Each tablet contains: Vildagliptin 50 mg.
Pharmacotherapeutic group: Drugs use in diabetes, dipeptidyl-peptidase-4 (DPP-4) inhibitors.
Pharmacology: Mechanism of actions: Vildagliptin, a member of the islet enhancer class, is a potent and selective dipeptidyl-peptidase-4 (DPP-4) inhibitor that improves glycemic control.
Pharmacodynamics: The administration of vildagliptin results in rapid and complete inhibition of DPP-4 activity. In patients with type 2 diabetes, administration of vildagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. Vildagliptin inhibition of DPP-4 results in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of the beta cells to glucose resulting in improved glucose-dependent insulin secretion. Treatment with 50 to 100 mg daily in patients with type 2 diabetes significantly improved glucose-dependent insulin secretion. The degree of improvement in beta-cell function is dependent on the initial degree of impairment; in non-diabetic (normal glycemic) individuals, vildagliptin does not stimulate insulin secretion or reduce glucose levels.
By increasing endogenous GLP-1 levels, vildagliptin enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion. The reduction in inappropriate glucagon during meals in turn attenuates insulin resistance. The enhanced increase in the insulin/glucagon ratio during hyperglycemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycemia.
The known effect of increased GLP-1 levels to delay gastric emptying is not observed with vildagliptin treatment. In addition, a reduction in postprandial lipemia that is not associated with vildagliptin's incretin mediated effect to improve islet function has been observed.
Pharmacokinetic: Linearity: Vildagliptin is rapidly absorbed. Peak plasma concentrations for vildagliptin and the area under the plasma concentration versus time curve (AUC) increased in an approximately dose-proportional manner over the therapeutic dose range.
Absorption: Following oral administration in the fasting state, vildagliptin is a rapidly absorbed with peak plasma concentration observed at 2 hours. Co-administration with food slightly decreases the rate of absorption of vildagliptin.
Distribution: The plasma protein binding of vildagliptin is low and vildagliptin distributes equally between plasma and red blood cells.
Metabolism: Metabolism is the major elimination pathway for vildagliptin in humans. The major metabolite, LAY151, is pharmacologically inactive and is the hydrolysis product of the cyano moiety, followed by the amide hydrolysis product. DPP-4 contributes partially to the hydrolysis of vildagliptin. Vildagliptin is not metabolized by cytochrome P450 enzymes to any quantifiable extent. Vildagliptin does not inhibit or induce cytochrome P450 enzymes.
Excretion and elimination: Following oral administration of vildagliptin, vildagliptin is predominantly excretion via the urine and excretion via the feces is low. The elimination half-life after oral administration is approximately 1.5 hours and is independent of dose.
Special populations: Gender: No differences in the pharmacokinetics of vildagliptin were observed between male and female subjects with a diverse range of age and body mass index (BMI). DPP-4 inhibition by vildagliptin was unaffected by gender.
Obesity: BMI does not show any impact on the pharmacokinetic parameters of vildagliptin. DPP-4 inhibition by vildagliptin was unaffected by BMI.
Hepatic impairment: The use of vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5 x the upper limit of normal.
Renal impairment: Elimination half-life of vildagliptin was not affected by renal impairment. No dosage adjustment is required in patients with mild renal impairment. In patient with moderate or severe renal impairment, the recommended dose is 50 mg once daily (see Precautions). Due to limited experience, the use of vildagliptin is not recommended in patients with moderate or severe renal impairment or in patients with end-stage renal disease (ESRD) on hemodialysis (see Precautions).
Elderly: DPP-4 inhibition by vildagliptin is not affected by age in the elderly.
Pediatric: No pharmacokinetic data available.
Ethnic group: There was no evidence that ethnicity affects the pharmacokinetics of vildagliptin.
Vildagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM): As monotherapy; In dual combination with metformin, a sulphonylurea (SU), a thiazolidinedione (TZD) when diet, exercise and a single antidiabetic agent do result in adequate glycemic control; In triple combination: In patients with uncontrolled use of sulphonylurea (at submaximal dose) and metformin when diet and exercise plus dual therapy with theses agents do not provide adequate glycemic control.
It is not recommended as initial therapy.
Vildagliptin is also indicated for use in combination with insulin (with or without metformin), when maximal tolerated dose of insulin (without metformin or with maximal tolerated dose of metformin) as an adjunct to diet and exercise do not provide adequate glycemic control.
The management of antidiabetic therapy should be individualized.
Monotherapy: The recommended dose of vildagliptin is 50 mg or 100 mg daily. The 50 mg dose should be administered once daily in the morning. The 100 mg dose should be administered as two divided doses of 50 mg given in the morning and evening.
Combination therapy: Combination therapy with other antidiabetic drugs such as metformin, an SU, a TZD or insulin may be given if a tighter glycemic control is required on the top of the maximum recommended daily dose of 100 mg vildagliptin monotherapy.
The recommended dose of vildagliptin is 50 mg or 100 mg daily in dual combination with metformin, an SU, or a TZD or insulin. The 50 mg dose should be administered once daily in the morning. The 100 mg dose should be administered as two divided doses of 50 mg given in the morning and evening.
The recommended dose of vildagliptin is 50 mg twice daily for triple combination with metformin and a SU.
When used in dual combination with a sulphonylurea, the recommended dose of vildagliptin is 50 mg once daily administered in the morning. In this patient population, vildagliptin 100 mg daily was no more effective than vildagliptin 50 mg once daily.
Vildagliptin can be administered with or without meal.
Patients with hepatic or renal impairment: Vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5 x the upper limit of normal.
No dosage adjustment of vildagliptin is required in patients with mild renal impairment, in patients with moderate or severe renal impairment the recommended dose of vildagliptin is 50 mg once daily (see also Pharmacology: Pharmacokinetics: Special population under Actions).
Vildagliptin is, however, not recommended in patients with end stage renal disease (ESRD) on hemodialysis (see also Pharmacology: Pharmacokinetics: Special populations under Actions and Precautions).
There is limited data on the use of combination therapy in patients with renal and hepatic impairment. Therefore, the use of vildagliptin in combination therapy is not recommended in these patients.
Elderly patients: In patients treated with vildagliptin ≥65 years of age and ≥75 years of age, no difference were observed in the overall safety, tolerability, or efficacy between this elderly population and younger patients. No dosage adjustments are therefore necessary in the elderly patients (see also Pharmacology: Pharmacokinetics: Special population under Actions).
Pediatric patients: Vildagliptin has not been studied in patients under 18 years of age; therefore; the use of vildagliptin in pediatric patients is not recommended (see also Pharmacology: Pharmacokinetics: Special population under Actions).
Signs and symptoms: Doses up to 200 mg were well tolerated. At 400 mg, there were cases of muscle pain, and individual cases of mild and transient paresthesia, fever, edema and transient increase in lipase level (2 x ULN). At 600 mg, there were cases of edema of the feet and hands, and an excessive increase in creatinine phosphokinase (CPK) levels, accompanied by elevations of aspartate aminotransferase (AST), C-reactive protein, and myoglobin. In this dose group there were cases of edema of both feet, accompanied by paresthesia in two cases. All symptoms and laboratory abnormalities resolved after study drug discontinuation.
Management: Vildagliptin is not dialyzable, however, the major hydrolysis metabolite (LAY151) can removed by hemodialysis.
Vildagliptin is contraindicated in patients with known hypersensitivity to vildagliptin or to any of the excipients.
General: Vildagliptin is not a substitute for insulin in insulin-requiring patients. Vildagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Renal impairment: There is limited experience in patients with moderate or severe renal impairment and in patients with end stage renal disease (ESRD) on hemodialysis. Therefore, the use of vildagliptin is not recommended in these patients.
Hepatic impairment: Vildagliptin is not recommended in patients with hepatic impairment, including patients with a pretreatment ALT or AST >2.5 x the upper limit of normal.
Liver enzyme monitoring: Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function tests (LFTs) returned to normal after discontinuation of treatment. LFTs should be performed prior to the initiation of treatment with vildagliptin. Vildagliptin is not recommended in patients with a pre-treatment ALT or AST >2.5 x the upper limit of normal. LFTs should be monitored during vildagliptin treatment at three-month intervals during the first year and periodically thereafter.
Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding and be followed thereafter with frequent liver function tests until the abnormality(ies) return to normal. Should an increase in AST or ALT of 3 x upper limit of normal or greater persist, withdrawal of therapy with vildagliptin is recommended. Patients who develop jaundice or other signs suggestive to liver dysfunction should discontinue vildagliptin and contact the physician immediately. Following withdrawal of treatment with vildagliptin and LFT normalization, vildagliptin treatment should not be reinitiated.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed. Patients who may experience dizziness should therefore avoid driving vehicles or using machines.
Pregnancy: Vildagliptin did not impaired fertility or early embryonic development. Vildagliptin was not teratogenic in either rats or rabbits. There are, however, no adequate and well-controlled studies in pregnant women and therefore, vildagliptin should not be used during pregnancy unless the benefit to the mother outweighs the potential risk to the fetus.
Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies as well increased neonatal morbidity and mortality, most experts recommend that insulin monotherapy be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Lactation: As it is known whether vildagliptin is excreted in human milk, vildagliptin should not be administered to breast-feeding women.
The majority of adverse reactions were mild and transient, not requiring treatment discontinuations. No association was found between adverse reactions and age, ethnicity, duration of exposure or daily dose.
Rare cases of angioedema have been reported on vildagliptin. A greater proportion of cases were reported when vildagliptin was administered in combination with an angiotensin converting enzyme inhibitor (ACE-inhibitor). The majority of events were mild in severity and resolved with ongoing vildagliptin treatment.
Rare cases of hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function tests (LFTs) returned to normal after discontinuation of treatment. In monotherapy and add-on therapy up to 24 weeks in duration the incidence of ALT or AST elevations ≥3 x ULN (classified as present on at least 2 consecutive measurements or at the final on-treatment visit) was 0.2%; 0.3% and 0.2% for vildagliptin 50 mg daily, non-progressive in nature and not associated with cholestasis or jaundice.
Adverse reactions reported in patients who received vildagliptin as monotherapy and add-on therapies, are listed as follows, for each indication, by system organ class and absolute frequency.
Monotherapy: In monotherapy use, hypoglycemia was uncommon. Vildagliptin is weight neutral when administered as monotherapy. (See Table 1.)
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Combination with metformin: Vildagliptin is weight neutral when administered in combination with metformin. (See Table 2.)
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Combination with a sulphonylurea: At the recommended dose of 50 mg, vildagliptin is weight neutral when administered in combination with glimepiride. (See Table 3.)
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Combination with a thiazolidinedione: See Table 4.
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Combination with insulin: See Table 5.
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Combination with metformin and SU: See Table 6.
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Post marketing experience: During post marketing experience the following additional adverse drug reactions have been reported: Rare case of hepatitis reversible upon drug discontinuation.
(Frequently not known)*: urticaria, pancreatitis, bullous and exfoliative skin lesion.
*Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as "not known".
Vildagliptin has a low potential for drug interactions. Since vildagliptin is not a cytochrome P(CYP) 450 enzyme substrate nor does it inhibits nor induces CYP 450 enzymes, it is not likely to interact with co-medications that are substrates, inhibitors or inducers of these enzymes.
Furthermore, vildagliptin does not affect metabolic clearance of co-medications metabolized by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1, and CYP 3A4/5. Drug-drug interaction studies were conducted with commonly co-prescribed medications for patients with type 2 diabetes or medications with a narrow therapeutic window. As a result of these studies no clinically relevant interactions with other oral antidiabetics (glibenclamide, pioglitazone, metformin), amlodipine, digoxin, ramipril, simvastatin, valsartan or warfarin were observed after co-administration with vildagliptin.
Store at temperature below 30°C.
A10BH02 - vildagliptin ; Belongs to the class of dipeptidyl peptidase 4 (DPP-4) inhibitors. Used in the treatment of diabetes.
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