Trajenta® [Linagliptin]
Boehringer Ingelheim
615 Items
2019-09-19
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Clinical Pharmacology
Trajenta - oral hypoglycemic drug. Linagliptin is an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), which is involved in the inactivation of hormones of incretins - glucagon-like peptide type 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (HIP). These hormones are rapidly destroyed by the enzyme DPP-4. Both of these incretin are involved in maintaining the glucose concentration at the physiological level. The basal concentrations of GLP-1 and HIP are low during the day, they quickly rise in response to food intake. GLP-1 and HIP enhance insulin biosynthesis and its secretion by pancreatic beta cells at normal or elevated blood glucose concentrations. In addition, GLP-1 decreases glucagon secretion by pancreatic alpha cells, which leads to a decrease in glucose production in the liver.
Linagliptin is actively associated with the enzyme DPP-4 (the connection is reversible), which causes a steady increase in the concentration of incretins and the long-term maintenance of their activity. Traction increases glucose-dependent insulin secretion and decreases glucagon secretion, which leads to normalization of blood glucose levels. Linagliptin binds selectively to the DPP-4 enzyme and has a 10,000-fold greater selectivity for DPP-4 than the in vitro dipetilpeptidase-8 or dipetilpeptidase-9 enzymes.
Indications
Type 2 diabetes:
- as monotherapy in patients with inadequate control of glycemia only on the background of diet and exercise, with intolerance to metformin, or when contraindicated for its use due to renal failure;
- as a two-component combination therapy with metformin, sulfonylurea derivatives or thiazolidinedione in the case of the ineffectiveness of diet therapy, exercise and monotherapy with these drugs;
- as a three-component combination therapy with metformin and sulfonylurea derivatives in case of ineffectiveness of diet therapy, physical exercises and combination therapy with these drugs.
Composition
1 tablet contains:
Active substance: linagliptin 5 mg;
Excipients: mannitol - 130.9 mg, pregelatinized starch - 18 mg, corn starch - 18 mg, copovidone - 5.4 mg, magnesium stearate - 2.7 mg;
Shell composition: Opadra pink (02F34337) - 5 mg (hypromellose 2910 - 2.5 mg, titanium dioxide (E171) - 1.25 mg, talc - 875 mcg, macrogol 6000 - 250 mcg, iron dye red oxide (E172) - 125 mcg).
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Dosage and Administration
The recommended dose of Trajenta® is 5 mg (1 tablet) 1 time per day, by mouth.
Traction can be taken regardless of the meal at any time of the day.
When skipping the next admission, the patient should take the drug as soon as he remembers. You should not take a double dose in one day.
Adverse reactions
The following side effects were observed with linagliptin monotherapy:
On the part of the immune system: hypersensitivity reactions.
On the part of the respiratory system: cough.
From the digestive system: pancreatitis.
Infectious diseases: nasopharyngitis.
When using linagliptin with metformin:
On the part of the immune system: hypersensitivity reactions.
On the part of the respiratory system: cough.
From the digestive system: pancreatitis.
Infectious diseases: nasopharyngitis.
When using linagliptin with sulfonylurea derivatives:
On the part of the immune system: hypersensitivity reactions.
Metabolic disorders: hypertriglyceridemia.
On the part of the respiratory system: cough.
From the digestive system: pancreatitis.
Infectious diseases: nasopharyngitis.
When using linagliptin with pioglitazone:
On the part of the immune system: hypersensitivity reactions.
Metabolic disorders: hyperlipidemia.
On the part of the respiratory system: cough.
From the digestive system: pancreatitis.
Infectious diseases: nasopharyngitis.
Other: weight gain.
When using linagliptin with insulin:
On the part of the immune system: hypersensitivity reactions.
On the part of the respiratory system: cough.
From the digestive system: pancreatitis, constipation.
Infectious diseases: nasopharyngitis.
When using linagliptin with metformin and sulfonylurea derivatives:
On the part of the immune system: hypersensitivity.
Metabolic disorders: hypoglycemia.
On the part of the respiratory system: cough.
From the digestive system: pancreatitis.
Infectious diseases: nasopharyngitis.
When using linagliptin with metformin and pioglitazone:
On the part of the immune system: hypersensitivity reactions.
Metabolic disorders: hyperlipidemia.
On the part of the respiratory system: cough.
From the digestive system: pancreatitis.
Infectious diseases: nasopharyngitis.
Other: weight gain.
Post-marketing application experience:
On the part of the immune system: angioedema, urticaria.
From the digestive system: acute pancreatitis.
On the part of the skin: rash.
Contraindications
- type 1 diabetes;
- diabetic ketoacidosis;
- pregnancy;
- breastfeeding period;
- children up to 18 years;
- Hypersensitivity to any component of the Trazent preparation.
Drug interactions
Evaluation of drug interactions in vitro
Linagliptin is a weak competitive inhibitor of the CYP3A4 isoenzyme.
Linagliptin does not inhibit other CYP isoenzymes and is not their inducer.
Linagliptin is a substrate for P-glycoprotein and inhibits the transport of digoxin to a small extent mediated by P-glycoprotein.
Evaluation of drug interactions in vivo
Linagliptin does not have a clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, and oral contraceptive drugs, which has been proven in vivo, and is based on the low ability of linagliptin to cause drug interactions with A4PP3. P-glycoprotein and transport molecules of organic cations.
Metformin. The combined use of metformin (repeated daily dose of 850 mg 3 times / day) and linagliptin 10 mg 1 time / day. (higher than therapeutic dose) in healthy volunteers did not lead to clinically significant changes in the pharmacokinetics of linagliptin or metformin.Thus, linagliptin is not an inhibitor of the transport of organic cations.
Sulfonylurea derivatives. The pharmacokinetics of linagliptin (5 mg) did not change when used together with glibenclamide (a single dose of glyburide 1.75 mg) and repeated intake of linagliptin orally (5 mg). However, there was a clinically insignificant decrease in AUC and Cmax values of glibenclamide by 14%. Since glibenclamide is metabolized mainly by CYP2C9, this data also supports the conclusion that linagliptin is not a CYP2C9 inhibitor. No clinically significant interactions are expected with other sulfonylurea derivatives (for example, glipizide and glimepiride), which, like glibenclamide, are mainly metabolized by CYP2C9.
Thiazolidinedione. The combined use of multiple doses of Linagliptin 10 mg / day. (higher than therapeutic dose) and pioglitazone 45 mg / day. (repeated administration), which is a substrate for CYP2C8 and CYP3A4, did not have a clinically significant effect on the pharmacokinetics of linagliptin or pioglitazone, or active metabolites of pioglitazone. This indicates that linagliptin in vivo is not an inhibitor of metabolism mediated by CYP2C8, and confirms the conclusion that there is no significant inhibitory effect of linagliptin in vivo on CYP3A4.
Ritonavir The combined use of linagliptin (single dose of 5 mg orally) and ritonavir (repeated intake of 200 mg orally), the active inhibitor of P-glycoprotein and the isoenzyme CYP3A4 increased the AUC and Cmax values of linagliptin approximately 2 times and 3 times, respectively. However, these changes in linagliptin pharmacokinetics were not considered significant. Therefore, a clinically significant interaction with other inhibitors of P-glycoprotein and CYP3A4 is not expected, and a dose change is not required.
Rifampicin. Repeated combined use of linagliptin and rifampicin, the active inducer of P-glycoprotein and CYP3A4 isoenzyme, led to a decrease in the AUC and Cmax values of linagliptin by 39.6% and 43.8%, respectively, and to a decrease in inhibition of the basal activity of dipeptidyl peptidase-4, by approximately 30%. Thus, it is expected that the clinical efficacy of linagliptin, which is used in combination with active inducers of P-glycoprotein, will be maintained, although it may not manifest fully.
Digoxin. The combined repeated use of linagliptin (5 mg / day) and digoxin (0.25 mg / day) in healthy volunteers did not affect the pharmacokinetics of digoxin. Thus, linagliptin in vivo is not an inhibitor of transport mediated by P-glycoprotein.
Warfarin. Linagliptin, administered repeatedly at a dose of 5 mg / day, did not change the pharmacokinetics of warfarin, which is a substrate for CYP2C9, which indicates that linagliptin does not have the ability to inhibit CYP2C9.
Simvastatin. Linagliptin, used in healthy volunteers many times at a dose of 10 mg / day. (higher therapeutic dose), had a minimal effect on the pharmacokinetic parameters of simvastatin, which is a sensitive substrate for CYP3A4. After taking linagliptin at a dose of 10 mg together with simvastatin, used at a daily dose of 40 mg for 6 days, the AUC value of simvastatin increased by 34%, and the Cmax value by 10%. Thus, linagliptin is a weak inhibitor of CYP3A4-mediated metabolism. Changes in dose while taking with drugs that are metabolized with the participation of CYP3A4, is considered inappropriate.
Oral contraceptive drugs. The combined use of linagliptin 5 mg with levonorgestrel or ethinyl estradiol did not change the pharmacokinetics of these drugs.
Pregnancy and Lactation
The use of linagliptin during pregnancy and during breastfeeding is contraindicated.
Special instructions
The drug Trajenta® is contraindicated in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
The incidence of hypoglycemia in the case of using linagliptin as monotherapy was comparable to placebo.
In clinical studies, it was reported that the incidence of hypoglycemia in the case of using linagliptin in combination with drugs that are not believed to cause hypoglycemia (metformin, thiazolidinedione derivatives) was similar to the corresponding placebo effect.
Sulfonylurea derivatives are known to cause hypoglycemia. Therefore, if linagliptin is used in combination with sulfonylurea derivatives, caution should be exercised. If necessary, reduce the dose of sulfonylurea derivatives.
Special clinical studies on the use of linagliptin in combination with insulin was not conducted.
Linagliptin does not increase the risk of developing cardiovascular diseases.
Linagliptin in combination therapy with other oral hypoglycemic drugs was used in patients with severe renal failure.
Linagliptin provided a significant decrease in the concentration of glycated hemoglobin and fasting glucose concentration.
Dose adjustment for use in patients with impaired renal function, liver, and in elderly patients is not required.
Influence on ability to drive vehicles and mechanisms
Studies of the effect of the drug Trajenta® on the ability to drive vehicles and mechanisms was not conducted. However, due to the possible development of vertigo, caution must be exercised when driving vehicles and machinery.
Overdosage
During controlled clinical trials in healthy volunteers, a single dose of 600 mg linagliptin (120 times the recommended dose) was well tolerated. Experience using linagliptin dose greater than 600 mg, no.
In case of overdose, it is recommended to use usual supportive measures, for example, removal of an unabsorbed Trazent preparation from the gastrointestinal tract, implementation of clinical monitoring and symptomatic treatment.
- Brand name: Trajenta
- Active ingredient: Linagliptin
Studies and clinical trials of Linagliptin (Click to expand)
- Binding to dipeptidyl peptidase-4 determines the disposition of linagliptin (BI 1356) – investigations in DPP-4 deficient and wildtype rats
- Design, statistical analysis and sample size calculation of a phase IIb/III study of linagliptin versus voglibose and placebo
- Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy
- Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers
- The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses
- Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients
- Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study
- 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
- The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type 2 diabetes mellitus
- 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
- Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin
- 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
- Efficacy and safety of linagliptin in persons with Type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study
- Linagliptin: new DPP-4 inhibitor for type 2 diabetes mellitus
- Linagliptin, a dipeptidyl peptidase-4 inhibitor in development for the treatment of type 2 diabetes mellitus: A phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male japanese subjects
- Pharmacokinetic, Pharmacodynamic, and Tolerability Profiles of the Dipeptidyl Peptidase-4 Inhibitor Linagliptin: A 4-Week Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase IIa Study in Japanese Type 2 Diabetes Patients
- A Randomized, Open-Label, Crossover Study Evaluating the Effect of Food on the Relative Bioavailability of Linagliptin in Healthy Subjects
- Review of Linagliptin for the Treatment of Type 2 Diabetes Mellitus
- Excretion of the dipeptidyl peptidase-4 inhibitor linagliptin in rats is primarily by biliary excretion and P-gp-mediated efflux
- Comparison of Direct and Indirect Antioxidant Effects of Linagliptin (BI 1356, ONDERO) with other Gliptins – Evidence for Anti-inflammatory Properties of Linagliptin
- Liraglutide and linagliptin improve glycemic control but show differential anti-obesity and hypolipidemic efficacy in a novel hamster model of diet-induced obesity and hypercholesterolemia
- Comparison of direct and indirect antioxidant effects of linagliptin with other gliptins — Evidence for antioxidant and antiinflammatory properties of linagliptin
- Pharmacokinetics of linagliptin in subjects with hepatic impairment
- Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: up to 2 years exposure in 24-week phase III trials followed by a 78-week open-label extension
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