Skip to Content

Linagliptin

Pronunciation

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
Brands: Tradjenta

Introduction

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

Uses for Linagliptin

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 receptorγ [PPARγ] 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

American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) suggests a DPP-4 inhibitor as one of several alternatives for initial monotherapy in patients with metformin contraindications (e.g., renal disease, hepatic disease, GI intolerance, risk of lactic acidosis).22 DPP-4 inhibitors also recommended as part of combination therapy, particularly when both postprandial and fasting plasma glucose concentrations are elevated.22

Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis.1

Linagliptin Dosage and Administration

Administration

Oral Administration

Administer once daily without regard to meals.1

If a dose is missed, do not double next dose to replace missed dose.1

Dosage

Adults

Diabetes Mellitus
Oral

Monotherapy: 5 mg once daily.1

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

Special Populations

Hepatic Impairment

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

Renal Impairment

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

Geriatric Patients

Dosage adjustment not routinely required.1

Cautions for Linagliptin

Contraindications

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

Warnings/Precautions

Pancreatitis and Pancreatic Precancerous Changes

Acute pancreatitis, including fatal pancreatitis, reported during postmarketing experience.1

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.)

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

Macrovascular Outcomes

Evidence of macrovascular risk reduction with linagliptin or any other antidiabetic agent not conclusively demonstrated in clinical trials.1

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in animals; not known whether distributed into human milk.1 Use caution.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Geriatric Use

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

Common Adverse Effects

Monotherapy: Nasopharyngitis.1

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

Interactions for Linagliptin

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 Transport

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

P-glycoprotein inducers decrease exposure to linagliptin, resulting in subtherapeutic and likely ineffective concentrations.1 23 Alternative to linagliptin strongly recommended when potent P-glycoprotein 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

Drug

Interaction

Comments

Digoxin

At high linagliptin concentrations, inhibition of P-glycoprotein-mediated transport of digoxin reported1

No appreciable change in digoxin pharmacokinetics at dosages used clinically1 15

No digoxin dosage adjustment necessary15

Hormonal contraceptives

Possible increased AUC and/or peak concentrations of ethinyl estradiol and levonorgestrel1

No dosage adjustments necessary for ethinyl estradiol or levonorgestrel1

Metformin

Increased linagliptin AUC and peak concentration1 10

Decreased metformin peak concentration; AUC not affected1 10

No dosage adjustment necessary for linagliptin or metformin10

Pioglitazone

Decreased pioglitazone AUC and peak concentration1 11

Increased linagliptin AUC and peak concentration1 11

No dosage adjustment necessary for linagliptin or pioglitazone11

Rifampin

Decreased linagliptin AUC and peak concentration; possible subtherapeutic and ineffective concentrations1 23

If rifampin required, an alternative to linagliptin is strongly recommended1

Ritonavir

Linagliptin AUC and peak concentration increased about twofold and threefold, respectively;1 increased exposure not associated with increased accumulation26

No adjustment of linagliptin dosage necessary1

Simvastatin

Increased simvastatin AUC and peak concentration;1 12 not considered clinically important12

No simvastatin dosage adjustment necessary1 12

Sulfonylureas

Possible hypoglycemia1

Glyburide: Decreased glyburide exposure;1 13 not considered clinically important13

Reduced sulfonylurea dosage may be required to reduce risk of hypoglycemia1

Glyburide: No dosage adjustments necessary for linagliptin or glyburide1

Warfarin

No apparent effect on AUC or peak concentration of R- or S-warfarin; no clinically relevant effect on INR or PT 1 14

No warfarin dosage adjustment necessary14

Linagliptin Pharmacokinetics

Absorption

Bioavailability

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

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 (Clcr 50 to <80 mL/minute): Exposure comparable to that in healthy individuals.1 16

Moderate renal impairment (Clcr 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 (Clcr <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 (Clcr 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 (Clcr <30 mL/minute) or normal renal function.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

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

  • 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 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

  • 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

  • Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C 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 HbA1C, 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.

Linagliptin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets; film-coated

5 mg

Tradjenta

Boehringer Ingelheim (comarketed by Lilly)

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: February 15, 2013
Last reviewed: December 07, 2015
Date modified: February 08, 2016

References

1. Boehringer Ingelheim. Tradjenta (linagliptin) tablets prescribing information. Ridgefield, CT; 2015 Aug.

2. Del Prato S, Barnett AH, Huisman H et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011; 13:258-67. [PubMed 21205122]

3. Taskinen MR, Rosenstock J, Tamminen I et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011; 13:65-74. [PubMed 21114605]

4. Gomis R, Espadero RM, Jones R et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011; 13:653-61. [PubMed 21410628]

5. Lewin AJ, Arvay L, Liu D, et al. Safety and efficacy of linagliptin as add-on therapy to a sulphonylurea in inadequately controlled type 2 diabetes. Poster presented at: European Association for the Study of Diabetes 46th Annual Meeting. Stockholm, Sweden: 2010 Sept 20-24. Poster 821.

6. Owens DR, Swallow R, Jones P, Dugi KA, Woerle HJ. Linagliptin improves glycemic control in type 2 diabetes patients inadequately controlled by metformin and sulfonylurea without weight gain or hypoglycemia. Poster presented at: 70th American Diabetes Association Scientific Sessions. Orlando, Florida: 2010 June 25-29. Poster 548.

7. Forst T, Uhlig-Laske B, Ring A et al. The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011; 13:542-50. [PubMed 21352464]

8. Barnett AH, Harper R, Toorawa R, Patel S, Woerle HJ. Linagliptin monotherapy improves glycaemic control in type 2 diabetes patients for whom metformin therapy is inappropriate. Poster presented at: European Association for the Study of Diabetes 46th Annual Meeting. Stockholm, Sweden: 2010 Sept 20-24. Poster 823.

9. Forst T, Uhlig-Laske B, Ring A et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet Med. 2010; 27:1409-19. [PubMed 21059094]

10. Graefe-Mody EU, Padula S, Ring A et al. Evaluation of the potential for steady-state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects. Curr Med Res Opin. 2009; 25:1963-72. [PubMed 19552619]

11. Graefe-Mody EU, Jungnik A, Ring A et al. Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers. Int J Clin Pharmacol Ther. 2010; 48:652-61. [PubMed 20875371]

12. Graefe-Mody U, Huettner S, Stähle H et al. Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin. Int J Clin Pharmacol Ther. 2010; 48:367-74. [PubMed 20497745]

13. Graefe-Mody U, Rose P, Ring A et al. Assessment of the Pharmacokinetic Interaction between the Novel DPP-4 Inhibitor Linagliptin and a Sulfonylurea, Glyburide, in Healthy Subjects. Drug Metab Pharmacokinet. 2011; 26:123-9. [PubMed 21084763]

14. Graefe-Mody EU, Brand T, Ring A et al. Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. Int J Clin Pharmacol Ther. 2011; 49:300-10. [PubMed 21543033]

15. Friedrich C, Ring A, Brand T et al. Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers. Eur J Drug Metab Pharmacokinet. 2011; 36:17-24. [PubMed 21340661]

16. Graefe-Mody U, Friedrich C, Port A, et al. Linagliptin, a novel DPP-4 inhibitor: no need for dose adjustment in patients with renal impairment. Poster presented at: European Association for the Study of Diabetes 46th Annual Meeting. Stockholm, Sweden: 2010 Sept 20-24. Poster 822.

17. Retlich S, Duval V, Ring A et al. Pharmacokinetics and pharmacodynamics of single rising intravenous doses (0.5 mg-10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (BI 1356) in healthy male subjects. Clin Pharmacokinet. 2010; 49:829-40. [PubMed 21053992]

18. Heise T, Graefe-Mody EU, Hüttner S et al. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes Metab. 2009; 11:786-94. [PubMed 19476474]

19. Thomas L, Eckhardt M, Langkopf E et al. (R) - 8 - (3 - amino - piperidin - 1 - yl) - 7 - but - 2 - ynyl - 3 - methyl - 1 - (4 - methyl - quinazolin - 2 - ylmethyl) - 3,7 - dihydro - purine - 2,6 - dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther. 2008; 325:175-82. [PubMed 18223196]

20. Blech S, Ludwig-Schwellinger E, Gräfe-Mody EU et al. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos. 2010; 38:667-78. [PubMed 20086031]

21. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006; 368:1696-705. [PubMed 17098089]

22. Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009 Sep-Oct; 15:540-59.

23. Niemi M, Backman JT, Fromm MF et al. Pharmacokinetic interactions with rifampicin : clinical relevance. Clin Pharmacokinet. 2003; 42:819-50. [PubMed 12882588]

24. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009; 32:193-203. [PubMed 18945920]

25. Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med. 2007; 147:386-99. [PubMed 17638715]

26. Boehringer Ingelheim, Ridgefield, CT: Personal communication.

27. Boehringer Ingelheim. Tradjenta (linagliptin) tablets medication guide. Ridgefield, CT; 2015 Aug.

36. Food and Drug Administration. Early communication: reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas. Silver Spring, MD; 2013 Mar 14. From FDA website.

37. Singh S, Chang HY, Richards TM et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013; 173:534-9. [PubMed 23440284]

41. Food and Drug Administration. FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Rockville, MD; 2015 Aug 28. From FDA website.

Hide