Linagliptin (Tablets) Instructions for Use

ATC Code

A10BH05 (Linagliptin)

Active Substance

Linagliptin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

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

Pharmacological Action

Hypoglycemic agent. Linagliptin is an inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), 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 a physiological level. Basal concentrations of GLP-1 and GIP are low throughout the day and increase 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 glucagon secretion by pancreatic alpha-cells, leading to decreased glucose production in the liver.

Linagliptin actively binds to the DPP-4 enzyme (the binding is reversible), causing a sustained increase in incretin concentrations and prolonged preservation of their activity. It 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.

Pharmacokinetics

The pharmacokinetics of linagliptin have been comprehensively studied in healthy volunteers and in patients with type 2 diabetes mellitus. In healthy volunteers, after taking a 5 mg dose of linagliptin, it was rapidly absorbed, with the plasma C_max of linagliptin 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 taken at a dose of 5 mg once daily, the plasma C_ss of linagliptin is reached after the third dose.

The pharmacokinetics of linagliptin in healthy volunteers and in patients with type 2 diabetes mellitus were 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 its 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 at pharmacokinetic steady state.

The V_d after a single intravenous administration of a 5 mg dose of linagliptin 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 to DPP-4), and 30-20% of linagliptin is in an unbound state in the plasma.

Approximately 5% of linagliptin is excreted by the kidneys. A minor portion of linagliptin is metabolized. Metabolism plays a secondary role in the elimination of linagliptin. One main metabolite of linagliptin is known, which does not possess pharmacological activity.

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

Indications

Type 2 diabetes mellitus: as monotherapy in patients with inadequate glycemic control on diet and exercise alone, in case of intolerance to metformin or contraindication to its use due to renal failure; as dual combination therapy with metformin, sulfonylurea derivatives, or thiazolidinedione in case of ineffectiveness of diet, exercise, and monotherapy with these drugs; as triple combination therapy with metformin and sulfonylurea derivatives in case of ineffectiveness of diet, exercise, and dual combination therapy with these drugs.

ICD codes

Dosage Regimen

Take orally once daily. The recommended dose is 5 mg.

Administer with or without food. Swallow the tablet whole with water; do not split or crush.

Use as monotherapy when diet and exercise alone provide inadequate glycemic control and metformin is not tolerated or is contraindicated.

For dual combination therapy, use with metformin, a sulfonylurea derivative, or a thiazolidinedione when monotherapy with these agents is insufficient.

For triple combination therapy, use with metformin and a sulfonylurea derivative when dual therapy is ineffective.

No dose adjustment is required for patients with impaired renal function or impaired hepatic function.

No dose adjustment is required for elderly patients.

Exercise caution when co-administering with a sulfonylurea derivative; a dose reduction of the sulfonylurea may be necessary to mitigate the risk of hypoglycemia.

Adverse Reactions

Metabolism and nutrition disorders in combination with sulfonylurea derivatives – hypertriglyceridemia; in combination with pioglitazone – weight gain.

Respiratory, thoracic and mediastinal disorders cough.

Gastrointestinal disorders pancreatitis.

Infections and infestations nasopharyngitis.

Immune system disorders hypersensitivity.

Contraindications

Type 1 diabetes mellitus; diabetic ketoacidosis; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to linagliptin.

Use in Pregnancy and Lactation

The use of linagliptin during pregnancy and breastfeeding is contraindicated.

Special Precautions

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

Clinical studies have reported that the incidence of hypoglycemia when linagliptin was used in combination with drugs not considered to cause hypoglycemia (metformin, thiazolidinedione derivatives) was similar to the corresponding placebo effect.

Sulfonylurea derivatives are known to cause hypoglycemia. Therefore, caution should be exercised when using linagliptin in combination with sulfonylurea derivatives. If necessary, a dose reduction of the sulfonylurea derivative may be considered.

No specific clinical studies have been conducted on the use of linagliptin in combination with insulin.

Linagliptin in combination therapy with other oral hypoglycemic drugs has been used in patients with severe renal failure.

Linagliptin provided a significant reduction in glycated hemoglobin concentration and fasting plasma glucose concentration.

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

Effect on ability to drive vehicles and operate machinery

Due to the possible development of dizziness while taking linagliptin, patients should exercise caution when driving vehicles and operating machinery.

Drug Interactions

Linagliptin is a substrate for P-glycoprotein and slightly inhibits P-glycoprotein-mediated transport of digoxin.

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

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 substrate of CYP3A4. After taking 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 inappropriate.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.