Tragenta® (Trajenta®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceLinaglyptinLinaglyptin
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  • Tragenta®
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    Boehringer Ingelheim International GmbH     Germany
    • Dosage form: & nbspfilm coated tablets
    Composition:

    1 tablet, film-coated, contains:

    active substance: linagliptin - 5 mg;

    auxiliary substances: mannitol - 130.9 mg, pregelatinized starch 18, mg, corn starch - 18 mg, copovidone - 5.4 mg, magnesium stearate - 2.7 mg;

    sheath: Opadrai Pink (02F34337) - 5 mg (hypromellose 2910-2.5 mg, titanium dioxide (E 171) 1.25 mg, talc 0.875 mg, macrogol 6000 0.25 mg, iron dye, red oxide (E 172) -0,125 mg) .

    Description:Round biconvex with bevelled edges of the tablet, covered with a film shell of light red color, with an engraved company symbol on one side and with an engraving "D5" on the other side of the pill.
    Pharmacotherapeutic group:Hypoglycemic agent - dipeptidyl peptidase-4 inhibitor (DPP-4)
    ATX: & nbsp
  • Linaglyptin
    • Pharmacodynamics:

    Linagliptin is an inhibitor of the enzyme dineitidyl neptidase-4 (DPP-4), which is involved in the inactivation of incretin hormones such as glucagon-like peptide type 1 (GLP-1) and a glucose-dependent insulinotropic polypeptide (GIP). These hormones are rapidly destroyed by the enzyme DPP-4. Both these incretins are involved in maintaining the glucose concentration at the physiological level.Basal concentrations of GLP-1 and HIP during the day are low, they quickly increase in response to food intake. GLP-1 and HIP enhance biosynthesis of insulin and its secretion by beta-cells of the pancreas at normal or elevated blood glucose concentrations. In addition, GLP-1 reduces the secretion of glucagon by the alpha-cells of the pancreas, which leads to a decrease in the production of glucose in the liver.

    Linagliptin actively binds to the enzyme DPP-4 (the link is reversible), which causes a steady increase in the incretin concentration and a prolonged retention of their activity. The tragic increases the glucose-dependent secretion of insulin and decreases the secretion of glucagon, which leads to a normalization of the blood glucose level. Linaglyptin selectively binds to the DPP-4 enzyme and has a 10,000-fold greater selectivity for DPP-4 than the enzymes dipeptidyl peptidase-8 or dipeptidyl-pentidase-9 in vitro.

    In clinical trials, where linaglyptin in the form of monotherapy, combination therapy with metformin, combination therapy with sulfonylurea drugs, combination therapy with insulin,combined therapy with metformin and sulfonylurea preparations, combined therapy with pioglitazone, combined therapy with metformin and pioglitazone, combined therapy with metformin in comparison with glimepiride showed a statistically significant reduction in glycosylated hemoglobin (HbA1c) and a decrease in the level of the GLP (fasting plasma glucose).

    The use of linagliptin in patients with severe renal failure who received adequate basic hypoglycemic therapy

    In clinical trials, where linaglyptin in addition to basic hypoglycemic therapy (including insulin, sulfonylurea derivatives, clay minerals or pioglitazone) a statistically significant reduction in glycosylated hemoglobin HbA1c (0.59% vs. placebo: baseline HbA1c was about 8.2%).

    The use of monotherapy with linagliptin and the initial combination therapy of linagliptin and metformin in patients with a recently established diagnosis of type 2 diabetes mellitus (with severe hyperglycemia)

    In clinical trials, it has been shown that, as a monotherapy with linagliptin,and combined therapy with linagliptin and metformin resulted in a statistically significant decrease in glycosylated hemoglobin (HbA1c) 2.0% and 2.8%, respectively (the initial value of HbA1c was 9.9% and 9.8%. respectively). The difference in treatment methods -0.8% (95% CI -1.1 to -0.5) demonstrated the advantages of the initial combination therapy with linagliptin and metformin over monotherapy with linagliptin (p <0.0001).

    Pharmacokinetics:

    The pharmacokinetics of linagliptin has been extensively studied when used 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 maximum concentration of linagliptin in plasma (Cmah) was achieved after 1.5 hours.

    The concentration of linagliptin in plasma decreases, at least two-phase.

    The terminal half-life is long, more than 100 hours, which is mainly due to the stable binding of linagliptin to the DPP-4 enzyme, however, since the link is reversible, no accumulation of linagliptin occurs. The effective half-life after repeated administration of linagliptin at a dose of 5 mg is approximately 12 hours.In the case of taking linagliptin at a dose of 5 mg once a day, stable concentrations of linagliptin in plasma are reached after the third dose.

    The pharmacokinetics of linagliptin in healthy volunteers and in patients with type 2 diabetes mellitus was generally similar.

    Suction

    The absolute bioavailability of linagliptin is approximately 30%. The intake of linagliptin along with food containing a large amount of fats does not have a clinically significant effect on pharmacokinetics. In vitro studies have shown that linaglyptin is a substrate for P-glycoprotein and isoenzyme CYP3A4. Ritonavir. As a potential inhibitor of P-glycoprotein and isoenzyme CYP3A4, it can double the AUC value (the area under the concentration-time curve).

    Rifampicin, as a potential inducer of the P-glycoprotein and isoenzyme CYP3A4, can reduce the AUC value during the equilibrium state of pharmacokinetics.

    Distribution

    The volume of distribution after a single intravenous injection of linagliptin at a dose of 5 mg to healthy volunteers is approximately 1110 liters, indicating an intensive distribution in tissues. The binding of linagliptin to plasma proteins depends on its concentration and is about 99% at a concentration of 1 nmol / L, and at a concentration of more than 30 nmol / l it is 75-89%which reflects the saturation of binding of linagliptin with DPP-4 as its concentration increases. At a high concentration, when full saturation of DPP-4 occurs, 70-80% of linagliptin binds to other plasma proteins (not with DPP-4), and 30-20% of linagliptin is in plasma in an unbound state.

    Metabolism

    Approximately 5% of linagliptin is excreted by the kidneys. An insignificant part of linagliptin is metabolized. Metabolism plays a secondary role in the induction of linagliptin. One major metabolite of linagliptin is known, which does not possess pharmacological activity.

    Excretion

    The primary way of excretion is through the intestine. 4 days after the oral administration of the labeled linagliptin [14C] in healthy volunteers, approximately 85% of the dose (through the intestine 80% and kidneys 5%) was excreted with the clearance of creatinine, approximately 70 ml / min.

    Indications:

    Diabetes mellitus type 2:

    - as monotherapy - in patients with inadequate control of glycemia only against the background of diet and exercise, with intolerance to metformin or in contraindication to its use due to renal failure;

    - as a two-component combination therapy with metformin, sulfonylurea derivatives or thiazolidinedione in the case of dietary inefficiency,physical exercises and monotherapy with these drugs;

    - as a three-component combination therapy with metformin and sulfonylurea derivatives in the case of ineffectiveness of diet therapy, exercise and combined therapy with these drugs;

    - as a two-component combination therapy with insulin or multicomponent therapy with insulin and metformin and / or pioglitazone and / or sulfonylurea derivatives in the case of ineffectiveness of diet therapy, exercise and combination therapy with these drugs.

    Contraindications:

    - Hypersensitivity to any component of the drug;

    - Type 1 diabetes mellitus;

    - Diabetic ketoacidosis;

    - Pregnancy and the period of breastfeeding;

    - Children under 18 years.

    Pregnancy and lactation:The use of linagliptin during pregnancy is contraindicated. The use of linagliptin during breastfeeding is contraindicated. Data obtained in pre-clinical studies in animals indicate the penetration of linagliptin and its metabolite into breast milk. The risk of exposure to newborns and infants during breastfeeding is not ruled out.If it is necessary to use linagliptin during breastfeeding, breast-feeding should be discontinued.
    Dosing and Administration:

    The recommended dose is 5 mg (1 tablet) 1 time per day, inside.

    A TRAITER can be taken regardless of meals at any time of the day.

    Actions when missing one or more doses of the drug:

    If a dose is missed, the patient should take the drug as soon as he remembers it. Do not take a double dose in one day.

    Side effects:

    The incidence of side effects with 5 mg of linagliptin was similar to that of placebo.

    The discontinuation of therapy due to adverse events was higher in the group of patients treated with placebo (4.4%) than in the group, who received linaglyptin in a dose of 5 mg (3.5%).

    With monotherapy with linaglyptin the following side effects were observed:

    Impaired immune system: hypersensitivity.

    Disturbances from the respiratory system, the organs of the difficult cell and mediastinum: cough.

    Disorders from the gastrointestinal tract: pancreatitis.

    Infectious and parasitic diseases: nasopharyngitis.

    When using linagliptin with metformin:

    Impaired immune system: hypersensitivity.

    Disturbances from the respiratory system, chest and mediastinum: cough.

    Disorders from the gastrointestinal tract: pancreatitis.

    Infectious and parasitic diseases: nasopharyngitis.

    When using linagliptin with sulfonylurea derivatives:

    Impaired immune system: hypersensitivity.

    Disorders from the metabolism and Pgt; hypertriglyceridemia.

    Disturbances from the respiratory system, chest organs and mediastinum: cough.

    Disorders from the gastrointestinal tract: pancreatitis.

    Infectious and parasitic diseases: nasopharyngitis.

    When using linagliptin with pioglitazone:

    Impaired immune system: hypersensitivity.

    Disorders from the metabolism and nutrition: hyperlipidemia.

    Disturbances from the respiratory system, chest and mediastinum: cough.

    Disorders from the gastrointestinal tract: pancreatitis.

    Infectious and parasitic diseases: nasopharyngitis

    Other: weight gain.

    When using linagliptin with insulin:

    Impaired immune system: hypersensitivity.

    Disturbances from the respiratory system, chest and mediastinum: cough.

    Disorders from the gastrointestinal tract: pancreatitis, constipation.

    Infectious and parasitic diseases: nasopharyngitis.

    When using linagliptin with metformin and derivatives sulfonylureas:

    Impaired immune system: hypersensitivity.

    Disorders from the metabolism and Pgt; hypoglycemia.

    Disturbances from the respiratory system, chest and mediastinum: cough.

    Disorders from the gastrointestinal tract: pancreatitis.

    Infectious and parasitic diseases: nasopharyngitis.

    When using linagliptin with metformin and pioglitazone:

    Impaired immune system: hypersensitivity.

    Disorders from the metabolism and nutrition: hyperlipidemia.

    Disturbances from the respiratory system, chest and mediastinum: cough.

    Disorders from the gastrointestinal tract: pancreatitis.

    Infectious and parasitic diseases: nasopharyngitis

    Other: weight gain.

    Postmarketing experience of application:

    Impaired immune system: angioedema, urticaria. Disorders from the gastrointestinal tract: ulceration of the oral mucosa.

    Impaired skin and subcutaneous tissue: rash.

    Overdose:

    During controlled clinical trials in healthy of the volunteers, single doses of linagliptin, reaching 600 mg (120 times the recommended dose), were tolerated well. The experience of dose application, exceeding 600 mg, no.

    In case of an overdose, it is recommended to use the usual measures of the supporting character, for example, removing a nonabsorbed preparation from the gastrointestinal tract, clinical control and symptomatic treatment.

    Interaction:

    Evaluation of drug interactions in vitro

    Linagliptin is a weak, competitive inhibitor of isoenzyme CYP3A4. Linaglyptin does not inhibit other isoenzymes CYP and is not their inductor. Linaglyptin is a substrate for P-glycoprotein (P-gp) and inhibits, to a small extent, the P-glycoprotein-mediated digoxin transport.

    Evaluation of drug interactions in vivo

    Linagliptin has no clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, and oral contraceptives, which is proved in conditions 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 (repeated daily dose intake of 850 mg 3 times a day) and linagliptin 10 mg once daily (above the therapeutic dose) in healthy volunteers did not lead to clinically significant changes in the pharmacokinetics of linagliptin or metformin. In this way, linaglyptin It is not an inhibitor of the transport of organic cations.

    Derivatives of sulfonylureas. The pharmacokinetics of linagliptin (5 mg) did not change when combined with glibenclamide (a single dose of glyburide 1.75 mg) and repeated intake of linagliptin by mouth (5 mg each): However, clinically, a slight decrease in the values AUC and CmOh glibenclamide by 14%. Because the glibenclamide is metabolized mainly by COR2C9, these data also support the conclusion that linaglyptin is not an inhibitor CYP2C9. Not expected clinically significant interactions with other derivatives of sulfonylurea (for example, glipizide and glimepiride), which, like glibenclamide, are mainly metabolized with participation CYP2C9. ,

    Thiazolidinediones. Joint use of several doses of linagliptin at 10 mg per day (above the therapeutic dose) and pioglitazone by, 45 mg per day (multiple administration); which is substratum for C YP2C8, and CYP3A4, had no clinically significant effect on the pharmacokinetics of linagliptin or pioglitazone, or active metabolites of pioglitazone. This indicates that linaglyptin in vivo is not an inhibitor of metabolism, mediated CYP2C8, and confirms the conclusion that there is no significant inhibitory effect of linagliptin in vivo on CYP3A4. Ritonavir. The combined use of linagliptin (a single dose of 5 mg orally) and ritonavir (multiple doses of 200 mg orally), active P-glycoprotein inhibitor (P-gp) and isoenzyme CYP3A4, magnified, values AUC and CmOh linagliptin, approximately, 2 times, and 3 times, respectively. However, these changes pharmacokinetics of linagliptin were not considered significant. Therefore, clinically significant interactions with other P-glycoprotein inhibitors and CYP3A4 is not expected, and dose changes are not required.

    Rifampicin. Multiple combined use of linagliptin and rifampicin, the active inducer of P-glycoprotein and isoenzyme CYP3A4, led to a decrease in AUC and CmOh ligagiptin, respectively, by 39.6% and 43.8%, 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, used in combination with active inducers of P-glycoprotein will persist, although it may not manifest itself in full.

    Digoxin. Joint repeated use in healthy volunteers of linagliptin (5 mg per day) and digoxin (0.25 mg per day) had no effect on the pharmacokinetics of digoxin. In this way, linaglyptin in vivo is not an inhibitor of transport mediated by P-glycoprotein.

    Warfarin. Linaglyptin, used repeatedly in a dose of 5 mg per day, did not alter the pharmacokinetics of warfarin, which is a substrate for CYP2C9, which indicates that linagliptin has no ability to inhibit CYP2C9.

    Simvastatin. Linaglyptin, used in healthy volunteers many times - in dose of 10 mg per day (above the therapeutic dose) had minimal effect on the pharmacokinetic parameters of simvastatin, which is a sensitive substrate for CYP3A4. After taking lignagliptin in a dose of 10 mg together with simvastatin, used in a daily dose of 40 mg for 6 days, the value AUC Simvastatin increased by 34%, and the value of CmOh - on 10%. In this way, linaglyptin is a weak inhibitor of metabolism, mediated CYP3A4. Dose changes when taken concomitantly with drugs that are metabolized with participation CYP3A4, is considered impractical.

    Oral contraceptive preparations. The combined use of linagliptin in a dose of 5 mg with levonorgestrel or ethinyl estradiol did not alter the pharmacokinetics of these drugs.

    Special instructions:

    The drug TRAGENT is contraindicated in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

    Hypoglycaemia

    The incidence of hypoglycemia in the case of monotherapy with linagliptin was comparable to placebo.

    In clinical studies, it has been reported that the incidence of hypoglycemia in the case of linagliptin in combination with drugs that are not believed to cause hypoglycemiametformin, thiazolidinedione derivatives), was similar to the corresponding placebo effect.

    Derivatives of sulfonylureas are known to cause hypoglycemia. Therefore, when using linagliptin in combination with sulfonylurea derivatives, care should be taken. If necessary, it is possible to reduce the dose of sulfonylurea derivatives.

    The use of linagliptin does not increase the risk of developing cardiovascular diseases. Linaglyptin in combination therapy with other oral hypoglycemic drugs was used in patients with severe renal failure. Linaglyptin provided a significant reduction in the concentration of glycosylated hemoglobin and fasting glucose concentration. Dose adjustments for patients with impaired renal, hepatic and elderly patients are not required. The use of linagliptin in patients older than 70 years The use of linagliptin resulted in a significant decrease in glycosylated hemoglobin A (HbAlc) (by 0.64% by compared with placebo; baseline HbA1c was about 7.8%). Application linagliptin also led to a significant reduction in fasting plasma glucose (GPN).

    Cardiovascular risk

    Treatment with linagliptin does not lead to an increase in cardiovascular risk. The primary endpoint (a combination of incidence or time that occurred before the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization due to unstable angina) was achieved in patients who received linaglyptin, significantly less than in the combined group of patients receiving active comparators and placebo (relative risk 0.34, 95% confidence interval 0.17, 0.70).

    Postmarketing experience of application:

    In patients receiving linaglyptin, cases of acute pancreatitis were documented. In case of suspicion of pancreatitis, the drug should be withdrawn.
    Effect on the ability to drive transp. cf. and fur:Studies of the effect of the drug on the ability to drive vehicles and mechanisms have not been conducted.However, in connection with the possible development of dizziness, care must be taken when driving vehicles and mechanisms.
    Form release / dosage:Film coated tablets 5 mg.
    Packaging:

    7 tablets per blister from Al/Al. For 2, 4 or 8 blisters together with instructions for use in a cardboard box.

    10 tablets per blister. For 3 blisters together with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years

    Do not take the drug after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001430
    Date of registration:12.01.2012 / 30.04.2013
    Expiration Date:12.01.2017
    The owner of the registration certificate:Boehringer Ingelheim International GmbHBoehringer Ingelheim International GmbH Germany
    Manufacturer: & nbsp
    Representation: & nbspBehringer Ingelheim, LLCBehringer Ingelheim, LLC
    Information update date: & nbsp24.06.2016
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