹ arthralgia,¹ upper respiratory tract infection,¹ headache,¹ pain in extremity.¹

Linagliptin in combination with empagliflozin: Urinary tract infection,⁷⁰ nasopharyngitis,⁷⁰ upper respiratory tract infection.⁷⁰

Linagliptin in combination with metformin hydrochloride: Nasopharyngitis,^{72 74} diarrhea.^{72 74}

Drug Interactions

Weak to moderate inhibitor of CYP3A4; does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 4A11 in vitro.¹

A P-glycoprotein substrate.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drug interactions unlikely with substrates of CYP isoenzymes 3A4, 2C9, or 2C8; no adjustment of linagliptin dosage recommended.¹

CYP3A4 inducers decrease exposure to linagliptin, resulting in subtherapeutic and likely ineffective concentrations.^{1 23} Alternative to linagliptin strongly recommended when potent CYP3A4 inducers must be used.¹

Drugs Affecting or Affected by P-glycoprotein (P-gp) Transport

Reported to inhibit P-gp-mediated transport at high concentrations (see Specific Drugs under Interactions).¹ However, at therapeutic concentrations, linagliptin considered unlikely to cause interactions with other P-gp substrates; no adjustment of linagliptin dosage recommended.¹

P-gp inducers decrease exposure to linagliptin, resulting in subtherapeutic and likely ineffective concentrations.^{1 23} Alternative to linagliptin strongly recommended when potent P-gp inducers must be used.¹

Drugs Affected by Organic Cation Transporter (OCT)

Drug interactions unlikely with substrates of OCT; no adjustment of linagliptin dosage recommended.¹

Specific Drugs

Linagliptin Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations usually attained within 1.5 hours.^{1 18 20} Absolute oral bioavailability approximately 30%.^{1 17}

Bioequivalence studies: Fixed-combination tablets of linagliptin and empagliflozin or linagliptin and immediate-release metformin hydrochloride are bioequivalent to single-entity tablets of linagliptin given concomitantly with single-entity tablets of empagliflozin or single-entity tablets of immediate-release metformin hydrochloride, respectively, in corresponding doses.^{70 72}

Food

High-fat meal reduced peak plasma concentration by 15% and increased AUC by 4%; not clinically relevant.¹

Special Populations

Mild hepatic impairment (Child-Pugh class A): AUC and peak plasma concentration reduced by 25 and 36%, respectively, compared with healthy individuals.¹

Moderate hepatic impairment (Child-Pugh class B): AUC and peak plasma concentration reduced by 14 and 8%, respectively, compared with healthy individuals.¹

Severe hepatic impairment (Child-Pugh class C): Peak plasma concentration reduced by 23% compared with healthy individuals; AUC values comparable.¹

Mild renal impairment (Cl_cr 50 to <80 mL/minute): Exposure comparable to that in healthy individuals.^{1 16}

Moderate renal impairment (Cl_cr 30 to <50 mL/minute): AUC and peak plasma concentration increased by 71 and 46%, respectively, compared with healthy individuals;^{1 16} not associated with prolonged accumulation half-life or increased accumulation factor.¹

Severe renal impairment (Cl_cr <30 mL/minute) and type 2 diabetes mellitus: AUC and peak plasma concentration increased by 42 and 35%, respectively, compared with patients with type 2 diabetes mellitus and normal renal function.¹

Distribution

Extent

Extensively distributes into tissues.¹

Plasma Protein Binding

Concentration dependent; 99% at 1 nmol/L and 75–89% at ≥30 nmol/L.¹

Special Populations

Renal or hepatic impairment does not alter plasma protein binding.¹

Elimination

Metabolism

Metabolism represents a minor elimination pathway.¹

Elimination Route

Approximately 90% of linagliptin dose excreted unchanged.^{1 20} Following administration of radiolabeled linagliptin, approximately 85% of administered radioactivity eliminated via enterohepatic system (80%) or in urine (5%).¹

Half-life

Terminal half life is >100 hours; at least biphasic decline in plasma concentrations.^{1 17 18 20} Effective half-life for accumulation based on 5-mg multiple oral dosing is approximately 12 hours.¹

Special Populations

Moderate renal impairment (Cl_cr 30 to <50 mL/minute) did not alter renal excretion of drug (<5% of dose).¹

Renal excretion <7% of dose in patients with type 2 diabetes mellitus and either severe renal impairment (Cl_cr <30 mL/minute) or normal renal function.¹

Stability

Storage

Oral

Tablets

Linagliptin, fixed combination of linagliptin and empagliflozin, and fixed combinations of linagliptin and immediate- or extended-release metformin hydrochloride: 25°C (may be exposed to 15–30°C).^{1 70 72 74}

Actions

• Inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).^{1 2 3 21}

• Increases concentrations of GLP-1 and GIP in a glucose-dependent manner.¹

• GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic β-cells in presence of normal and elevated blood glucose concentrations.^{1 21}

• GLP-1 also reduces glucagon secretion from pancreatic α-cells, resulting in a reduction in hepatic glucose output.^{1 21}

• Selectively inhibits DPP-4 with no effect on DPP-8 or DDP-9 in vitro at concentrations approximating those achieved with therapeutic dosages.^{1 19}

• Linagliptin monotherapy usually not associated with hypoglycemia or substantial changes in body weight.^{2 7 8}

Advice to Patients

• Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.^{1 27}

• Importance of informing patients of the potential risks and benefits of linagliptin and of alternative therapies.^{1 27} Importance of not using linagliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.^{1 27}

• Risk of acute pancreatitis; may be severe or fatal.^{1 27} Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or high triglyceride levels.^{1 27} Importance of patients discontinuing linagliptin and promptly informing clinician if persistent, severe abdominal pain that may radiate to the back and may or may not be accompanied by vomiting occurs.¹

• Importance of informing patients about possibility of heart failure with linagliptin therapy.¹ Importance of patients informing clinicians about a history of heart failure or renal impairment.¹ Importance of informing patients about signs and symptoms of heart failure (e.g., shortness of breath, weight gain, edema) and of immediately contacting a clinician if manifestations of heart failure occur.¹

• Importance of informing patients of the possibility of severe and disabling joint pain.^{1 27 41} Advise patients to contact a clinician promptly if severe and persistent joint pain occurs; patients should not discontinue therapy without consulting their clinician.^{1 27 41}

• Importance of informing patients that bullous pemphigoid may occur with use of a DPP-4 inhibitor.¹ Advise patients to contact a clinician if blisters or erosions occur.¹

• Increased risk of hypoglycemia when linagliptin is used in combination with a sulfonylurea or insulin.¹ Importance of informing patients that a lower sulfonylurea or insulin dosage may be required to reduce the risk of hypoglycemia.¹

• Risk of serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions.¹ If signs or symptoms of such reactions occur (e.g., rash, blisters, skin flaking or peeling/erosion, hives, swelling of the skin, swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing), importance of discontinuing linagliptin-containing therapy and informing clinician promptly.¹

• Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA_1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of complications of diabetes mellitus.¹

• Importance of seeking medical advice promptly during periods of stress (e.g., fever, trauma, infection, surgery) as medication requirements may change.^{1 27}

• Importance of informing patients that response to all antidiabetic therapies should be monitored by periodic measurements of blood glucose and HbA_1C, with a goal of decreasing these levels toward the normal range.^{1 27}

• Importance of informing clinicians if any unusual symptom develops or if any existing symptom persists or worsens.^{1 27}

• Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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