Trajenta^® (Tablets) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

West-Ward Columbus, Inc. (USA)

Or

Dragenopharm Apotheker Pueschl, GmbH (Germany)

ATC Code

A10BH05 (Linagliptin)

Active Substance

Linagliptin (Rec.INN registered by WHO)

Dosage Form

Trajenta®

Film-coated tablets, 5 mg: 14, 28, 30, or 56 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets light red in color, round, biconvex, with beveled edges, engraved with the company symbol on one side and engraved with “D5” on the other side.

Excipients: mannitol – 130.9 mg, pregelatinized starch – 18 mg, corn starch – 18 mg, copovidone – 5.4 mg, magnesium stearate – 2.7 mg.

Film coating composition Opadry^® pink (02F34337) – 5 mg (hypromellose 2910 – 2.5 mg, titanium dioxide (E171) – 1.25 mg, talc – 0.875 mg, macrogol 6000 – 0.25 mg, iron oxide red dye (E172) – 0.125 mg).

7 pcs. – blisters (2) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.
7 pcs. – blisters (8) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Hypoglycemic drug – dipeptidyl peptidase-4 inhibitor

Pharmacotherapeutic Group

Drugs for the treatment of diabetes mellitus; hypoglycemic drugs, other than insulins; dipeptidyl peptidase-4 (DPP-4) inhibitors

Pharmacological Action

Linagliptin is an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, which is involved in the inactivation of the incretin hormones – glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are rapidly degraded by the DPP-4 enzyme. Both of these incretins are involved in maintaining blood glucose at physiological levels. Basal concentrations of GLP-1 and GIP are low throughout the day but increase rapidly in response to food intake. GLP-1 and GIP enhance insulin biosynthesis and its secretion by pancreatic β-cells at normal or elevated blood glucose concentrations. In addition, GLP-1 reduces glucagon secretion by pancreatic α-cells, leading to decreased glucose production in the liver. Linagliptin actively binds to the DPP-4 enzyme (reversible binding), causing a sustained increase in incretin concentrations and prolonged preservation of their activity. The drug Trajenta^® increases glucose-dependent insulin secretion and reduces glucagon secretion, leading to normalization of blood glucose levels. Linagliptin selectively binds to the DPP-4 enzyme and has 10,000 times greater selectivity for DPP-4 compared to dipeptidyl peptidase-8 or dipeptidyl peptidase-9 enzymes in vitro.

In clinical studies where Linagliptin was used as monotherapy, combination therapy with metformin, combination therapy with sulfonylurea drugs, combination therapy with insulin, combination therapy with metformin and sulfonylurea drugs, combination therapy with pioglitazone, combination therapy with metformin and pioglitazone, and combination therapy with metformin compared to glimepiride, a statistically significant reduction in glycated hemoglobin (HbA_1c) and a decrease in fasting plasma glucose (FPG) levels were demonstrated.

Use of linagliptin in patients with severe renal impairment receiving adequate baseline hypoglycemic therapy

In clinical studies where Linagliptin was used in addition to baseline hypoglycemic therapy (including insulin, sulfonylureas, glinides, and pioglitazone), a statistically significant reduction in HbA_1c was demonstrated (by 0.59% compared to placebo; baseline HbA_1c was approximately 8.2%).

Use of linagliptin monotherapy and initial combination therapy with linagliptin and metformin in patients with newly diagnosed type 2 diabetes (with marked hyperglycemia)

Clinical studies have demonstrated that both linagliptin monotherapy and combination therapy with linagliptin and metformin led to a statistically significant reduction in HbA_1c of 2.0% and 2.8%, respectively (baseline HbA_1c was 9.9% and 9.8%, respectively). The treatment difference of -0.8% (95% CI from -1.1 to -0.5) demonstrated the benefits of initial combination therapy with linagliptin and metformin over linagliptin monotherapy (p<0.0001).

Use of linagliptin in combination with metformin and empagliflozin

In clinical studies where Linagliptin was used in addition to hypoglycemic therapy with a combination of metformin and empagliflozin (at doses of 10 mg and 25 mg), a clinically significant reduction in HbA_1c was demonstrated (by 0.97% for 10 mg empagliflozin and 1.16% for 25 mg empagliflozin, respectively, compared to placebo; baseline HbA_1c was 8.5% and above).

Pharmacokinetics

The pharmacokinetics of linagliptin have been comprehensively studied in healthy volunteers and in patients with type 2 diabetes (T2D). In healthy volunteers, after taking linagliptin at a dose of 5 mg, it was rapidly absorbed, with the C_max of linagliptin in plasma reached within 1.5 hours.

The plasma concentration of linagliptin decreases in a triphasic manner. The terminal T_1/2 is long, more than 100 hours, which is mainly due to the stable binding of linagliptin to the DPP-4 enzyme; however, since the binding is reversible, accumulation of linagliptin does not occur. The effective T_1/2 after multiple doses of linagliptin 5 mg is approximately 12 hours. When linagliptin is administered at a dose of 5 mg once daily, steady-state plasma concentrations of linagliptin are achieved after the 3rd dose.

The pharmacokinetics of linagliptin in healthy volunteers and in patients with T2D were generally similar.

Absorption

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 (Pgp) and the CYP3A4 isoenzyme. Ritonavir, as a potential inhibitor of Pgp and the CYP3A4 isoenzyme, may double the AUC value. Rifampicin, as a potential inducer of Pgp and the CYP3A4 isoenzyme, may reduce the AUC value at pharmacokinetic steady state.

Distribution

The V_d after a single intravenous administration of linagliptin 5 mg to healthy volunteers is approximately 1110 L, indicating extensive distribution into tissues. The binding of linagliptin to plasma proteins is concentration-dependent and is about 99% at a concentration of 1 nmol/L, and 75-89% at concentrations above 30 nmol/L, reflecting saturation of linagliptin binding 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 20-30% of linagliptin is in an unbound state in plasma.

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. One main metabolite of linagliptin is known, which does not possess pharmacological activity.

Excretion

The predominant route of elimination is via the intestine. Four days after oral administration of labeled linagliptin [¹⁴C] to healthy volunteers, approximately 85% of the dose was excreted (80% via the intestine and 5% via the kidneys) with a CrCl of approximately 70 ml/min.

Pharmacokinetics in special patient groups

Renal impairment. In patients with mild renal impairment (CrCl from 50 to <80 ml/min), exposure to linagliptin at steady state was comparable to exposure in healthy subjects. In moderate renal impairment (CrCl from 30 to <50 ml/min), a slight increase in exposure was observed (approximately 1.7 times compared to healthy subjects). Exposure to linagliptin in patients with T2D and severe renal impairment (CrCl <30 ml/min) was increased approximately 1.4 times compared to patients with diabetes and normal renal function. Modeling of linagliptin AUC values in patients with end-stage renal disease showed that exposure in these cases is comparable to exposure in patients with moderate or severe renal impairment. Hemodialysis or peritoneal dialysis is not expected to achieve clinically significant elimination of linagliptin. Therefore, no dose adjustment of linagliptin is required in patients with any degree of renal impairment.

Hepatic impairment. In patients with mild, moderate, and severe hepatic impairment (according to Child-Pugh classification), the mean AUC and C_max values of linagliptin after its multiple administration at a dose of 5 mg were similar to the corresponding values in comparable healthy subjects. No dose adjustment of linagliptin is required in patients with mild, moderate, or severe hepatic impairment.

BMI. No dose adjustment of linagliptin based on BMI is required.

Gender. No dose adjustment of linagliptin based on gender is required.

Elderly patients. No dose adjustment of linagliptin based on age is required, as age did not have a clinically significant effect on the pharmacokinetics of linagliptin according to a population pharmacokinetic analysis conducted in clinical studies. Plasma concentrations of linagliptin were comparable in both elderly patients (age 65-80 years) and younger patients.

Children. The pharmacokinetics of linagliptin in children has not been studied.

Race. No dose adjustment of linagliptin based on race is required. Race did not have a significant effect on plasma concentrations of linagliptin according to a combined analysis of pharmacokinetic data obtained in Caucasian, African American, and patients of Latino and Asian origin. Furthermore, similarity of the pharmacokinetic characteristics of linagliptin was established in special studies conducted in healthy Caucasian volunteers and residents of Japan and China, as well as in African American patients with T2D.

Indications

For the treatment of type 2 diabetes in adult patients as an adjunct to diet and exercise to improve glycemic control as

• Monotherapy, in case of intolerance to metformin or contraindication to its use due to renal impairment;
• Combination therapy with other hypoglycemic drugs, including insulin, in case adequate glycemic control is not achieved with therapy with these drugs.

ICD codes

Dosage Regimen

Take orally. The recommended dose is 5 mg (1 tablet) once daily. 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 sulfonylureas and/or insulin, it may be possible to reduce the dose of sulfonylureas or insulin to reduce the risk of hypoglycemia.

The drug Trajenta^® can be taken regardless of meals at any time of the day.

Actions in case of missing one or more doses of the drug: if a dose is missed, the patient should take the drug as soon as they remember. A double dose should not be taken on the same day.

Special patient groups

For patients with renal impairment, no dose adjustment of linagliptin is required.

For patients with impaired liver function, no dose adjustment of linagliptin is required; however, clinical experience in such patients is insufficient.

For elderly patients, no dose adjustment is required. However, clinical experience in patients over 80 years of age is limited, so treatment of these patient groups should be carried out with caution.

For children and adolescents under 18 years of age, the use of the drug is contraindicated due to lack of data on efficacy and safety.

Adverse Reactions

In a pooled analysis of placebo-controlled studies, the incidence of adverse events with linagliptin 5 mg was similar to the incidence of adverse events with placebo.

Discontinuation of therapy due to adverse events was higher in the group of patients receiving placebo (4.3%) than in the group receiving Linagliptin at a dose of 5 mg (3.4%). The most frequently occurring adverse event was hypoglycemia: in the case of using a triple drug combination (Linagliptin + metformin + sulfonylurea), it was observed in 22.9% of patients, while with placebo it was observed in 14.8% of patients.

Adverse reactions (ARs) observed in patients receiving Linagliptin as monotherapy and combination therapy with other hypoglycemic agents in placebo-controlled studies, as well as based on post-marketing surveillance results, are presented in the table below (ARs are classified by organ system and according to MedDRA preferred terms) with their absolute frequency.

Frequency categories are defined as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000) or very rare (<1/10000); ARs with unknown frequency (cannot be estimated from the available data) are also highlighted.

Table. Adverse reactions observed in patients receiving Linagliptin 5 mg as once-daily monotherapy or in combination therapy in clinical studies and during post-marketing use

* based on post-marketing surveillance

** based on data on lipase elevation more than 3 times the upper limit of normal obtained in clinical studies

^#based on data obtained in the CARMELINA clinical trial

¹ARs observed when used in combination with metformin and a sulfonylurea

² ARs observed when used in combination with insulin

Contraindications

• Hypersensitivity to linagliptin and/or to any of the excipients of the drug;
• Type 1 diabetes mellitus;
• Diabetic ketoacidosis;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (due to lack of data on the efficacy and safety of linagliptin use in children and adolescents under 18 years of age).

With caution

• History of pancreatitis;
• Patients over 80 years of age;
• Use in combination with sulfonylureas and/or insulin.

Use in Pregnancy and Lactation

The use of linagliptin during pregnancy is contraindicated. The use of linagliptin during breastfeeding is contraindicated.

Data obtained from preclinical animal studies indicate the excretion of linagliptin and its metabolite into breast milk. A risk to newborns and infants during breastfeeding cannot be excluded.

If it is necessary to use linagliptin during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

No dose adjustment is required when using the drug in patients with impaired liver function.

Use in Renal Impairment

No dose adjustment is required when using the drug in patients with impaired renal function.

Pediatric Use

The use of the drug in children and adolescents under 18 years of age is contraindicated.

Geriatric Use

No dose adjustment is required when using the drug in elderly patients.

The drug should be prescribed with caution to patients over 80 years of age.

Special Precautions

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

Hypoglycemia

The incidence of hypoglycemia when using linagliptin as monotherapy was comparable to placebo.

Clinical studies reported that the incidence of hypoglycemia when using linagliptin in combination with drugs not thought to cause hypoglycemia (metformin, thiazolidinediones) was similar to the corresponding effect of placebo.

Sulfonylureas and insulin are known to cause hypoglycemia. Therefore, caution should be exercised when using linagliptin in combination with sulfonylureas and/or insulin. If necessary, it may be possible to reduce the dose of sulfonylureas or insulin.

Renal Impairment

Linagliptin in combination therapy with other oral hypoglycemic agents was used in patients with severe renal failure.

Linagliptin provided a significant reduction in HbA_1c and FPG concentrations.

No dose adjustment is required when used in patients with renal or hepatic impairment, or in elderly patients.

Use of Linagliptin in Patients Over 70 Years of Age

Use of linagliptin led to a significant reduction in HbA_1c (by 0.64% compared to placebo; baseline HbA_1c was approximately 7.8%). Use of linagliptin also led to a substantial decrease in FPG levels. However, clinical experience in patients over 80 years of age is limited, so treatment of such patient groups should be conducted with caution.

Cardiovascular Risk

Treatment with linagliptin does not lead to an increase in cardiovascular risk. In the CARMELINA trial, a large placebo-controlled cardiovascular outcomes study in patients with type 2 diabetes and high cardiovascular risk, the primary endpoint (a composite of the incidence or time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) was achieved in patients receiving Linagliptin without an increased risk compared to patients receiving placebo (HR 1.02; 95% CI 0.89; 1.17).

Pancreatitis

Cases of acute pancreatitis have been reported in patients taking Linagliptin. If pancreatitis is suspected, use of the drug should be discontinued.

Bullous Pemphigoid

Cases of bullous pemphigoid have been reported in patients taking Linagliptin. If bullous pemphigoid is suspected, the drug should be discontinued.

Effect on Ability to Drive and Operate Machinery

No studies on the effect of the drug on the ability to drive and operate machinery have been conducted. However, due to the potential development of hypoglycemia (which may manifest as headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, rapid heartbeat, sweating, panic attacks), especially when linagliptin is taken in combination with a sulfonylurea derivative and/or insulin, caution should be exercised when driving and operating machinery.

Overdose

During controlled clinical trials in healthy volunteers, single doses of linagliptin up to 600 mg (120 times the recommended dose) were well tolerated. There is no experience with linagliptin at doses exceeding 600 mg.

Treatment in case of overdose, standard supportive measures are recommended, such as removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring, and symptomatic treatment.

Drug Interactions

In vitro Drug Interaction Assessment

Linagliptin is a weak competitive inhibitor of the CYP3A4 isoenzyme. Linagliptin does not inhibit other CYP isoenzymes and is not an inducer of them.

Linagliptin is a substrate for P-gp and weakly inhibits P-gp-mediated transport of digoxin.

In vivo Drug Interaction Assessment

Linagliptin has no clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, and oral contraceptive drugs, as proven in in vivo conditions, and is based on the low potential of linagliptin to cause drug interactions with substrates for CYP3A4, CYP2C9, CYP2C8, P-gp, and organic cation transporter molecules.

Metformin. Concomitant administration of metformin (multiple daily doses of 850 mg 3 times/day) and linagliptin at a dose of 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. Thus, Linagliptin is not an inhibitor of organic cation transport.

Sulfonylurea Derivatives. The pharmacokinetics of linagliptin (5 mg) were not altered when co-administered with glibenclamide (a single dose of glibenclamide 1.75 mg) and multiple oral doses of linagliptin (5 mg each). However, a clinically insignificant decrease in glibenclamide AUC and C_max values of 14% was noted. Since glibenclamide is metabolized primarily by CYP2C9, these data also support the conclusion that Linagliptin is not an inhibitor of CYP2C9. No clinically significant interaction is expected with other sulfonylurea derivatives (e.g., glipizide and glimepiride), which, like glibenclamide, are primarily metabolized by CYP2C9.

Thiazolidinediones. Concomitant 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, had no 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 confirms the conclusion that linagliptin has no significant inhibitory effect in vivo on CYP3A4.

Ritonavir. Concomitant administration of linagliptin (single 5 mg oral dose) and ritonavir (multiple 200 mg oral doses), a potent inhibitor of P-gp and the CYP3A4 isoenzyme, increased linagliptin AUC and C_max values approximately 2-fold and 3-fold, respectively. However, these changes in linagliptin pharmacokinetics were not considered significant. Therefore, no clinically significant interaction with other P-gp and CYP3A4 inhibitors is expected, and no dose adjustment is required.

Rifampicin. Multiple concomitant administration of linagliptin and rifampicin, a potent inducer of P-gp and the CYP3A4 isoenzyme, resulted in a decrease in linagliptin AUC and C_max values by 39.6% and 43.8%, respectively, and a decrease in inhibition of basal DPP-4 activity by approximately 30%. Thus, the clinical efficacy of linagliptin used in combination with potent P-gp inducers is expected to be maintained, although it may not be fully manifested.

Digoxin. Multiple concomitant administration in healthy volunteers of linagliptin (5 mg/day) and digoxin (0.25 mg/day) had no effect on the pharmacokinetics of digoxin. Thus, Linagliptin in vivo is not an inhibitor of P-gp-mediated transport.

Warfarin. Linagliptin, administered multiple times at a dose of 5 mg/day, did not alter 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 multiple times at a dose of 10 mg/day (above the therapeutic dose), had a minimal effect on the pharmacokinetic parameters of simvastatin, which is a sensitive substrate for CYP3A4. After administration of linagliptin 10 mg concomitantly with simvastatin, administered at a daily dose of 40 mg for 6 days, the AUC of simvastatin increased by 34%, and the C_max by 10%. Thus, Linagliptin is a weak inhibitor of CYP3A4-mediated metabolism. Dose adjustment when co-administered with drugs that are metabolized by CYP3A4 is considered unnecessary.

Oral Contraceptive Drugs. Concomitant administration of linagliptin at a dose of 5 mg with levonorgestrel or ethinylestradiol did not alter the pharmacokinetics of these drugs.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.