Krijenta

Dark brown coloured circular biconvex film-coated plain on both the sides.
Each film-coated tablet contains: Linagliptin 5 mg.
Excipients/Inactive Ingredients: q.s.
Colour: Red Oxide of Iron, Titanium Dioxide BP.

Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors. ATC code: A10BH05.
Pharmacology: Pharmacodynamics: Mechanism of action: Linagliptin is an inhibitor of the enzyme DPP-4 (dipeptidyl peptidase 4, EC 3.4.14.5) an enzyme which is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide1, glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by the enzyme DPP-4. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretins are secreted at a low basal level throughout the day and levels rise immediately after meal intake.
GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Linagliptin binds very effectively to DPP-4 in a reversible manner and thus leads to a sustained increase and a prolongation of active incretin levels. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in an overall improvement in the glucose homeostasis. Linagliptin binds selectively to DPP-4 and exhibits a >10,000 fold selectivity versus DPP-8 or DPP-9 activity in vitro.
Pharmacokinetics: Absorption: The absolute bioavailability of linagliptin is approximately 30%. Co-administration of a high-fat meal with linagliptin prolonged the time to reach C_max by 2 hours and lowered C_max by 15% but no influence on AUC_0-72h was observed. No clinically relevant effect of C_max and T_max changes is expected; therefore linagliptin may be administered with or without food.
Distribution: As a result of tissue binding, the mean apparent volume of distribution at steady-state following a single 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1,110 litres, indicating that linagliptin extensively distributes to the tissues.
Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/l to 75-89% at ≥30 nmol/l, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70-80% of linagliptin was bound to other plasma proteins than DPP-4, hence 30-20% were unbound in plasma.
Biotransformation: Following a [¹⁴C] linagliptin oral 10 mg dose, approximately 5% of the radioactivity was excreted in urine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite with a relative exposure of 13.3% of linagliptin at steady-state was detected which was found to be pharmacologically inactive and thus does not contribute to the plasma DPP-4 inhibitory activity of linagliptin.
Excretion: Following administration of an oral [¹⁴C] linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated in faeces (80%) or urine (5%) within 4 days of dosing.
Renal clearance at steady-state was approximately 70 ml/min.

Linagliptin is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control as: Monotherapy: when metformin is inappropriate due to intolerance, or contraindicated due to renal impairment.
Combination therapy: in combination with other medicinal products for the treatment of diabetes, including insulin, when these do not provide adequate glycaemic control.

Posology: The dose of linagliptin is 5 mg once daily. When linagliptin is added to metformin, the dose of metformin should be maintained, and linagliptin administered concomitantly.
When linagliptin is used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin, may be considered to reduce the risk of hypoglycaemia.
Special populations: Renal impairment: For patients with renal impairment, no dose adjustment for linagliptin is required.
Hepatic impairment: Pharmacokinetic studies suggest that no dose adjustment is required for patients with hepatic impairment but clinical experience in such patients is lacking.
Elderly: No dose adjustment is necessary based on age.
However, clinical experience in patients >80 years of age is limited and caution should be exercised when treating this population.
Paediatric population: The safety and efficacy of linagliptin in children and adolescents has not yet been established. No data are available.
Mode of Administration: Oral.

Symptoms: During controlled clinical trials in healthy subjects, single doses of up to 600 mg linagliptin (equivalent to 120 times the recommended dose) were generally well tolerated. There is no experience with doses above 600 mg in humans.
Therapy: In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring and institute clinical measures if required.

Hypersensitivity to the active substance or to any of the excipients listed.

General: Linagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Hypoglycaemia: Linagliptin alone showed a comparable incidence of hypoglycaemia to placebo.
In clinical trials of linagliptin as part of combination therapy with medicinal products not known to cause hypoglycaemia (metformin), rates of hypoglycaemia reported with linagliptin were similar to rates in patients taking placebo.
When linagliptin was added to a sulphonylurea (on a background of metformin), the incidence of hypoglycaemia was increased over that of placebo.
Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised when linagliptin is used in combination with a sulphonylurea and/or insulin. A dose reduction of the sulphonylurea or insulin may be considered.
Acute pancreatitis: Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. In post-marketing experience of linagliptin there have been spontaneously reported adverse reactions of acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, linagliptin should be discontinued; if acute pancreatitis is confirmed, linagliptin should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Bullous pemphigoid: There have been post-marketing reports of bullous pemphigoid in patients taking linagliptin. If bullous pemphigoid is suspected, linagliptin should be discontinued.

Pregnancy: The use of linagliptin has not been studied in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of linagliptin during pregnancy.
Breast-feeding: Available pharmacokinetic data in animals have shown excretion of linagliptin/metabolites in milk. A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from linagliptin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Adverse reactions reported in patients who received linagliptin 5 mg daily as monotherapy or as add-on therapies (frequencies identified from pooled analysis of placebo-controlled studies) in clinical trial and from post-marketing experience. (See table.)

Click on icon to see table/diagram/image

In vitro assessment of interactions: Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4 but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes.
Linagliptin is a P-glycoprotein substrate and inhibits P-glycoprotein mediated transport of digoxin with low potency. Based on these results and in vivo interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates.
In vivo assessment of interactions: Effects of other medicinal products on linagliptin: Clinical data described as follows suggest that the risk for clinically meaningful interactions by co-administered medicinal products is low.
Rifampicin: Multiple co-administration of 5 mg linagliptin with rifampicin, a potent inductor of P-glycoprotein and CYP3A4, resulted in a 39.6% and 43.8% decreased linagliptin steady-state AUC and C_max, respectively, and about 30% decreased DPP-4 inhibition at trough. Thus, full efficacy of linagliptin in combination with strong P-gp inducers might not be achieved, particularly if these are administered long-term. Co-administration with other potent inducers of P-glycoprotein and CYP3A4, such as carbamazepine, phenobarbital and phenytoin has not been studied.
Ritonavir: Co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, increased the AUC and C_max of linagliptin approximately two-fold and three-fold, respectively. The unbound concentrations, which are usually less than 1% at the therapeutic dose of linagliptin, were increased 4-5-fold after co-administration with ritonavir. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavir indicated that the increase in exposure will be not associated with an increased accumulation. These changes in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, clinically relevant interactions would not be expected with other P-glycoprotein/CYP3A4 inhibitors.
Metformin: Co-administration of multiple three times daily doses of 850 mg metformin with 10 mg linagliptin once daily did not clinical meaningfully alter the pharmacokinetics of linagliptin in healthy volunteers.
Sulphonylureas: The steady-state pharmacokinetics of 5 mg linagliptin was not changed by concomitant administration of a single 1.75 mg dose glibenclamide (glyburide).
Effects of linagliptin on other medicinal products: In clinical studies, as described as follows, linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin or oral contraceptives providing in vivo evidence of a low propensity for causing medicinal product interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cationic transporter (OCT).
Metformin: Co-administration of multiple daily doses of 10 mg linagliptin with 850 mg metformin, an OCT substrate, had no relevant effect on the pharmacokinetics of metformin in healthy volunteers. Therefore, linagliptin is not an inhibitor of OCT-mediated transport.
Sulphonylureas: Co-administration of multiple oral doses of 5 mg linagliptin and a single oral dose of 1.75 mg glibenclamide (glyburide) resulted in clinically not relevant reduction of 14% of both AUC and C_max of glibenclamide. Because glibenclamide is primarily metabolised by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically meaningful interactions would not be expected with other sulphonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glibenclamide, are primarily eliminated by CYP2C9.
Digoxin: Co-administration of multiple daily doses of 5 mg linagliptin with multiple doses of 0.25 mg digoxin had no effect on the pharmacokinetics of digoxin in healthy volunteers. Therefore, linagliptin is not an inhibitor of P-glycoprotein-mediated transport in vivo.
Warfarin: Multiple daily doses of 5 mg linagliptin did not alter the pharmacokinetics of S(-) or R(+) warfarin, a CYP2C9 substrate, administered in a single dose.
Simvastatin: Multiple daily doses of linagliptin had a minimal effect on the steady-state pharmacokinetics of simvastatin, a sensitive CYP3A4 substrate, in healthy volunteers. Following administration of a supratherapeutic dose of 10 mg linagliptin concomitantly with 40 mg of simvastatin daily for 6 days, the plasma AUC of simvastatin was increased by 34%, and the plasma C_max by 10%.
Oral contraceptives: Co-administration with 5 mg linagliptin did not alter the steady-state pharmacokinetics of levonorgestrel or ethinylestradiol.

Store at temperatures not exceeding 30°C.
Shelf Life: 36 months.

Antidiabetic Agents

A10BH05 - linagliptin ; Belongs to the class of dipeptidyl peptidase 4 (DPP-4) inhibitors. Used in the treatment of diabetes.

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