Presentation
Linajen 5 Tablet: Each film coated tablet contains 5 mg Linagliptin INN.

Pharmacology
Linagliptin is an inhibitor of Dipeptidyl Peptidase-4 (DPP-4), an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, Linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones 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.

Pharmacokinetics
Absorption and Bioavailability: The absolute bioavailability of Linagliptin is approximately 30%.

Distribution: The mean apparent volume of distribution at steady state following a single intravenous dose of Linagliptin 5 mg to healthy subjects is approximately 1110 L, 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% to 80% of Linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.

Metabolism: Following oral administration, the majority (about 90%) of Linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed Linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to Linagliptin.

Elimination: Following administration of an oral Linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min.

Indications
Linagliptin is indicated for use in type 2 diabetes as monotherapy (if Metformin Hydrochloride inappropriate), or in combination with Metformin Hydrochloride (when treatment with Metformin Hydrochloride alone fails to achieve adequate glycaemic control), or both Metformin Hydrochloride and a Sulfonylurea (when dual therapy with these drugs fails to achieve adequate glycaemic control). Linagliptin may also be used in combination with Insulin (with or without Metformin Hydrochloride) when a stable dose of Insulin has not provided adequate glycaemic control.

Contraindications
History of hypersensitivity reaction to Linagliptin, such as Anaphylaxis, Angioedema, exfoliative skin conditions, urticaria or bronchial hyperreactivity.

Dosage and 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 Sulphonyl urea or with Insulin, a lower dose of the sulphonyl urea 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.

Gender: No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of Linagliptin based on a population pharmacokinetic analysis.

Race: No dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of Linagliptin based on available pharmacokinetic data, including subjects of White, Hispanic, Black, and Asian racial groups.

Body Mass Index (BMI)/Weight: No dose adjustment is necessary based on
BMI/weight. BMI/weight had no clinically meaningful effect on the pharmacokinetics of Linagliptin based on a population pharmacokinetic analysis. The clinical trials before marketing authorization have been performed up to a BMI equal to 40 kg/m2.

Prescription Only

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.

Precautions

• There have been post marketing reports of acute pancreatitis, If pancreatitis is suspected, promptly discontinue Linagliptin.
• When used with an insulin secretagogue (e.g., Sulfonylurea) or Insulin, consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
• There have been post marketing reports of serious hypersensitivity reactions in patients treated with Linagliptin including anaphylaxis, angioedema, and exfoliative skin conditions. In such cases, promptly discontinue Linagliptin, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate.
• There have been post marketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. If bullous pemphigoid is suspected, discontinue Linagliptin.

Use in Pregnancy and Lactation
Pregnancy Category B. 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. Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Linagliptin is administered to a nursing woman.

Use in Children and Adolescents
The safety and effectiveness of Linagliptin in children and adolescents has not yet been established.

Adverse Effects
Adverse reactions reported in ?5% of patients treated with Linagliptin and more commonly than in patients treated with placebo included nasopharyngitis. Hypoglycemia was more commonly reported in patients treated with the combination of Linagliptin and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea.

Overdosage
In the event of an overdose with Linagliptin immediately hospitalize the patients. Employ the usual supportive measures like remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring and institute supportive treatment etc. as dictated by the patient’s clinical status. Removal of Linagliptin by hemodialysis or peritoneal dialysis is unlikely. During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of Linagliptin (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans.

Drug Interactions
Rifampin decreased Linagliptin exposure, suggesting that the efficacy of Linagliptin may be reduced when administered in combination with a strong P-gp. or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when Linagliptin is to be administered with a strong P-gp or CYP3A4 inducer.

Pharmaceutical Precautions
Store at below 30oC in a dry place protected from light. Keep out of reach of children.

Commercial Pack
Linajen 5 Tablet: Each box contains 3 X 10 tablets in Alu-Alu blister pack.