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.

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.

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.

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.

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.

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).

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.

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). 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.

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.

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. 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.

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.

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

Linagliptin Dosage and Administration

Administration

Oral Administration

Linagliptin: Administer once daily without regard to meals.

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

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

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

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.

Dosage

Adults

Type 2 Diabetes Mellitus

Linagliptin Monotherapy

Oral

5 mg once daily.

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.

Linagliptin/Empagliflozin Fixed-combination Therapy

Oral

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

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

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

Oral

Individualize dosage based on effectiveness and patient tolerability. 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).

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).

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).

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.

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.

Special Populations

Hepatic Impairment

Linagliptin Monotherapy

Dosage adjustment not routinely required. (See Pharmacokinetics.)

Linagliptin/Empagliflozin Fixed-combination Therapy

May be used in patients with hepatic impairment.

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

Use not recommended in patients with hepatic impairment.

Renal Impairment

Linagliptin Monotherapy

Dosage adjustment not routinely required. (See Pharmacokinetics.)

Linagliptin/Empagliflozin Fixed-combination Therapy

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

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

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

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

eGFR of 30–45 mL/minute per 1.73 m²: Initiation of the fixed combination not recommended. 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.

eGFR <30 mL/minute per 1.73 m²: Contraindicated.

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.

Geriatric Patients

Linagliptin Monotherapy

Dosage adjustment of linagliptin not required based solely on age.

Cautions for Linagliptin

Contraindications

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

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal pancreatitis, reported.

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. FDA will notify healthcare professionals of its conclusions and recommendations when the review is complete, or when the agency has additional information to report.

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

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

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

Severe Arthralgia

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

Consider DPP-4 inhibitors as a possible cause of severe joint pain and discontinue if appropriate. (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.

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). Monitor patients for manifestations of heart failure. (See Advice to Patients.) If heart failure develops, institute appropriate evaluation and management according to current standards of care and consider discontinuance of linagliptin.

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.

Dermatologic and Sensitivity Reactions

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

If serious hypersensitivity reaction is suspected, promptly discontinue drug, assess other potential causes for event, and initiate alternative antidiabetic therapy. (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.

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

Macrovascular Outcomes

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

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).

Specific Populations

Pregnancy

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

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

Lactation

Linagliptin distributed into milk in animals; not known whether distributed into human milk. 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.

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.

Geriatric Use

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

Common Adverse Effects

Linagliptin monotherapy: Nasopharyngitis.

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

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

Linagliptin in combination with metformin hydrochloride: Nasopharyngitis, diarrhea.

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.

A P-glycoprotein substrate.

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.

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

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). However, at therapeutic concentrations, linagliptin considered unlikely to cause interactions with other P-gp substrates; no adjustment of linagliptin dosage recommended.

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

Drugs Affected by Organic Cation Transporter (OCT)

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

Specific Drugs

Linagliptin Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations usually attained within 1.5 hours. Absolute oral bioavailability approximately 30%.

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.

Food

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

Special Populations

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

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

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

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

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; not associated with prolonged accumulation half-life or increased accumulation factor.

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.

Distribution

Extent

Extensively distributes into tissues.

Plasma Protein Binding

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

Special Populations

Renal or hepatic impairment does not alter plasma protein binding.

Elimination

Metabolism

Metabolism represents a minor elimination pathway.

Elimination Route

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

Half-life

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

Special Populations

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

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.

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).

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).

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

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

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

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

• Linagliptin monotherapy usually not associated with hypoglycemia or substantial changes in body weight.

Advice to Patients

• Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.

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

• Risk of acute pancreatitis; may be severe or fatal. Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or high triglyceride levels. 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.

• Importance of informing patients about possibility of heart failure with linagliptin therapy. Importance of patients informing clinicians about a history of heart failure or renal impairment. 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.

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

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

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

• Risk of serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions. 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.

• 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.

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

• 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.

• Importance of informing clinicians if any unusual symptom develops or if any existing symptom persists or worsens.

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

• 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.

• Importance of informing patients of other important precautionary information. (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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