Linagliptin

Trajenta is not indicated in combination with insulin due to an increase in cardiovascular risk, which cannot be excluded.

Insulin secretagogues and insulin are known to cause hypoglycemia. The use of Tradjenta in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. The use of Tradjenta in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia. Therefore, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with Tradjenta.

Rifampin decreased linagliptin exposure, suggesting that the efficacy of Tradjenta may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer.

Sulfonylureas and insulin are known to cause hypoglycemia. Therefore, caution is advised when linagliptin is used in combination with a sulfonylurea and/or insulin. A dose reduction of the sulfonylurea or insulin, may be considered.

Linagliptin is a weak to moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4; however, it does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 4A11 in vitro. In vivo studies indicate that drug interactions are unlikely with substrates of CYP isoenzymes 3A4, 2C9, or 2C8. No adjustment of linagliptin dosage is recommended based on results of pharmacokinetic studies. Inducers of CYP3A4 (e.g., rifampin) decrease exposure to linagliptin, resulting in subtherapeutic and likely ineffective concentrations. The manufacturer states that alternatives to linagliptin are strongly recommended in patients who require therapy with potent CYP3A4 inducers.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3,100(SRC), determined from a structure estimation method(2), indicates that linagliptin is expected to have slight mobility in soil(SRC). The pKa of linagliptin is 8.6(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of linagliptin from moist soil surfaces is not expected to be an important fate process because linagliptin exists as a cation and cations do not volatilize(SRC). Linagliptin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.6X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2014).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3,100(SRC), determined from a structure estimation method(2), indicates that linagliptin is expected to adsorb to suspended solids and sediment(SRC). A pKa of 8.6(3) indicates linagliptin will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces and bioconcentration are not expected to be important fate processes. Biodegradation data in water were not available(SRC, 2014).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), linagliptin, which has an estimated vapor pressure of 5.6X10-17 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase linagliptin may be removed from the air by wet and dry deposition(SRC). Linagliptin contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

IDENTIFICATION AND USE: Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, but should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. HUMAN EXPOSURE AND TOXICITY: In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in > or = 2% of patients receiving Tradjenta (Linagliptin) (n = 3625) were nasopharyngitis (7.0%), diarrhea (3.3%), and cough (2.1%). Other adverse reactions reported in clinical studies with treatment of Tradjenta (Linagliptin) were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity), and myalgia. Additional adverse reactions have been identified during postapproval use of Tradjenta (Linagliptin); acute pancreatitis, including fatal pancreatitis, hypersensitivity reactions including anaphylaxis, angioedema, exfoliative skin conditions, and rash. ANIMAL STUDIES: Linagliptin did not increase the incidence of tumors in male and female rats in a 2-year study at doses of 6, 18, and 60 mg/kg. Linagliptin did not increase the incidence of tumors in mice in a 2-year study at doses up to 80 mg/kg (males) and 25 mg/kg (females). Higher doses of Linagliptin in female mice (80 mg/kg) increased the incidence of lymphoma. In fertility studies in rats, Linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240 mg/kg. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits and available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of linagliptin can be estimated to be 3,100(SRC). According to a classification scheme(2), this estimated Koc value suggests that linagliptin is expected to have slight mobility in soil. The pKa of linagliptin is 8.6(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] =80 mL/min), 6 patients with mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl <30 mL/min), and 11 patients with type 2 diabetes mellitus and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula. Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects. In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUCt,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. Patients with type 2 diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes mellitus and normal renal function (increase in AUCt,ss by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose.

/HUMAN EXPOSURE STUDIES/ In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5-mg dose.

/SIGNS AND SYMPTOMS/ In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in > or = 2% of patients receiving Tradjenta (Linagliptin) (n = 3625) were nasopharyngitis (7.0%), diarrhea (3.3%), and cough (2.1%). ... Other adverse reactions reported in clinical studies with treatment of Tradjenta (Linagliptin) were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity), and myalgia.

/SIGNS AND SYMPTOMS/ Adverse reactions have been identified during postapproval use of Tradjenta: acute pancreatitis, including fatal pancreatitis; hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions; and rash.

For more Human Toxicity Excerpts (Complete) data for Linagliptin (11 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Linagliptin

vLess-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

A pKa of 8.6(1) indicates linagliptin will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process. Linagliptin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.6X10-12 mm Hg(SRC), determined from a fragment constant method(2).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Linagliptin did not increase the incidence of tumors in male and female rats in a 2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately 418 times the clinical dose of 5 mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in a 2-year study at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately 35- and 270-times the clinical dose based on AUC exposure. Higher doses of linagliptin in female mice (80 mg/kg) increased the incidence of lymphoma at approximately 215-times the clinical dose based on AUC exposure

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A two-year carcinogenicity study was conducted in male and female rats given oral doses of linagliptin of 6, 18, and 60 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 60 mg/kg/day. This dose results in exposures approximately 400 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 5 mg/day based on AUC comparisons. A two-year carcinogenicity study was conducted in male and female mice given oral doses of 8, 25 and 80 mg/kg/day. There was no evidence of a carcinogenic potential up to 80 mg/kg/day, approximately 240 times human clinical exposure.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in the rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240 mg/kg (approximately 943-times the clinical dose based on AUC exposure).

For more Non-Human Toxicity Excerpts (Complete) data for Linagliptin (11 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including linagliptin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

MEDICATION

Hypoglycemic Agents

Jentadueto is a combination of linagliptin and metformin hydrochloride. Jentadueto tablets are available in the following dosage forms and strengths: 2.5 mg linagliptin/500 mg metformin hydrochloride; 2.5 mg linagliptin/850 mg metformin hydrochloride tablets; 2.5 mg linagliptin/1000 mg metformin hydrochloride tablets.

Oral: Tablet, film coated: 5 mg, Tradjenta (Boehringer Ingelheim, comarketed by Lilly)