Gliptus 50

White, round, flat tablet, bevelled on both sides with engraved 50 on one side and plain on the other.

Antidiabetic agents.
Pharmacology: Vildagliptin, a member of the islet enhancer class, is a potent and selective DPP-4 inhibitor. The administration of Vildagliptin results in a rapid and complete inhibition of DPP-4 activity, resulting 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 the incretin hormones, Vildagliptin enhances the sensitivity of beta cells to glucose, resulting in improved glucose-dependent insulin secretion. Treatment with Vildagliptin 50-100 mg daily in patients with type 2 diabetes significantly improved markers of beta cell function including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio and measures of beta cell responsiveness from the frequently-sampled meal tolerance test. In non-diabetic (normal glycemic) individuals, Vildagliptin does not stimulate insulin secretion or reduce glucose levels.
By increasing endogenous GLP-1 levels, Vildagliptin also enhances the sensitivity of alpha cells to glucose, resulting in more glucose-appropriate glucagon secretion.
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 delaying gastric emptying is not observed with Vildagliptin treatment.
Pharmacokinetics: Absorption: Following oral administration in the fasting state, Vildagliptin is rapidly absorbed, with peak plasma concentrations observed at 1.7 hours. Food slightly delays the time to peak plasma concentration to 2.5 hours, but does not alter the overall exposure (AUC). Administration of Vildagliptin with food resulted in a decreased C_max (19%). However, the magnitude of change is not clinically significant, so that Vildagliptin can be given without food. The absolute bioavailability is 85%.
Distribution: The plasma protein binding of Vildagliptin is low (9.3%) and Vildagliptin distributes equally between plasma and red blood cells. The mean volume of distribution of Vildagliptin at steady-state after intravenous administration (V_ss) is 71 litres, suggesting extravascular distribution.
Biotransformation: Metabolism is the major elimination pathway for Vildagliptin in humans, accounting for 69% of the dose. The major metabolite (LAY 151) is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the glucuronide (BQS867) and the amide hydrolysis products (4% of dose). In vitro data in human kidney microsomes suggest that the kidney may be one of the major organs contributing to the hydrolysis of Vildagliptin to its major inactive metabolite, LAY 151. DPP-4 contributes partially to the hydrolysis of Vildagliptin based on an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by CYP 450 enzymes to any quantifiable extent. Accordingly, the metabolic clearance of Vildagliptin is not anticipated to be affected by co-medications that are CYP 450 inhibitors and/or inducers. In vitro studies demonstrated that Vildagliptin does not inhibit/induce CYP 450 enzymes. Therefore, Vildagliptin is not likely to affect metabolic clearance of co-medications metabolized by CYP 1A2, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 or CYP 3A4/5.
Elimination: Following oral administration of [¹⁴C] Vildagliptin, approximately 85% of the dose was excreted into the urine and 15% of the dose is recovered in feces. Renal excretion of the unchanged Vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of Vildagliptin are 41 and 13 L/h, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours.
Linearity/non-linearity: The C_max for Vildagliptin and the area under the plasma concentrations versus time curves (AUC) increased in an approximately dose proportional manner over the therapeutic dose range.
Characteristics in specific group of patients: Gender: No clinically relevant differences in the pharmacokinetics of Vildagliptin were observed between male and female healthy subjects within a wide range of age and body mass index (BMI). DPP-4 inhibition by Vildagliptin is not affected by gender.
Elderly: In healthy elderly subjects (≥ 70 years), the overall exposure of Vildagliptin (100 mg once daily) was increased by 32%, with an 18% increase in peak plasma concentration as compared to young healthy subjects (18-40 years). These changes are, however, not considered to be clinically relevant. DPP-4 inhibition by Vildagliptin is not affected by age.
Hepatic impairment: The effect of impaired hepatic function on the pharmacokinetics of Vildagliptin was studied in patients with mild, moderate and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison with healthy subjects. The exposure to Vildagliptin after a single dose in patients with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure to Vildagliptin for patients with severe impairment was increased by 22%. The maximum change (increase or decrease) in the exposure to Vildagliptin is ~30%, which is not considered to be clinically relevant. There was no correlation between the severity of the hepatic disease and changes in the exposure to Vildagliptin.
Renal impairment: A multiple-dose, open-label trial was conducted to evaluate the pharmacokinetics of the lower therapeutic dose of Vildagliptin (50 mg once daily) in patients with varying degrees of chronic renal impairment defined by creatinine clearance (mild: 50 to < 80 mL/min, moderate: 30 to < 50 mL/min and severe: < 30 mL/min) compared to normal healthy control subjects.
Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe renal impairment, respectively, compared to normal healthy subjects. AUC of the metabolites LAY151 and BQS867 increased on average about 1.5, 3 and 7-fold in patients with mild, moderate and severe renal impairment, respectively. Limited data from patients with end stage renal disease (ESRD) indicate that Vildagliptin exposure is similar to that in patients with severe renal impairment. LAY151 concentrations were approximately 2-3 fold higher than in patients with severe renal impairment.
Vildagliptin was removed by hemodialysis to a limited extent (3% over a 3-4 hour hemodialysis session starting 4 hours post dose)
Ethnic group: Limited data suggest that race does not have any major influence on Vildagliptin pharmacokinetics.

Vildagliptin is indicated in the treatment of type 2 diabetes mellitus in adults: As monotherapy: In patients inadequately controlled by diet and exercise alone and for whom Metformin is inappropriate due to contraindications or intolerance.
As dual oral therapy in combination with: Metformin, in patients with insufficient glycemic control despite maximal tolerated dose of monotherapy with Metformin.
A Sulphonylurea, in patients with insufficient glycemic control despite maximal tolerated dose of a Sulphonylurea and for whom Metformin is inappropriate due to contraindications of intolerance.
A Thiazolidinedione, in patients with insufficient glycemic control and for whom the use of a Thiazolidinedione is appropriate.
As triple oral therapy in combination with: A Sulphonylurea and Metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycemic control.
Vildagliptin is also indicated for use in combination with insulin (with or without Metformin) when diet and exercise plus a stable dose of insulin do not provide adequate glycemic control.

Adults: When used as monotherapy, in combination with Metformin, in combination with Thiazolidinedione, in combination with Metformin and a Sulphonylurea, or in combination with insulin (with or without Metformin), the recommended daily dose of Vildagliptin is 100 mg, administered as one dose of 50 mg in the morning and one dose of 50 mg in the evening.
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.
When used in combination with a Sulphonylurea, a lower dose of the Sulphonylurea may be considered to reduce the risk of hypoglycemia.
Doses higher than 100 mg are not recommended.
If a dose of Vildagliptin is missed, it should be taken as soon as the patient remembers. A double dose should not be taken on the same day.
The safety and efficacy of Vildagliptin as triple oral therapy in combination with Metformin and a Thiazolidinedione have not been established.
Additional information on special populations: Elderly (≥ 65 years): No dose adjustments are necessary in elderly patients.
Renal impairment: No dose adjustment is required in patients with mild renal impairment (creatinine clearance ≥ 50 mL/min). In patients with moderate or severe renal impairment or with end-stage renal disease (ESRD), the recommended dose of Vildagliptin is 50 mg once daily.
Hepatic impairment: Vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3x the upper limit of normal (ULN).
Pediatric population: Vildagliptin is not recommended for use in children and adolescents (< 18 years). The safety and efficacy of Vildagliptin in children and adolescents (< 18 years) have not been established. No data are available.
Method of administration: Oral use.
Vildagliptin can be administered with or without a meal.

Information regarding overdose with Vildagliptin is limited.
Symptoms: Information on the likely symptoms of overdose was taken from a rising dose to tolerability study in healthy subjects given Vildagliptin for 10 days. At 400 mg, there were three cases of muscle pain, and individual cases of mild and transient paraesthesia, fever, edema and a transient increase in lipase levels. At 600 mg, one subject experienced edema of the feet and hands, and increases in creatinine phosphokinase (CPK), aspartate aminotransferase (AST), C-reactive protein (CRP) and myoglobin levels. Three other subjects experienced edema of the feet, with paraesthesia in two cases. All symptoms and laboratory abnormalities resolved without treatment after discontinuation of the study medicinal product.
Management: In the event of an overdose, supportive management is recommended. Vildagliptin cannot be removed by hemodialysis. However, the major hydrolysis is metabolite (LAY 151) can be removed by hemodialysis.

Hypersensitivity to the active substance 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.
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 test results returned to normal after discontinuation of treatment. Liver function tests should be performed prior to the initiation of treatment with Vildagliptin in order to know the patient's baseline value. Liver function should be monitored during treatment with Vildagliptin 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(s) to normal. Should an increase in AST or ALT of 3x ULN or greater persist, withdrawal of Vildagliptin therapy is recommended.
Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue Vildagliptin. Following withdrawal of treatment with Vildagliptin and LFT normalization, treatment with Vildagliptin should not be reinitiated.
Cardiac failure: A clinical trial of Vildagliptin in patients showed that treatment with Vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing congestive heart failure (CHF) versus placebo. Clinical experience in patients treated with Vildagliptin is still limited and results are inconclusive.
There is no experience of Vildagliptin use and therefore use is not recommended in these patients.
Skin disorders: Skin lesions, including blistering and ulceration have been reported in extremities of monkeys in non-clinical toxicology studies. Although skin lesions were not observed at an increased incidence in clinical trials, there was limited experience in patients with diabetic skin complications. Furthermore, there have been post-marketing reports of bullous and exfoliative skin lesions. Therefore, in keeping with routine care of the diabetic patient, monitoring for skin disorders, such as blistering or ulceration, is recommended.
Acute pancreatitis: Use of Vildagliptin has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis.
If pancreatitis is suspected, Vildagliptin should be discontinued; if acute pancreatitis is confirmed, Vildagliptin should not be restarted. Caution should be exercised in patients with a history of acute pancreatitis.
Hypoglycemia: Sulphonylureas are known to cause hypoglycemia. Patients receiving Vildagliptin in combination with a Sulphonylurea may be at risk for hypoglycemia. Therefore, a lower dose of Sulphonylurea may be considered to reduce the risk of hypoglycemia.
Excipients: This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Renal impairment: There is limited experience in patients with ESRD on hemodialysis. Therefore, Vildagliptin should be used with caution in these patients.
Hepatic impairment: Vildagliptin should not be used in patients with hepatic impairment, including patients with pre-treatment ALT or AST > 3 x ULN.
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 experienced dizziness as an adverse reaction should avoid driving vehicles or using machines.

Pregnancy: There are no adequate data from the use of Vildagliptin in pregnant women. Studies in animals have shown reproductive toxicity at high doses. The potential risk for humans is unknown. Due to lack of human data, Vildagliptin should not be used during pregnancy.
Breastfeeding: It is unknown whether Vildagliptin is excreted in human milk. Animal studies have shown excretion of Vildagliptin in milk. Vildagliptin should not be used during breastfeeding.
Fertility: No studies on the effect on human fertility have been conducted for Vildagliptin.

Summary of the safety profile: Safety data were obtained from a total of 3,784 patients exposed to Vildagliptin at a daily dose of 50 mg (once daily) or 100 mg (50 mg twice daily or 100 mg once daily) in controlled trials of at least 12 weeks duration. Of these patients, 2,264 patients received Vildagliptin as monotherapy and 1,520 patients received Vildagliptin in combination with another medicinal product. 2,682 patients were treated with Vildagliptin 100 mg daily (either 50 mg twice daily or 100 mg once daily) and 1,102 patients were treated with Vildagliptin 50 mg once daily.
The majority of adverse reactions in these trials 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 hepatic dysfunction (including hepatitis) have been reported. In these cases, the patients were generally asymptomatic without clinical sequelae and liver function returned to normal after discontinuation of treatment. In data from controlled monotherapy and add-on therapy trials of up to 24 weeks in duration, the incidence of ALT or AST elevations ≥ 3x 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 once daily, Vildagliptin 50 mg twice daily and all comparators, respectively. These elevations in transaminases were generally asymptomatic, non-progressive in nature and not associated with cholestasis or jaundice.
Rare cases of angioedema have been reported on Vildagliptin at a similar rate to controls. A greater proportion of cases were reported on Vildagliptin at a similar rate to controls. A greater proportion 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.
Tabulated list of adverse reactions: Adverse reactions reported in patients who received Vildagliptin in double-blind studies as monotherapy and add-on therapies are listed as follows for each indication by system organ class and absolute frequency. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥1 /1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Combination with Metformin: See Table 1.

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Description of selected adverse effects: In controlled clinical trials with the combination of Vildagliptin 100 mg daily + Metformin, no withdrawal due to adverse reactions was reported in either the Vildagliptin 100 mg daily + Metformin or the placebo + Metformin treatment groups.
In clinical trials, the incidence of hypoglycemia was common in patients receiving Vildagliptin 100 mg daily in combination with Metformin (1%) and uncommon in patients receiving placebo + Metformin (0.4%). No severe hypoglycemic events were reported in the Vildagliptin arms.
In clinical trials, weight did not change from baseline when Vildagliptin 100 mg daily was added to Metformin (+0.2 Kg and -1.0 Kg for Vildagliptin and placebo, respectively). Clinical trials of up to more than 2 years' duration did not show any additional safety signals or unforeseen risks when Vildagliptin was added on to Metformin.
Combination with a Sulphonylurea: See Table 2.

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Description of selected adverse effects: In controlled clinical trials with the combination of Vildagliptin 50 mg + a Sulphonylurea, the overall incidence of withdrawals due to adverse reactions was 0.6% in the Vildagliptin 50 mg + Sulphonylurea vs 0% in the placebo + Sulphonylurea treatment group.
In clinical trials, the incidence of hypoglycemia when Vildagliptin 50 mg once daily was added to Glimepiride was 1.2% versus 0.6% for placebo + Glimepiride. No severe hypoglycemic events were reported in the Vildagliptin arms.
In clinical trials, weight did not change from baseline when Vildagliptin 50 mg daily was added to Glimepiride (-0.1 Kg and -0.4 Kg for Vildagliptin and placebo, respectively).
Combination with a Thiazolidinedione: See Table 3.

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Description of selected adverse reactions: In controlled clinical trials with the combination of Vildagliptin 100 mg daily + a Thiazolidinedione, no withdrawal due to adverse reactions was reported in either the Vildagliptin 100 mg daily + Thiazolidinedione or the placebo + Thiazolidinedione treatment groups.
In clinical trials, the incidence of hypoglycemia was uncommon in patients receiving Vildagliptin + Pioglitazone (0.6%) but common in patients receiving placebo + Pioglitazone (1.9%). No severe hypoglycemic events were reported in the Vildagliptin arms.
In the Pioglitazone add-on study, the absolute weight increases with placebo, Vildagliptin 100 mg daily were 1.4 and 2.7 Kg, respectively.
The incidence of peripheral edema when Vildagliptin 100 mg daily was added to a maximum dose of background Pioglitazone (45 mg once daily) was 7.0%, compared to 2.5% for background Pioglitazone alone.
Monotherapy: See Table 4.

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Description of selected adverse reactions: In addition, in controlled monotherapy trials with Vildagliptin the overall incidence of withdrawals due to adverse reactions was no greater for patients treated with Vildagliptin at doses of 100 mg daily (0.3%) than for placebo (0.6%) or comparators (0.5%).
In comparative controlled monotherapy studies, hypoglycemia was uncommon, reported in 0.4% (7 of 1,855) of patients treated with Vildagliptin 100 mg daily compared to 0.2% (2 of 1,082) of patients in the groups treated with an active comparator or placebo, with no serious or severe events reported.
In clinical trials, weight did not change from baseline when Vildagliptin 100 mg daily was administered as monotherapy (-0.3 Kg and -1.3 Kg for Vildagliptin and placebo, respectively). Clinical trials of up to 2 years' duration did not show any additional safety signals or unforeseen risks with Vildagliptin monotherapy.
Combination with Metformin and a Sulphonylurea: See Table 5.

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Description of selected adverse reactions: There were no withdrawals due to adverse reactions reported in the Vildagliptin + Metformin + Glimepiride treatment group versus 0.6% in the placebo + Metformin + Glimepiride treatment group.
The incidence of hypoglycemia was common in both treatment groups (5.1% for the Vildagliptin + Metformin + Glimepiride group versus 1.9% for the placebo + Metformin + Glimepiride group). One severe hypoglycemic event was reported in the Vildagliptin group.
At the end of the study, effect on mean body weight was neutral (+0.6 Kg in the Vildagliptin group and -0.1 Kg in the placebo group).
Combination with insulin: See Table 6.

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Description of selected adverse reactions: In controlled clinical trials using Vildagliptin 50 mg twice daily in combination with insulin, with or without concomitant Metformin, the overall incidence of withdrawals due to adverse reactions was 0.3% in the Vildagliptin treatment group and there were no withdrawals in the placebo group.
The incidence of hypoglycemia was similar in both treatment groups (14.0% in the Vildagliptin group vs 16.4% in the placebo group). Two patients reported severe hypoglycemic events in the Vildagliptin group, and 6 patients in the placebo group.
At the end of the study, effect on mean body weight was neutral (+0.6 Kg change from baseline in the Vildagliptin group and no weight change in the placebo group).
Post-marketing experience: See Table 7.

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Seek medical attention immediately at the first sign of any adverse drug reaction.

Vildagliptin has a low potential for interactions with co-administered medicinal products. Since Vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate and does not inhibit or induce CYP 450 enzymes, it is not likely to interact with active substances that are substrates, inhibitors or inducers of these enzymes.
Combination with Pioglitazone, Metformin and Glyburide: Results from studies conducted with these oral antidiabetics have shown to clinically relevant pharmacokinetic interactions.
Digoxin (Pgp substrate), Warfarin (CYP2C9 substrate): Clinical studies performed with healthy subjects have shown no clinically relevant pharmacokinetic interactions. However, this has not been established in the target population.
Combination with Amlodipine, Ramipril, Valsartan or Simvastatin: Drug-drug interaction studies in healthy subjects were conducted with Amlodipine, Ramipril, Valsartan and Simvastatin. In these studies, no clinically relevant pharmacokinetic interactions were observed after co-administration with Vildagliptin.
Combination with ACE-inhibitors: There may be an increased risk of angioedema in patients concomitantly taking ACE-inhibitors. As with other oral antidiabetic medicinal products the hypoglycemic effect of Vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics.

Store at temperatures not exceeding 30°C.

Antidiabetic Agents

A10BH02 - vildagliptin ; Belongs to the class of dipeptidyl peptidase 4 (DPP-4) inhibitors. Used in the treatment of diabetes.

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