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Trajenta, 30 pcs., 5 mg, film-coated tablets
The pharmacokinetics of linagliptin have been extensively studied when used in healthy volunteers and patients with type 2 diabetes mellitus. In healthy volunteers, after taking linagliptin at a dose of 5 mg, it was rapidly absorbed, the Cmax of linagliptin in plasma was reached after 1.5 hours.
The concentration of linagliptin in plasma decreases in three phases. Terminal T1/2 is long, more than 100 hours, which is mainly due to the stable binding of linagliptin to the DPP-4 enzyme, however, since the relationship is reversible, accumulation of linagliptin does not occur.
The effective T1/2 after repeated doses of linagliptin at a dose of 5 mg is approximately 12 hours. When taking linagliptin at a dose of 5 mg 1 time per day, steady-state plasma concentrations of linagliptin are achieved after the third dose.
The pharmacokinetics of linagliptin in healthy volunteers and patients with type 2 diabetes mellitus were generally similar.
Suction.
The absolute bioavailability of linagliptin is approximately 30%.
Taking linagliptin with a high-fat meal does not have a clinically significant effect on pharmacokinetics. In vitro
studies have shown that linagliptin is a substrate for P-gp and the CYP3A4 isoenzyme. Ritonavir, as a potential inhibitor of P-gp and the CYP3A4 isoenzyme, may double the AUC value. Rifampin, as a potential inducer of P-gp and the CYP3A4 isoenzyme, may reduce the AUC value during steady-state pharmacokinetics.
Distribution.
Vd after a single intravenous administration of linagliptin at a dose of 5 mg to healthy volunteers is approximately 1.11 L, indicating extensive tissue distribution. The binding of linagliptin to plasma proteins depends on its concentration and is about 99% at a concentration of 1 nmol/l, and 75–89% at a concentration of more than 30 nmol/l, which reflects the saturation of the binding of linagliptin to DPP-4 as its concentration increases. At high concentrations, when complete saturation of DPP-4 occurs, 70–80% of linagliptin is bound to other plasma proteins (not DPP-4), and 30–20% of linagliptin is in the plasma in an unbound state.
Metabolism.
Approximately 5% of linagliptin is excreted by the kidneys. A small portion of linagliptin is metabolized. Metabolism plays a minor role in the elimination of linagliptin. There is one known major metabolite of linagliptin, which has no pharmacological activity.
Excretion.
The predominant route of elimination is through the intestines. 4 days after oral administration of [14C] labeled linagliptin in healthy volunteers, approximately 85% of the dose was excreted (80% intestinal and 5% renal) with a creatinine Cl of approximately 70 ml/min.
Pharmacokinetics in special groups of patients
Kidney failure.
In patients with mild renal impairment (Cl creatinine 50 to <80 mL/min), steady-state exposure to linagliptin was comparable to exposure in healthy subjects. In moderate renal impairment (creatinine Cl 30 to <50 ml/min), a slight increase in exposure was observed (approximately 1.7 times compared with healthy subjects). Exposure to linagliptin in patients with type 2 diabetes mellitus and severe renal impairment (Cl creatinine <30 mL/min) was increased approximately 1.4-fold compared with patients with diabetes mellitus and normal renal function. Modeling of linagliptin AUC values in patients with end-stage renal disease showed that exposure in these cases was comparable to exposure in patients with moderate or severe renal impairment. The use of hemodialysis or peritoneal dialysis is not expected to eliminate linagliptin to a therapeutically significant extent. Therefore, no changes in linagliptin dosage are required in patients with any degree of renal impairment.
Liver failure.
In patients with mild, moderate, and severe hepatic impairment (Child-Pugh classification), the mean AUC and Cmax values of linagliptin after multiple doses of 5 mg were similar to those in matched healthy subjects. No dosage changes are required for linagliptin in patients with mild, moderate or severe hepatic impairment.
BMI.
No changes in linagliptin dosage are required based on BMI.
Floor.
No changes in linagliptin dosing are required depending on gender.
Elderly patients.
No age-related dosing changes for linagliptin are required as age did not have a clinically significant effect on the pharmacokinetics of linagliptin in a population pharmacokinetic analysis performed in clinical studies. Plasma concentrations of linagliptin were comparable in both older patients (age 65–80 years) and younger patients.
Children.
The pharmacokinetics of linagliptin in children has not been studied.
Race.
There are no changes in linagliptin dosing based on race. Race did not significantly influence linagliptin plasma concentrations in a combined analysis of pharmacokinetic data obtained from Caucasian, Hispanic, African American, and Asian patients. In addition, the pharmacokinetic characteristics of linagliptin were similar in special studies conducted in healthy Caucasian volunteers and residents of Japan and China, as well as in African-American patients with type 2 diabetes mellitus.
Trajenta®
In vitro assessment of drug interactions
Linagliptin is a weak competitive inhibitor of the CYP3A4 isoenzyme.
Linagliptin does not inhibit other CYP isoenzymes and is not an inducer.
Linagliptin is a substrate for P-glycoprotein and inhibits to a small extent P-glycoprotein-mediated transport of digoxin.
In vivo assessment of drug interactions
Linagliptin does not have a clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin and oral contraceptives, which has been proven in vivo, and is based on the low ability of linagliptin to lead to drug interactions with substrates for CYP3A4, CYP2C9, CYP2C8, P-glycoprotein and transport molecules of organic cations.
Metformin.
The combined use of metformin (multiple daily doses of 850 mg 3 times/day) and linagliptin at a dose of 10 mg 1 time/day (above the 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 organic cation transport.
Sulfonylurea derivatives.
The pharmacokinetics of linagliptin (5 mg) did not change when combined with glibenclamide (single dose of glyburide 1.75 mg) and repeated oral administration of linagliptin (5 mg each). However, there was a clinically insignificant decrease in the AUC and Cmax values of glibenclamide by 14%. Because glibenclamide is metabolized primarily by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically significant interactions are not expected with other sulfonylureas (for example, glipizide and glimepiride), which, like glibenclamide, are mainly metabolized by CYP2C9.
Thiazolidinediones.
Co-administration of multiple doses of linagliptin 10 mg/day (above the therapeutic dose) and pioglitazone 45 mg/day (multiple doses), which is a substrate for CYP2C8 and CYP3A4, did not have a clinically significant effect on the pharmacokinetics of linagliptin or pioglitazone, or the active metabolites of pioglitazone. . This indicates that linagliptin in vivo is not an inhibitor of CYP2C8-mediated metabolism and supports the conclusion that linagliptin does not have a significant inhibitory effect on CYP3A4 in vivo.
Ritonavir.
Co-administration of linagliptin (single dose 5 mg orally) and ritonavir (multiple doses of 200 mg orally), an active inhibitor of P-glycoprotein and the CYP3A4 isoenzyme, increased the AUC and Cmax values of linagliptin by approximately 2-fold and 3-fold, respectively. However, these changes in linagliptin pharmacokinetics were not considered significant. Therefore, clinically significant interactions with other P-gp and CYP3A4 inhibitors are not expected and no dose adjustment is required.
Rifampicin.
Repeated co-administration of linagliptin and rifampicin, an active inducer of P-glycoprotein and the 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 the inhibition of basal dipeptidyl peptidase-4 activity by approximately 30%. Thus, the clinical efficacy of linagliptin when used in combination with active P-glycoprotein inducers is expected to be maintained, although it may not be fully realized.
Digoxin.
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 is not an inhibitor of P-glycoprotein-mediated transport in vivo.
Warfarin.
Linagliptin, administered repeatedly at a dose of 5 mg/day, did not change the pharmacokinetics of warfarin, which is a substrate for CYP2C9, indicating that linagliptin does not have the ability to inhibit CYP2C9.
Simvastatin.
Linagliptin, administered repeatedly to healthy volunteers at a dose of 10 mg/day (above the therapeutic dose), had 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 increased by 10%. Thus, linagliptin is a weak inhibitor of CYP3A4-mediated metabolism. Dose changes when taken concomitantly with drugs that are metabolized by CYP3A4 are considered inappropriate.
Oral contraceptives.
Co-administration of linagliptin at a dose of 5 mg with levonorgestrel or ethinyl estradiol did not change the pharmacokinetics of these drugs.
Description of the drug TRAZHENTA® (TRAZHENTA)
The pharmacokinetics of linagliptin have been extensively studied in healthy volunteers and in patients with type 2 diabetes mellitus. In healthy volunteers, after taking linagliptin at a dose of 5 mg, it was rapidly absorbed, the Cmax of linagliptin in plasma was reached after 1.5 hours.
The concentration of linagliptin in plasma decreases in three phases. Terminal T1/2 is long, more than 100 hours, which is mainly due to the stable binding of linagliptin to the DPP-4 enzyme, however, because the relationship is reversible, accumulation of linagliptin does not occur. The effective T1/2 after repeated doses of linagliptin at a dose of 5 mg is approximately 12 hours. When taking linagliptin at a dose of 5 mg 1 time / day, Css of linagliptin in plasma are achieved after the third dose.
The pharmacokinetics of linagliptin in healthy volunteers and in patients with type 2 diabetes mellitus was generally similar.
The absolute bioavailability of linagliptin is approximately 30%. Taking linagliptin with a high-fat meal does not have a clinically significant effect on pharmacokinetics. In vitro studies have shown that linagliptin is a substrate for P-glycoprotein and the CYP3A4 isoenzyme. Ritonavir, as a potential inhibitor of P-glycoprotein and the CYP3A4 isoenzyme, may double the AUC value. Rifampicin, as a potential inducer of P-glycoprotein and the CYP3A4 isoenzyme, may reduce the AUC value during the period of equilibrium pharmacokinetics.
Vd after a single intravenous administration of linagliptin at a dose of 5 mg to healthy volunteers is approximately 1110 L, indicating intensive tissue distribution. The binding of linagliptin to plasma proteins depends on its concentration and is about 99% at a concentration of 1 nmol/l, and 75-89% at a concentration of more than 30 nmol/l, which reflects the saturation of the binding of linagliptin to DPP-4 as its concentration increases. At high concentrations, when complete saturation of DPP-4 occurs, 70-80% of linagliptin is bound to other plasma proteins (not DPP-4), and 30-20% of linagliptin is in the plasma in an unbound state.
Approximately 5% of linagliptin is excreted by the kidneys. A small portion of linagliptin is metabolized. Metabolism plays a minor role in the elimination of linagliptin. There is one known major metabolite of linagliptin, which has no pharmacological activity.
The predominant route of elimination is through the intestines. 4 days after oral administration of [14C] labeled linagliptin in healthy volunteers, approximately 85% of the dose was excreted (80% intestinal and 5% urinary) with a clearance clearance of approximately 70 ml/min.
Trajenta 5mg tab No. 30
Dosage
5 mg
Active substance
Linagliptin
Manufacturer
West Word Columbus Inc. (USA)
Shelf life
3 years
Storage conditions
At a temperature not exceeding 25 °C
Registration certificate number
LP-001430 dated 02/06/2017
Compound
| Film-coated tablets | 1 table |
| 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 | |
| film shell: Opadry® pink (02F34337) (hypromellose 2910 - 2.5 mg, titanium dioxide (E171) - 1.25 mg, talc - 0.875 mg, macrogol 6000 - 0.25 mg, iron dye red oxide (E172) - 0.125 mg) – 5 mg |
Characteristic
| Film-coated tablets | 1 table |
| 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 | |
| film shell: Opadry® pink (02F34337) (hypromellose 2910 - 2.5 mg, titanium dioxide (E171) - 1.25 mg, talc - 0.875 mg, macrogol 6000 - 0.25 mg, iron dye red oxide (E172) - 0.125 mg) – 5 mg |
Description of the dosage form
Round, biconvex, beveled, light red film-coated tablets, debossed with the company symbol on one side and “D5” on the other side.
Pharmacokinetics
The pharmacokinetics of linagliptin have been extensively studied when used in healthy volunteers and patients with type 2 diabetes mellitus. In healthy volunteers, after taking linagliptin at a dose of 5 mg, it was rapidly absorbed, the Cmax of linagliptin in plasma was reached after 1.5 hours.
The concentration of linagliptin in plasma decreases in three phases. Terminal T1/2 is long, more than 100 hours, which is mainly due to the stable binding of linagliptin to the DPP-4 enzyme, however, since the relationship is reversible, accumulation of linagliptin does not occur.
The effective T1/2 after repeated doses of linagliptin at a dose of 5 mg is approximately 12 hours. When taking linagliptin at a dose of 5 mg 1 time per day, steady-state plasma concentrations of linagliptin are achieved after the third dose.
The pharmacokinetics of linagliptin in healthy volunteers and patients with type 2 diabetes mellitus were generally similar.
Suction.
The absolute bioavailability of linagliptin is approximately 30%.
Taking linagliptin with a high-fat meal does not have a clinically significant effect on pharmacokinetics. In vitro
studies have shown that linagliptin is a substrate for P-gp and the CYP3A4 isoenzyme. Ritonavir, as a potential inhibitor of P-gp and the CYP3A4 isoenzyme, may double the AUC value. Rifampin, as a potential inducer of P-gp and the CYP3A4 isoenzyme, may reduce the AUC value during steady-state pharmacokinetics.
Distribution.
Vd after a single intravenous administration of linagliptin at a dose of 5 mg to healthy volunteers is approximately 1.11 L, indicating extensive tissue distribution. The binding of linagliptin to plasma proteins depends on its concentration and is about 99% at a concentration of 1 nmol/l, and 75–89% at a concentration of more than 30 nmol/l, which reflects the saturation of the binding of linagliptin to DPP-4 as its concentration increases. At high concentrations, when complete saturation of DPP-4 occurs, 70–80% of linagliptin is bound to other plasma proteins (not DPP-4), and 30–20% of linagliptin is in the plasma in an unbound state.
Metabolism.
Approximately 5% of linagliptin is excreted by the kidneys. A small portion of linagliptin is metabolized. Metabolism plays a minor role in the elimination of linagliptin. There is one known major metabolite of linagliptin, which has no pharmacological activity.
Excretion.
The predominant route of elimination is through the intestines. 4 days after oral administration of [14C] labeled linagliptin in healthy volunteers, approximately 85% of the dose was excreted (80% intestinal and 5% renal) with a creatinine Cl of approximately 70 ml/min.
Pharmacokinetics in special groups of patients
Kidney failure.
In patients with mild renal impairment (Cl creatinine 50 to <80 mL/min), steady-state exposure to linagliptin was comparable to exposure in healthy subjects. In moderate renal impairment (creatinine Cl 30 to <50 ml/min), a slight increase in exposure was observed (approximately 1.7 times compared with healthy subjects). Exposure to linagliptin in patients with type 2 diabetes mellitus and severe renal impairment (Cl creatinine <30 mL/min) was increased approximately 1.4-fold compared with patients with diabetes mellitus and normal renal function. Modeling of linagliptin AUC values in patients with end-stage renal disease showed that exposure in these cases was comparable to exposure in patients with moderate or severe renal impairment. The use of hemodialysis or peritoneal dialysis is not expected to eliminate linagliptin to a therapeutically significant extent. Therefore, no changes in linagliptin dosage are required in patients with any degree of renal impairment.
Liver failure.
In patients with mild, moderate, and severe hepatic impairment (Child-Pugh classification), the mean AUC and Cmax values of linagliptin after multiple doses of 5 mg were similar to those in matched healthy subjects. No dosage changes are required for linagliptin in patients with mild, moderate or severe hepatic impairment.
BMI.
No changes in linagliptin dosage are required based on BMI.
Floor.
No changes in linagliptin dosing are required depending on gender.
Elderly patients.
No age-related dosing changes for linagliptin are required as age did not have a clinically significant effect on the pharmacokinetics of linagliptin in a population pharmacokinetic analysis performed in clinical studies. Plasma concentrations of linagliptin were comparable in both older patients (age 65–80 years) and younger patients.
Children.
The pharmacokinetics of linagliptin in children has not been studied.
Race.
There are no changes in linagliptin dosing based on race. Race did not significantly influence linagliptin plasma concentrations in a combined analysis of pharmacokinetic data obtained from Caucasian, Hispanic, African American, and Asian patients. In addition, the pharmacokinetic characteristics of linagliptin were similar in special studies conducted in healthy Caucasian volunteers and residents of Japan and China, as well as in African-American patients with type 2 diabetes mellitus.
Pharmacodynamics
Linagliptin is an inhibitor of the DPP-4 enzyme, which is involved in the inactivation of the incretin hormones GLP-1 and GIP. These hormones are quickly destroyed by the DPP-4 enzyme. Both of these incretins are involved in maintaining glucose concentrations at physiological levels. Basal concentrations of GLP-1 and GIP are low throughout the day and rise rapidly in response to food intake. GLP-1 and GIP enhance insulin biosynthesis and its secretion by pancreatic beta cells at normal or elevated blood glucose concentrations. In addition, GLP-1 reduces the secretion of glucagon by alpha cells of the pancreas, which leads to a decrease in glucose production in the liver. Linagliptin actively binds to the DPP-4 enzyme (the relationship is reversible), which causes a steady increase in the concentration of incretins and long-term preservation of their activity.
Tragenta® increases glucose-dependent insulin secretion and reduces glucagon secretion, which leads to normalization of blood glucose concentrations. Linagliptin binds selectively to the DPP-4 enzyme and has 10,000 times greater selectivity for DPP-4 compared to DPP-8 or DPP-9 enzymes in vitro
.
In clinical studies where linagliptin was used as monotherapy, combination therapy with metformin, combination therapy with sulfonylureas, combination therapy with insulin, combination therapy with metformin and sulfonylureas, combination therapy with pioglitazone, combination therapy with metformin and pioglitazone, combination therapy with Metformin compared with glimepiride showed a statistically significant decrease in HbA1c and a decrease in fasting plasma glucose (FPG) concentrations.
The use of linagliptin in patients with severe renal failure who received adequate basic hypoglycemic therapy.
In clinical studies where linagliptin was used in addition to basic hypoglycemic therapy (including insulin, sulfonylureas, glinides or pioglitazone), a statistically significant reduction in HbA1c was demonstrated (0.59% compared with placebo; baseline HbA1c was approximately 8.2% ).
Use of linagliptin monotherapy and initial combination therapy of linagliptin and metformin in patients with newly diagnosed type 2 diabetes mellitus (with severe hyperglycemia).
In clinical studies, it was proven that both monotherapy with linagliptin and combination therapy with linagliptin and metformin led to a statistically significant decrease in HbA1c by 2 and 2.8%, respectively (baseline HbA1c was 9.9 and 9.8%, respectively). A treatment difference of −0.8% (95% CI: −1.1 to −0.5) demonstrated superiority of initial linagliptin and metformin combination therapy over linagliptin monotherapy (p<0.0001).
Contraindications
hypersensitivity to any component of the drug;
diabetes mellitus type 1;
diabetic ketoacidosis;
pregnancy and breastfeeding;
children under 18 years of age.
Carefully:
history of pancreatitis; patients over 80 years of age; use in combination with sulfonylurea derivatives and/or insulin.
Use during pregnancy and breastfeeding
The use of linagliptin during pregnancy is contraindicated. The use of linagliptin during breastfeeding is contraindicated. Data obtained from preclinical studies in animals indicate the penetration of linagliptin and its metabolite into breast milk. The risk of exposure to newborns and children during breastfeeding cannot be excluded. If it is necessary to use linagliptin during breastfeeding, breastfeeding should be discontinued.
Directions for use and doses
Inside
, regardless of meals, at any time of the day. The recommended dose is 5 mg (1 tablet) 1 time per day.
When prescribed in addition to metformin, linagliptin is taken simultaneously with metformin, maintaining the previously prescribed dose of metformin.
When using linagliptin in combination with sulfonylurea derivatives and/or insulin, it is possible to reduce the dose of sulfonylurea derivatives or insulin to reduce the risk of hypoglycemia.
What to do if you miss one or more doses of the drug
If a dose is missed, the patient should take the drug as soon as he remembers. Do not take a double dose on the same day.
Special patient groups
Kidney failure.
For patients with renal failure, no dose adjustment of linagliptin is required.
Liver dysfunction.
For patients with impaired liver function, no dose adjustment of linagliptin is required, but clinical experience in such patients is insufficient.
Elderly age.
For elderly patients, no dose adjustment is required. However, clinical experience in patients over 80 years of age is limited and such patients should be treated with caution.
Side effects
The incidence of side effects with linagliptin 5 mg was similar to the rate of side effects with placebo. Discontinuation due to adverse events was higher in the placebo group (4.3%) than in the linagliptin 5 mg group (3.4%). Adverse reactions observed in patients receiving linagliptin as monotherapy and combination therapy with other hypoglycemic agents in placebo-controlled studies are presented in the table below (adverse reactions were classified by organ system and according to MedDRA
terms) indicating their absolute frequency. Frequency categories are defined as follows: very often (≥1/10); often (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (≥1/10000 to <1/1000) or very rare (<1/10000); Adverse reactions are also highlighted, the frequency of which is unknown (cannot be estimated based on the available data).
Table
Classification of side effects by type and frequency of occurrence
| System-organ class | Frequency of occurrence | By-effect |
| With linagliptin monotherapy | ||
| From the immune system | infrequently | hypersensitivity |
| From the respiratory system, chest organs and mediastinum | infrequently | cough |
| From the gastrointestinal tract | frequency unknown | pancreatitis |
| Infectious and parasitic diseases | infrequently | nasopharyngitis |
| Laboratory and instrumental data | rarely | increase in amylase in blood plasma |
| When using linagliptin with metformin | ||
| From the immune system | infrequently | hypersensitivity |
| From the respiratory system, chest organs and mediastinum | infrequently | cough |
| From the gastrointestinal tract | frequency unknown | pancreatitis |
| Infectious and parasitic diseases | infrequently | nasopharyngitis |
| Laboratory and instrumental data | infrequently | increase in amylase in blood plasma |
| When using linagliptin with sulfonylurea derivatives | ||
| From the immune system | frequency unknown | hypersensitivity |
| Metabolism and nutrition | frequency unknown | hypertriglyceridemia |
| From the respiratory system, chest organs and mediastinum | frequency unknown | cough |
| From the gastrointestinal tract | frequency unknown | pancreatitis |
| Infectious and parasitic diseases | frequency unknown | nasopharyngitis |
| Laboratory and instrumental data | frequency unknown | increase in amylase in blood plasma |
| When using linagliptin with pioglitazone | ||
| From the immune system | infrequently | hypersensitivity |
| Metabolism and nutrition | frequency unknown | hyperlipidemia |
| From the respiratory system, chest organs and mediastinum | frequency unknown | cough |
| From the gastrointestinal tract | frequency unknown | pancreatitis |
| Infectious and parasitic diseases | frequency unknown | nasopharyngitis |
| Laboratory and instrumental data | often | weight gain |
| infrequently | increase in amylase in blood plasma | |
| When using linagliptin with insulin | ||
| From the immune system | infrequently | hypersensitivity |
| From the respiratory system, chest organs and mediastinum | infrequently | cough |
| From the gastrointestinal tract | infrequently | pancreatitis, constipation |
| Infectious and parasitic diseases | infrequently | nasopharyngitis |
| Laboratory and instrumental data | frequency unknown | increase in amylase in blood plasma |
| When using linagliptin with metformin and sulfonylureas | ||
| From the immune system | infrequently | hypersensitivity |
| Metabolism and nutrition | Often | hypoglycemia |
| From the respiratory system, chest organs and mediastinum | frequency unknown | cough |
| From the gastrointestinal tract | frequency unknown | pancreatitis |
| Infectious and parasitic diseases | frequency unknown | nasopharyngitis |
| Laboratory and instrumental data | infrequently | increase in amylase in blood plasma |
| Post-marketing experience of use | ||
| From the immune system | rarely | angioedema, urticaria |
| From the gastrointestinal tract | rarely | ulceration of the oral mucosa |
| From the skin and subcutaneous tissues | infrequently | rash |
| frequency unknown | bullous pemphigoid | |
The safety profile of combination therapy with linagliptin, metformin and pioglitazone was comparable to that of linagliptin monotherapy, combination therapy with linagliptin and metformin, and combination therapy with linagliptin and pioglitazone.
Interaction
In vitro assessment of drug interactions
Linagliptin is a weak competitive inhibitor of the CYP3A4 isoenzyme. Linagliptin does not inhibit other CYP isoenzymes and is not an inducer. Linagliptin is a substrate for P-gp and inhibits to a small extent P-gp-mediated transport of digoxin.
In vivo assessment of drug interactions
Linagliptin does not have a clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin and oral contraceptives, which has been proven in vivo
and is based on the low ability of linagliptin to lead to drug interactions with substrates for CYP3A4, CYP2C9, CYP2C8, P-gp and transport molecules of organic cations.
Metformin.
Co-administration of metformin (multiple daily doses of 850 mg 3 times a day) and linagliptin at a dose of 10 mg 1 time per day (above the 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 organic cation transport.
Sulfonylurea derivatives.
The pharmacokinetics of linagliptin (multiple oral doses of 5 mg) did not change when combined with glibenclamide (single dose of glyburide 1.75 mg). However, there was a clinically insignificant decrease in the AUC and Cmax values of glibenclamide by 14%. Because glibenclamide is metabolized primarily by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically significant interactions are not expected with other sulfonylurea derivatives (for example, glipizide and glimepiride), which, like glibenclamide, are mainly metabolized by CYP2C9.
Thiazolidinediones.
Coadministration of multiple doses of linagliptin 10 mg per day (above the therapeutic dose) and pioglitazone 45 mg per day (multiple doses), which is a substrate for CYP2C8 and CYP3A4, did not have a clinically significant effect on the pharmacokinetics of linagliptin or pioglitazone, or the active metabolites of pioglitazone. .
This indicates that linagliptin in vivo
is not an inhibitor of CYP2C8-mediated metabolism and supports the conclusion that linagliptin does not have a significant inhibitory effect
in vivo
.
Ritonavir.
Co-administration of linagliptin (single dose 5 mg orally) and ritonavir (multiple doses 200 mg orally), an active P-gp inhibitor and CYP3A4 isoenzyme, increased the AUC and Cmax values of linagliptin by approximately 2-fold and 3-fold, respectively. However, these changes in linagliptin pharmacokinetics were not considered significant. Therefore, clinically significant interactions with other P-gp and CYP3A4 inhibitors are not expected and no dose adjustment is required.
Rifampicin.
Repeated co-administration of linagliptin and rifampicin, an active P-gp inducer and CYP3A4 isoenzyme, led to a decrease in the AUC and Cmax of linagliptin by 39.6 and 43.8%, respectively, and a decrease in the inhibition of basal DPP-4 activity by approximately 30%. Thus, the clinical efficacy of linagliptin when used in combination with active P-gp inducers is expected to be maintained, although it may not be fully realized.
Digoxin.
Co-administration of linagliptin (5 mg per day) and digoxin (0.25 mg per day) in healthy volunteers had no effect on the pharmacokinetics of digoxin.
Thus, linagliptin
is not an inhibitor of P-gp-mediated transport in vivo
Warfarin.
Linagliptin, administered multiple times at a dose of 5 mg per day, did not change the pharmacokinetics of warfarin, which is a substrate for CYP2C9, indicating that linagliptin does not have the ability to inhibit CYP2C9.
Simvastatin.
Linagliptin, administered to healthy volunteers at multiple doses of 10 mg per day (above the therapeutic dose), had minimal effect on the pharmacokinetics 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. Changing the dose when taken concomitantly with drugs that are metabolized by CYP3A4 is considered inappropriate.
Oral contraceptives.
Co-administration of linagliptin at a dose of 5 mg with levonorgestrel or ethinyl estradiol did not change the pharmacokinetics of these drugs.
Overdose
In controlled clinical studies in healthy volunteers, single doses of linagliptin up to 600 mg (120 times the recommended dose) were well tolerated. There is no experience with doses exceeding 600 mg.
Treatment:
in case of overdose, it is recommended to use the usual supportive measures, such as removing unabsorbed drug from the gastrointestinal tract, clinical monitoring and symptomatic treatment.
special instructions
Tragenta® is contraindicated in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Hypoglycemia
The incidence of hypoglycemia when linagliptin was used as monotherapy was comparable to placebo. In clinical studies, it was reported that the incidence of hypoglycemia when linagliptin was used in combination with drugs that are not considered to cause hypoglycemia (metformin, thiazolidinedione derivatives) was similar to the corresponding effect of placebo.
Sulfonylureas and insulin are known to cause hypoglycemia. Therefore, when using linagliptin in combination with sulfonylureas and/or insulin, caution should be exercised. If necessary, it is possible to reduce the dose of sulfonylurea derivatives or insulin. The use of linagliptin does not increase the risk of developing cardiovascular diseases.
Linagliptin in combination therapy with other oral hypoglycemic drugs has been used in patients with severe renal failure. Linagliptin provided a significant reduction in HbA1c and FPG concentrations.
No dose adjustment is required when used in patients with impaired renal function, liver function or in elderly patients.
Use of linagliptin in patients over 70 years of age
Linagliptin resulted in a significant reduction in HbA1c (0.64% compared with placebo; baseline HbA1c was approximately 7.8%). The use of linagliptin also led to a significant decrease in FPG concentrations. However, clinical experience in patients over 80 years of age is limited, so treatment of such groups of patients must be carried out with caution.
Cardiovascular risk
Treatment with linagliptin does not increase cardiovascular risk. The primary endpoint (a composite of the incidence or time to first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) was met at a rate that was not significantly lower in patients receiving linagliptin than in the combined group of patients receiving active drugs. comparison and placebo (relative risk 0.78; 95% CI: 0.55, 1.12).
Post-marketing experience of use
Cases of acute pancreatitis have been reported in patients taking linagliptin. If pancreatitis is suspected, the drug should be discontinued.
Impact on the ability to drive vehicles and machinery.
No studies have been conducted on the effect of the drug on the ability to drive vehicles and operate machinery. However, due to the possible development of hypoglycemia (which can manifest itself in the form of headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, rapid heartbeat, sweating, panic attacks), especially when taking linagliptin in combination with sulfonylureas and/or insulin, you must be careful when driving vehicles and machinery.
Conditions for dispensing from pharmacies
On prescription.
Pharmgroups
Hypoglycemic agent - dipeptidyl peptidase-4 inhibitor (Synthetic hypoglycemic and other agents)
Pharmaceutical actions
hypoglycemic
