COMPOSITION AND EXCIPIENTS
Each film coated tablet contains 5 mg linagliptin.
Mannitol, Pregelatinised starch, Starch, Copovidone, Magnesium Stearate, Hypromellose, Titanium Dioxide, Talc, Macrogol.
MECHANISM OF ACTION
Linagliptin is an inhibitor of the enzyme DPP-4 (dipeptidyl peptidase 4) an enzyme which is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1,glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by the enzyme DPP-4.
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.
The pharmacokinetics of linagliptin has been extensively characterised in healthy subjects and patients with type 2 diabetes. After oral administration of a 5 mg dose to healthy volunteers or patients, linagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hours post-dose. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg linagliptin, is approximately 12 hours. After once daily dosing of 5 mg linagliptin, steady-state plasma concentrations are reached by the third dose. The pharmacokinetics of linagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.
The absolute bioavailability of linagliptin is approximately 30%.Co-administration of a high-fat meal with linagliptin prolonged the time to reach Cmax by 2 hours and lowered Cmax by 15% but no influence on AUC 0-72h was observed.
Linagliptin may be administered with or without food.
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 1110 liters, indicating that linagliptin extensively distributes to the tissues.
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.
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:
when metformin is inappropriate due to intolerance, or contraindicated due to renal impairment.
in combination with other medicinal products for the treatment of diabetes, including insulin, when these do not produce adequate glycaemic control.
Hypersensitivity to the active substance or to any of the excipients.
WARNINGS AND PRECAUTIONS
Linagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
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, the incidence of hypoglycaemia was increased over that of placebo.
A dose reduction of the sulphonylurea or insulin may be considered.
Use of DPP-4 inhibitors has been associated with a risk of developing 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.
The use of linagliptin has not been studied in pregnant women. Animal studies do not indicate direct or indirect harm effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of linagliptin during pregnancy.
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 benefits of therapy for the woman.
INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION
Effects of other medicinal products on linagliptin:
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 Cmax, respectively, and about 30% decreased DPP-4 inhibition. 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 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 Cmax of linagliptin approximately two fold and three fold respectively.
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.
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, 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 cause medicinal product interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gly-coprotein,and organic cationic transporter (OCT).
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.
multiple daily doses of 5 mg linagliptin did not alter strate the pharmacokinetics of S(-) or R(+) warfarin, a CYP2 substrate, administered in a single dose.
multiple daily doses of linagliptin had a minimal effect on the steady-state pharmacokinetics of simvastatin a sensitive CYP3A4 substrate, in healthy volunteers.
co-administration with 5 mg linagliptin did not alter the steady-state pharmacokinetics of levonorgestrel or ethinylestradiol.
POSOLOGY AND METHOD OF ADMINISTRATION
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
Patients with Renal Impairment:
For patients with renal impairment, no dose adjustment for linagliptin is required.
Patients with Hepatic Impairment:
Pharmacokinetic studies suggest that no dose adjustment is required for patients with hepatic impairment.
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.
The safety and efficacy of linagliptin in children and adolescents has not yet been established. No data are available
Method of administration:
The tablets can be taken with or without a meal at any time of the day. If a dose is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
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.
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.
Store at temperature between (15-30) ℃.
Linaptin 5 mg is supplied as blister strips (Aluminum – White P.V.D.C),each strip contains 10 F.C. Tablets and each pack contains 1 , 2 or 3 strips with enclosed leaflet ( 10 , 20 or 30 F.C. Tablets per pack).