GildaGen-50

Vildagliptin 50 mg Tablet appears as white to off-white circular tablet, biconvex, with break line on one side and plain on the other side.
Each tablet contains: Vildagliptin 50 mg.

Dipeptidyl Peptidase 4 (DPP-4) Inhibitor.
Pharmacology: Mechanism of action: Vildagliptin, a member of the islet enhancer class, is a potent and selective dipeptidyl-peptidase-4 (DPP-4) inhibitor that improves glycemic control. Vildagliptin inhibition of DPP-4 results in increased fasting and postprandial endogenous level of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
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.
By increasing the endogenous levels of these incretin hormones; vildagliptin enhances the sensitivity of 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 markers of beta cell function. 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 of 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 to function has been observed.
Pharmacokinetics: Absorption: Following oral administration in the fasting state, vildagliptin is rapidly absorbed with peak plasma concentrations observed at 1.75 hours. Coadministration with food slightly decreases the rate of absorption of vildagliptin, as characterized by a 19% decrease in peak concentrations, and a delay in the time to peak plasma concentration to 2.5 hours. There is no change in the extent of absorption, and food does not alter the overall exposure (AUC).
Distribution: The plasma protein binding of vildagliptin is low (9.3%), and vildagliptin is distributed equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady state after intravenous administration (V_ss) is 71 liter, suggesting extravascular distribution.
Biotransformation/metabolism: Metabolism is the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose. The major metabolite, LAY151, is pharmacologically inactive and is the hydrolysis product of cyano moiety, accounting for 57% of the dose, followed by the amide hydrolysis product (4% of the dose). DPP-4 contributes partially to the hydrolysis of vildagliptin as shown in an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by cytochrome P450 enzymes to any quantifiable extent. In vitro studies demonstrated that vildagliptin does not inhibit or induce cytochrome P450 enzymes.
Elimination: Following oral administration of [¹⁴C]-vildagliptin, approximately 85% of the dose is excreted into the urine and 15% of the dose is recovered in the feces. Renal excretion of unchanged vildagliptin accounts for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 liters/hour and 13 liters/hour, respectively. The mean elimination half-life after intravenous administration is approximately 2 hours. The elimination half-life after oral administration is approximately 3 hours and is independent of the dose.
Linearity/non-linearity: Vildagliptin is rapidly absorbed with an absolute oral bioavailability of 85%. 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.
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 effect of impaired hepatic function on the pharmacokinetics of vildagliptin was studied in subjects with mild, moderate, and severe hepatic impairment based on the Child-Pugh scores (ranging from 6 for mild to 12 for severe) in comparison to subjects with normal hepatic function. The exposure to vildagliptin (100 mg) after a single dose in subjects with mild and moderate hepatic impairment was decreased (20% and 8%, respectively), while the exposure for subjects 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 hepatic function impairment and changes in exposure to vildagliptin.
Use is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AT >2.5X the upper limit of normal.
Renal Impairment: The AUC of vildagliptin 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. The AUC of the metabolites LAY151 increased 1.6, 3.2 and 7.3-fold and that of BQS867 increased 1.4, 2.7 and 7.3-fold in patients with mild, moderate and severe renal impairment, respectively, compared to healthy volunteers. 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 in ESRD patients were approximately 2 to 3-fold higher than in patients with severe renal impairment. Dosage adjustment may be required in patients with renal impairment.
Vildagliptin was removed by hemodialysis to a limited extent (3% over a 3-4 hour hemodialysis session starting 4 hours post dose).
Geriatric patients (65 years or above): In otherwise, healthy elderly subjects (≥70 years), the overall exposure to vildagliptin (100 mg once daily) was increased by 32% with an 18% increase in peak plasma concentration compared to younger healthy subjects (18 to 40 years). These changes are not considered to be clinically relevant. DPP-4 inhibition by vildagliptin is not affected by age in the age groups studied.
Pediatric patients (below 18 years): No pharmacokinetic data available.
Ethnicity: There was no evidence that ethnicity affects the pharmacokinetics of vildagliptin.

Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM).
As monotherapy.
In dual combination: with metformin, when diet, exercise and metformin alone do not result in adequate glycemic control; with a sulfonylurea (SU), when diet, exercise and a SU do not result in adequate glycemic control; with a thiazolidinedione (TZD) when diet, exercise and a TZD do not result in adequate control.
In triple combination: with a sulfonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycemic control.
In combination with insulin (with or without metformin) when diet, exercise and a stable dose of insulin do not result in adequate glycemic control.
As initial combination therapy with metformin in patients with T2DM whose diabetes is not adequately controlled by diet and exercise alone.

Dosage Regimen: The management of antidiabetic therapy should be individualized. The recommended dose is 50 mg once or twice daily. The maximum daily dose is 100 mg. For monotherapy, and for combination with metformin, with a thiazolidinedione (TZD) or with insulin (with or without metformin), the recommended dose is 50 mg or 100 mg daily.
When used in dual combination with a sulfonylurea, the recommended dose of vildagliptin is 50 mg once daily. In this patient population, vildagliptin 100 mg daily was no more effective that the vildagliptin 50 mg once daily.
For triple combination with metformin and a sulfonylurea (SU), the recommended dose is 100 mg daily.
If tighter glycemic control is required on the top of the maximum recommended daily dose of vildagliptin, the addition of other antidiabetic drugs such as metformin, an SU, a TZD or insulin may be considered.
General target populations: Adults 18 years of age and above.
Special Populations: Renal Impairment: No dosage adjustment is required in patients with mild renal impairment. In patients with moderate or severe renal impairment or End Stage Renal Disease (ESRD), the recommended dose is 50 mg once daily.
Hepatic Impairment: Not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5x the upper limit of normal (ULN).
Pediatric patients (below 18 years): Vildagliptin has not been studied in patients under 18 years of age; therefore, the use in pediatric patients is not recommended.
Geriatric patients (65 years or above): In treated patients of ≥65 years of age and ≥75 years of age, no differences were observed in overall safety, tolerability, or efficacy between this elderly population and younger patients.
Method of Administration: For oral use.
Administer with or without meals.
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.
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.

Signs and Symptoms: In healthy subjects (seven to fourteen subjects per treatment group), vildagliptin was administered once-daily doses of 25, 50, 100, 200, 400, and 600 mg for up to 10 consecutive days. Doses up to 200 mg were well tolerated. At 400 mg, there were three cases of muscle pain, and individual cases of mild and transient increase in lipase levels (2x ULN). At 600 mg, one subject experienced edema of the feet and hand, and an excessive increase in creatinine phosphokinase (CPK) levels, accompanied by elevations of aspartate aminotransferase (AST), C-reactive protein, and myoglobin. Three additional subjects in this dose group presented with 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 be removed by hemodialysis.

Patients with known hypersensitivity to vildagliptin or to any of the excipients.

General: Vildagliptin is not a substitute for insulin in patients requiring insulin. It should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Special populations: Patients with Hepatic impairment: Not recommended in patients with hepatic impairment. Including patients with a pre-treatment ALT or AST >2.5x ULN.
Hepatic 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. LFTs should be monitored during 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 3x ULN or greater persist, withdrawal of therapy is recommended. Patients who develop jaundice or other signs suggestive of liver dysfunction should discontinue treatment and contact their physician immediately. Following withdrawal of treatment and LFT normalization, vildagliptin treatment should not be reinitiated.
Heart failure: A clinical trial of vildagliptin in patients with New York Association (NYHA) functional class I-III 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 with NYHA functional class III treated with vildagliptin is still limited and the results are inconsecutive.
There is no experience of vildagliptin use in clinical trials in patients with NYHA functional class IV and therefore use is not recommended in these patients.

Pregnancy: Risk summary: There is insufficient experience with vildagliptin in pregnant women. Vildagliptin was not teratogenic in either rats or rabbits. Vildagliptin should not be used during pregnancy unless the benefit to the mother outweighs the potential risk to the fetus.
Lactation: Risk summary: As it is not known whether vildagliptin is excreted in human milk, it should not be administered to breast-feeding women.
Females and males of reproductive potential: No studies on the effect on human fertility have been conducted for vildagliptin. Fertility studies have been performed in rats and doses up to 200 times the human dose and have revealed no evidence of impaired fertility or early embryonic development.

Summary of the safety profile: The safety and tolerability of vildagliptin (50 mg qd, 50 mg bid and 100 mg qd) have been assessed by pooling data from more than 11,000 patients from 36 Phase II and III studies (including 3 open label studies) ranging in duration from 12 to more than 104 weeks. The studies used in this pooled analysis have assessed vildagliptin as monotherapy, add-on therapy to other oral anti-diabetic agents (metformin, TZD, SU, and insulin) and as an initial combination therapy with metformin or pioglitazone. Patients not receiving vildagliptin (all comparators group) were taking only placebo or metformin, TZD, SU, acarbose, or insulin. For the calculation of frequency of adverse drug reactions for the individual indications, safety data from a subset of pivotal controlled trials of at least 12 week's duration was considered. Safety data were obtained from 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) who received vildagliptin as monotherapy or in combination with another agent.
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 angioedema have been reported on vildagliptin at a similar rate to controls. 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. In data from controlled monotherapy and add-on therapy trials 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 daily, vildagliptin 50 mg twice a day and all comparators, respectively. These elevations in transaminases were generally asymptomatic, nonprogressive in nature and not associated with cholestasis or jaundice.
Monotherapy: The overall incidence of withdrawal from monotherapy trials due to adverse reactions was no greater for patients treated with vildagliptin at a dose of 50 mg once daily (0.2%) or vildagliptin at a dose of 50 mg twice daily (0.1%) than for placebo (0.6%) or comparators (0.5%).
In monotherapy studies, hypoglycemia was uncommon, reported in 0.5% (2 of 409) of patients treated with vildagliptin 50 mg once daily and 0.3% (4 of 1,373) of patients treated with vildagliptin 50 mg twice 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.
Vildagliptin is weight neutral when administered as monotherapy. (See Table 1.)

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Long term clinical trials of up to 2 years did not show any additional safety signals or unforeseen risks with vildagliptin monotherapy.
Combination with metformin: In clinical trials with the combination of vildagliptin + metformin, 0.4% of patients withdrew due to adverse reactions in the vildagliptin 50 mg once daily + metformin treatment group, and no withdrawal due to adverse reactions was reported in either the vildagliptin 50 mg twice daily + metformin or the placebo + metformin treatment groups. (See Table 2.)

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Long term clinical trials of up to more than 2 years did not show any additional safety signal or unforeseen risks when vildagliptin was added on to metformin.
When vildagliptin was studies as an initial combination therapy with metformin, no additional safety signal or unforeseen risk was observed.
Combination with a sulfonylurea: In clinical trials with the combination of vildagliptin 50 mg + glimepiride, the overall incidence of withdrawals due to adverse reactions was 0.6% in the vildagliptin 50 mg + glimepiride treatment group versus 0% in the placebo + glimepiride treatment group.
In clinical trials, the incidence of hypoglycaemia when vildagliptin 50 mg once daily was added to glimepiride was 1.2% versus 0.6% placebo + glimepiride. No severe hypoglycemic events were reported in the vildagliptin arms.
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: In clinical trials with the combination of vildagliptin and a thiazolidinedione, 0.7% of patients withdrew for adverse reactions in the vildagliptin 50 mg once daily + pioglitazone group, and there were no withdrawals due to adverse reactions reported in either the vildagliptin 50 mg twice daily + pioglitazone or the placebo + pioglitazone treatment groups.
In clinical trials, no hypoglycaemia events were reported in patients receiving vildagliptin 50 mg once daily + pioglitazone 45 mg, hypoglycaemia was uncommon in patients receiving vildagliptin 50 mg twice daily + pioglitazone 45 mg (0.6%) but common in patients receiving placebo + pioglitazone 45 mg (1.9%). No severe hypoglycemic events were reported in the vildagliptin arms.
In pioglitazone add-on study, the change in body weight compared to placebo was + 0.1 kg and +1.3 kg for vildagliptin 50 mg daily and vildagliptin 50 mg twice daily, respectively.
The incidence of peripheral edema when vildagliptin was added to a maximum dose of background pioglitazone (45 mg once daily) was 8.2% as 50 mg once daily and 7.0% as 50 mg twice daily compared to 2.5% for background pioglitazone alone. The incidence of edema when vildagliptin was added to pioglitazone as dual initial therapy in drug naïve patients was, however, less than for pioglitazone alone (50 mg once daily 3.5%, 50 mg twice daily 6.1% vs. pioglitazone 30 mg 9.3%). (See Table 4.)

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Combination with insulin: In controlled clinical trials using vildagliptin 50 mg twice daily in combination with insulin, with or without concomitant metformin, the overall incidence or withdrawal due to adverse reactions was 0.3% in the vildagliptin treatment group and there were no cases of withdrawal in the placebo group.
The incidence of hypoglycemia was similar in both treatment groups (14.0% in the vildagliptin group versus 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, the 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). (See Table 5.)

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Combination with metformin and SU: There were no cases of withdrawal reported due to adverse reactions in the vildagliptin + metformin + glimepiride treatment group versus. 0.6% in the placebo + metformin + glimepiride treatment group.
The incidence of hypoglycaemia was common in both treatment groups (5.1% for the vildagliptin + metformin + glimepiride vs. 1.9% for the placebo + metformin + glimepiride). One severe hypoglycemic event was reported in the vildagliptin group.
At the end of the study, the effect on mean body weight was neutral (+ 0.6 kg in the vildagliptin group and -0.1 kg in the placebo group). (See Table 6.)

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Adverse drug reactions from spontaneous reports and literature cases - Post-marketing Experience (frequency not known): The following adverse drug reactions have been derived from postmarketing experience via spontaneous case reports and literature cases. 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.
Hepatitis reversible upon drug discontinuation; Urticaria, bullous and exfoliative skin lesions, including bullous pemphigoid; Pancreatitis; Arthralgia, sometimes severe.

Vildagliptin has low potential for drug interactions. Since vildagliptin is not a cytochrome P (CYP) 450 enzyme substrate nor does it inhibit or induce 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 comedications metabolized by CYP 1A2, CYP 2C8, 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 temperatures not exceeding 30°C. Protect from light and moisture.

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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