Glipten

Glipten

Manufacturer:

Ajanta Pharma Phil

Distributor:

Ajanta Pharma Phil
Full Prescribing Info
Contents
Teneligliptin hydrobromide hydrate.
Description
Each film-coated tablet contains: Teneligliptin hydrobromide hydrate equivalent to Teneligliptin 20 mg.
Action
Pharmacology: Pharmacodynamics: Mechanism of action: Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gastrointestinal tract in response to a meal. Incretin hormones regulate plasma glucose levels by stimulating glucose-dependent insulin release from pancreatic beta cells and inhibiting glucagon secretion from pancreatic alpha cells. The enzyme Dipeptidyl Peptidase IV (DPP-4) however, rapidly degrades both GLP-1 and GIP within a few minutes. Teneligliptin exerts its hypoglycemic action by suppressing the degradation of GLP-1 via inhibition of dipeptidyl peptidase-4 (DPP-4) enzymes thereby increasing blood concentrations of active GLP-1. Teneligliptin inhibits human plasma DPP-4 activity in a concentration-dependent manner with an in vitro IC50 value (95% confidence interval) of 1.75 (1.62-1.89) nmol/L.
In subjects with Type 2 diabetes, Teneligliptin 20 mg once daily inhibits DPP-4 activity by 89.7% 2 hours after oral administration and by 61.8% 24-hours post dose. Teneligliptin 20 mg once daily in the morning significantly increases plasma GLP-1 and significantly decreases plasma glucagon levels after breakfast, lunch and dinner. Once daily morning administration of Teneligliptin 20 mg improves fasting blood glucose levels and 2 hr post prandial blood glucose levels after each meal (breakfast, lunch and dinner).
Pharmacokinetics: Teneligliptin is rapidly absorbed. Peak Teneligliptin plasma concentrations (Tmax) occur 1.8 hrs and 1 hr after single oral administration of a 20 mg and 40 mg dose, respectively. Plasma AUC0-inf of Teneligliptin increases in a dose proportional manner; following single oral 20 mg and 40 mg dose in healthy volunteers, mean plasma AUC0-inf of Teneligliptin was 2,028.9 ng.hr/mL and 3,705.1 ng.hr/mL, Cmax was 187.2 ng/mL and 382.4 ng/mL, and apparent terminal half-life (t1/2) was 24.2 and 20.8 hrs, respectively (see Table 1).

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Plasma Cmax, AUC0-inf of Teneligliptin increases at steady-state compared to the first dose (see Table 2).

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Coadministration of Teneligliptin with food reduces Cmax by 20%, increases Tmax from 1.1 to 2.6 hours but does not affect AUC0-inf of Teneligliptin compared with coadministration without food (fasting state). This change is not clinically meaningful. Teneligliptin can be taken before or after a meal, however administration 1 hour before a meal is preferable (see Table 3). The plasma protein binding rate is 77.6 - 82.2%.

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Metabolism: After a single oral dose of [14C]-labeled Teneligliptin 20 mg, 5 metabolites, M1, M2, M3, M4, and M5, are observed in plasma.
In-vitro studies indicate that CYP3A4 and flavin-containing monooxygenase 3 (FMO3) are the major and CYP2D6 and flavin-containing monooxygenase 1 (FMO1) are the minor enzymes responsible for the metabolism of Teneligliptin. In addition, Teneligliptin is a weak inhibitor of CYP2D6, CYP3A4, and FMO; IC50 values: 489.4, 197.5 and 467.2 µmol/L, respectively. In vitro Teneligliptin does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C8/9, CYP2C19, and CYP2E1. Teneligliptin does not induce CYP1A2 and CYP3A4.
Excretion: Two hundred and sixteen (216) hours after a single 20 mg oral dose of [14C] Teneligliptin, 45.4% of the administered radioactivity was excreted in urine and 46.5% in feces. Approximately 21.5% of an oral dose of Teneligliptin is excreted unchanged in the urine. The renal clearance rate for Teneligliptin is 37-39 mL/hr/kg. The cumulative urinary excretion rates 120 hrs post dose for un-metabolized, M1, M2, and M3 were 14.8%, 17.7%, 1.4% and 1.9% respectively while the cumulative fecal excretion rates 120 hrs post dose for un-metabolized, M1, M3, M4 and M5 were 26.1%, 4.0%, 1.6%, 0.3% and 1.3% respectively.
Renal Impairment: Compared with healthy adult subjects, Cmax and t1/2 are not significantly changed in subjects with mild (50≤CrCl≤80 mL/min), moderate (30≤CrCl<50 mL/min), or severe (CrCl<30 mL/min) renal impairment (see Table 4). AUC0-inf, significantly increases 1.25-fold, 1.68-fold, and 1.49-fold in subjects with mild, moderate, and severe renal impairment, respectively, relative to healthy adult subjects. Compared with healthy adult subjects, Cmax and t1/2 are not significantly changed in subjects with end stage failure but AUC0-inf increases 1.16-fold (see Table 5). Renal impairment does not have a clinically meaningful effect on the pharmacokinetics of Teneligliptin, dose adjustments are not required in subjects with any degree of renal impairment.

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Hepatic Impairment: Compared with healthy adult subjects, Cmax and t1/2 are not significantly increased in subjects with mild (Child-Pugh Score 5-6) and moderate hepatic impairment (Child-Pugh Score 7-9), see Table 6. AUC0-inf is however increased 1.46-fold and 1.59-fold in subjects with mild and moderate hepatic impairment, respectively. Mild to moderate hepatic impairment does not have a clinically meaningful effect on the pharmacokinetics of Teneligliptin, dose adjustments are not required in subjects with mild to moderate hepatic impairment. There is no clinical experience with Teneligliptin in patients with severe hepatic impairment (Child-Pugh Score > 9).

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Elderly: The pharmacokinetics of Teneligliptin in healthy elderly subjects (>65 years of age) is not significantly different compared to healthy non-elderly subjects (age < 65 years of age); geometric least mean square ratio (elderly: non-elderly) of Cmax, AUC0-inf, and t1/2 are 1.006 (0.871-1.163), 1.090 (0.975-1.218) and 1.054 (0.911-1.219), respectively. No dosage adjustment is required in elderly subjects.
Indications/Uses
Teneligliptin is indicated for the treatment of type 2 diabetes mellitus as monotherapy or in combination with other oral hypoglycemic agents (e.g., metformin, pioglitazone, sulfonylureas, glinides, and α glucosidase inhibitors) and insulin.
Dosage/Direction for Use
Recommended dose is 20 mg, taken orally once a day in adults. If the effect is insufficient, the dose can be increased to 40 mg once a day.
Or as prescribed by the physician.
Overdosage
In the event of overdose, employ the usual supportive measures e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Contraindications
Teneligliptin is contraindicated in the following: Any patient with known hypersensitivity to Teneligliptin or any of the components in the formulation; Severe ketosis, diabetic coma or history of diabetic coma, Type 1 diabetic patients; Patients with severe infection, surgery, severe trauma (blood sugar control should preferably be done by insulin).
Special Precautions
Patients with severe hepatic impairment (Safety has not been investigated/established).
Patients with heart failure NYHA classification III-IV (Safety has not been investigated/established).
Patients with pituitary or adrenal insufficiency, poor nutritional state, starvation, irregular food intake, or debilitating condition, intensive exercise or excessive alcohol intake (may enhance blood glucose lowering effect).
Patients taking medication that may enhance the blood glucose lowering effect of Teneligliptin (β-blockers, MAO Inhibitors, etc.) or attenuate the blood glucose lowering effect of Teneligliptin (steroids, thyroid hormones, etc.).
History of bowel obstruction or a history of abdominal surgery. (Rare cases of intestinal obstruction have been reported with the use of DPP-4 Inhibitors, including Teneligliptin).
Patients taking sulfonylureas or insulin (The risk of hypoglycemia is increased). Reduce dose of sulfonylurea or insulin.
In a randomized, double-blind, placebo and moxifloxacin-controlled thorough QT/QTc comparative study (n=240), supratherapeutic doses of Teneligliptin 160 mg once daily (8 times the usual dose and 4 times the maximum recommended daily dose) momentarily prolonged QTc interval by 9.3 msec at around the time of Tmax. No clinically significant change in QTc interval was observed with the maximum recommended dose of Teneligliptin 40 mg once daily (3.9 msec). In clinical trials involving up to 904 subjects with Type 2 diabetes, no adverse events related to QTc prolongation were detected with Teneligliptin when used up to its maximum daily dose of 40 mg/day. Nevertheless, Teneligliptin should be used with caution in subjects who are prone to QT prolongation; patients with or with a medical history of arrhythmia, bradycardia, heart failure, low serum potassium, Torsades de pointes, or patients using antiarrhythmic drugs (Class IA and III antiarrhythmics).
Use In Pregnancy & Lactation
Teneligliptin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Safe use of Teneligliptin during pregnancy has not been established. Teneligliptin should be avoided by breastfeeding mothers (transition to milk has been reported in laboratory animals).
Adverse Reactions
Hypoglycemia: In clinical trials using Teneligliptin as monotherapy, the incidence of hypoglycemia was 1.1%. The incidence of hypoglycemia when Teneligliptin was used in combination with metformin, pioglitazone, and α-glucosidase inhibitors was 1.1%, 1.5%, and 1.3%, respectively, and not significantly different from incidence rates in placebo treated subjects. Hypoglycemic episodes were of mild intensity, not dose related, and did not cause any subjects to discontinue treatment. The incidence of hypoglycemia is increased when Teneligliptin is added to treatment with a glinide (3.8%) and a sulfonylurea (8.9%). Serious hypoglycemic symptoms with or without loss of consciousness have been reported when DPP-4 inhibitors are combined with sulfonylureas. Therefore, when Teneligliptin is used in combination with sulfonylurea, the dose of the sulfonylurea should be reduced. (See Table 7.)

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Drug Interactions
CYP3A4 and flavin monooxygenase 3 (FMO3) are the major and CYP2D6 and flavin monooxygenase 1 (FMO1) are the minor hepatic enzymes responsible for the metabolism of Teneligliptin. Teneligliptin is a weak inhibitor of CYP2D6, CYP3A4, and FMP (IC50 values; 489.4, 197.5, and 467.2 µmol/L, respectively) but shows no inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C8/9, CYP2C19, and CYP2E1. Teneligliptin does not induce CYP3A4 or CYP1A2.
Ketoconazole (400 mg) a potent inhibitor of CYP3A4 increased Cmax and AUC of Teneligliptin by 1.37-fold and 1.49-fold, respectively which was less than 2-fold and not considered clinically significant (see Tables 8 and 9). The half-life (t1/2) of Teneligliptin was unchanged with ketoconazole coadministration. The combination of Teneligliptin with drugs and food that inhibit CYP3A4 are not expected to cause marked, clinically significant increases in the exposure to Teneligliptin. No dose adjustments are required.
The pharmacokinetics of Teneligliptin is not significantly affected by coadministration with pioglitazone or metformin. Teneligliptin does increase the exposure to metformin by a non-clinically relevant 20.5% (see Tables 8 and 9). No dosage adjustment is needed when Teneligliptin is combined with either pioglitazone or metformin.
When coadministered, neither Teneligliptin nor glimepiride affect each other's pharmacokinetic profile in any clinically meaningful way (see Tables 8 and 9). The risk of hypoglycemia may be increased when Teneligliptin is used concomitantly with insulin and insulin secretagogues such as sulfonylureas and glinides. The dosage of insulin or the insulin secretagogue should be adjusted.

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Storage
Store at temperatures below 30°C.
MIMS Class
ATC Classification
A10BH08 - teneligliptin ; Belongs to the class of dipeptidyl peptidase 4 (DPP-4) inhibitors. Used in the treatment of diabetes.
Presentation/Packing
FC tab 20 mg (yellow colored, circular biconvex film-coated tablets plain on both sides) x 30's.
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