Galvusmet Mechanism of Action

Pharmacology: Mechanism of action (MOA): Vildagliptin + metformin HCl (Galvus Met) combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: vildagliptin, a member of the DPP-4 (dipeptidyl-peptidase-4) inhibitor class and metformin hydrochloride, a member of the biguanide class.
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 levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase and increase the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4).
Pharmacodynamics: Vildagliptin/Metformin: The efficacy and safety of the separate components have been previously established and the co-administration of the separate components have been evaluated for efficacy and safety in clinical studies. These clinical studies established an added benefit of vildagliptin in patients with inadequately controlled type 2 diabetes while on metformin hydrochloride therapy (see CLINICAL STUDIES as follows).
Vildagliptin: 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 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.
Metformin Hydrochloride: Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Unlike sulfonylureas, metformin hydrochloride does not cause hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances), and does not cause hyperinsulinemia. With metformin hydrochloride therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
In humans, metformin hydrochloride has favourable effects on lipid metabolism, independent of its action on glycemia. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, LDLc and triglyceride levels.
Clinical Studies: Vildagliptin/Metformin: In a double-blind, placebo-controlled study in patients with type 2 diabetes whose hyperglycemia was inadequately controlled on a maximum dose of metformin hydrochloride alone, the addition of vildagliptin (50 mg once daily or 100 mg in divided doses) for 24 weeks led to statistically significant reductions in HbA_1c and increased the proportion of patients achieving at least a 0.7% reduction in HbA_1c when compared to patients who were continued on metformin hydrochloride alone. Group mean baseline HbA_1c (%) ranged from 8.3% (placebo plus metformin hydrochloride) to 8.4% (in both vildagliptin plus metformin hydrochloride groups). Vildagliptin combined with metformin hydrochloride resulted in additional statistically significant mean reductions in HbA_1c compared to placebo (between group differences of -0.7% to -1.1% for vildagliptin 50 mg and 100 mg, respectively). The proportion of patients who achieved a clinically meaningful and robust decrease in HbA_1c (defined as a decrease ≥0.7% from baseline) was statistically significantly higher in both vildagliptin plus metformin hydrochloride groups (46% and 60%, respectively) versus the metformin hydrochloride plus placebo group (20%). Patients on the combination of vildagliptin plus metformin hydrochloride did not experience a meaningful change in body weight compared to baseline. After 24 weeks, there was a decrease from baseline for both systolic and diastolic blood pressure in the vildagliptin treatment groups combined with metformin hydrochloride. Mean changes from baseline were -2.0/-0.8 mmHg, -3.5/-2.2 mmHg, and -0.8/-0.1 mmHg, in patients receiving metformin hydrochloride combined with vildagliptin 50 mg once daily, vildagliptin 50 mg twice daily or placebo, respectively. The incidence of gastrointestinal side effects ranged from 10% to 15% in the vildagliptin plus metformin hydrochloride groups as compared to 18% in the metformin hydrochloride plus placebo group.
The effect of vildagliptin in combination with metformin hydrochloride was evaluated in another, double-blind, placebo-controlled clinical study lasting 52 weeks in total (12-week core study plus a 40-week extension) involving 132 patients with type 2 diabetes on stable doses of metformin hydrochloride (1,500 mg to 3,000 mg daily). The addition of vildagliptin (50 mg once daily) to metformin hydrochloride resulted in an additional statistically significant reduction in mean HbA_1c (-0.6%) from baseline compared to placebo plus metformin hydrochloride (+0.1%) at the end of the 12-week study interval (mean baseline HbA_1c of 7.7% and 7.9%, respectively). Of these patients, 71 continued add-on treatment with vildagliptin or placebo for an additional 40 weeks (placebo-controlled, double-blind extension). At 52 weeks, mean change from baseline in HbA_1c was statistically significantly greater and sustained with vildagliptin (50 mg) plus metformin hydrochloride versus patients continued on metformin hydrochloride alone (between group difference of -1.1%) indicating a durable effect on glycemic control. In contrast, glycemic control in the metformin hydrochloride plus placebo group deteriorated over the course of the study.
In a 24-week study (LAF2354) vildagliptin (50 mg twice daily) was compared to pioglitazone (30 mg once daily) in patients inadequately controlled with metformin. Mean reductions from baseline HbA_1c of 8.4% were -0.9% with vildagliptin added to metformin and -1.0% with pioglitazone added to metformin. The decrease in HbA_1c from baseline >9.0% was greater (-1.5%) in both treatment groups. Patients receiving pioglitazone in addition to metformin experienced an increase in weight of 1.9 kg. Patients receiving vildagliptin in addition to metformin experienced an increase in weight of 0.3 kg. In a 28 week extension, HbA_1c reductions were similar between treatment groups and the body weight difference further increased.
In a long-term study of up to more than 2 years (LAF2308), vildagliptin (100 mg/day) was compared to glimepiride (up to 6 mg/day) in patients treated with metformin. After 1-year mean reductions in HbA_1c were -0.4% with vildagliptin added to metformin and -0.5% with glimepiride added to metformin. Body weight change with vildagliptin was -0.2 kg vs +1.6 kg with glimepiride. The incidence of hypoglycemia was significantly lower in the vildagliptin group (1.7%) than in the glimepiride group (16.2%). At study endpoint (2 years), the HbA_1c was similar to baseline values in both treatment groups and the body weight changes and hypoglycemia differences were maintained.
In a 52-week study (LAF237A2338), vildagliptin (50 mg twice daily) was compared to gliclazide (up to 320 mg/day) in patients inadequately controlled with metformin. After 1 year, mean reductions in HbA_1c were -0.81% with vildagliptin added to metformin (mean baseline HbA_1c 8.4%) and -0.85% with gliclazide added to metformin (mean baseline HbA_1c 8.5%); statistical non-inferiority was achieved. Body weight change with vildagliptin was +0.1 kg compared to a weight gain of +1.4 kg with gliclazide. The number of patients experiencing hypoglycemic events was the same in both treatment groups, however the number of patients experiencing two or more hypoglycemic events was higher in the gliclazide plus metformin group (0.8%) than in the vildagliptin plus metformin group (0.2%).
In a 24-week trial (LMF237A2302) the efficacy of the fixed dose combination of vildagliptin and metformin (gradually titrated to a dose of 50 mg/500 mg twice daily or 50 mg/1,000 mg twice daily) as initial therapy in drug-naïve patients was evaluated. The mean HbA_1c reductions were significantly greater with vildagliptin plus metformin combination therapy compared to either monotherapy. Vildagliptin/metformin 50 mg/1,000 mg twice daily reduced HbA_1c by -1.82% and vildagliptin/metformin 50 mg/500 mg twice daily by -1.61% from a mean baseline HbA_1c of 8.6%. The decrease in HbA_1c observed in patients with a baseline ≥10.0% was greater. Body weight decreased in all groups, with a mean reduction of -1.2 kg for both vildagliptin plus metformin combinations. The incidence of hypoglycemia was similar across treatment groups (0% with vildagliptin plus metformin combinations and 0.7% with each monotherapy).
A five year multi-center, randomized, double blind study (VERIFY) was conducted in patients with type 2 diabetes to evaluate the durability of an early combination therapy with vildagliptin and metformin (N=998) against standard-of-care initial metformin monotherapy followed by combination with vildagliptin (sequential treatment group) (N=1003) in newly diagnosed patients with type 2 diabetes. The initiation of an early combination regimen of vildagliptin 50 mg bid plus metformin resulted in a statistically and clinically significant reduction in the relative risk for "time to confirmed initial treatment failure" (HbA1c value ≥7%) vs metformin monotherapy in treatment-naïve patients with T2DM over the 5-year study duration. The incidence of initial treatment failure (HbA1c value ≥7%) was 429 (43.6%) patients in the combination treatment group and 614 (62.1%) patients in the sequential treatment group (HR [95%CI]: 0.51 [0.45, 0.58]; p<0.001).
Consistently lower HbA1c was observed with the combination treatment group compared with the sequential treatment group throughout the study duration. An early combination treatment approach with vildagliptin plus metformin in patients with newly diagnosed type 2 diabetes significantly and consistently improved long-term glycaemic durability compared with sequential treatment. The incidence of adverse events (AE) was comparable between the treatment groups (83.5% in the early combination therapy group vs. 83.2% in the sequential treatment group, respectively). The proportion of newly diagnosed patients who experienced hypoglycemic events over the entire study was low in both treatment groups (1.1% in early combination group and 0.6% in sequential treatment group). Both the treatment groups reported microvascular or macrovascular complications in a comparable proportion of patients (30.5% of patients in the early combination group, and 33.1% of patients in the sequential treatment group). The overall safety and tolerability profile was similar between treatment approaches, with no unexpected safety findings reported.
A 24-week randomized, double-blind, placebo-controlled study was conducted in 449 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with a stable dose of basal or premixed insulin (mean daily dose 41 U), with (N=276) or without (N=173) concomitant metformin. Vildagliptin in combination with insulin significantly decreased HbA1c compared with placebo: In the overall population, the placebo-adjusted mean reduction from a mean baseline HbA1c 8.8% was -0.72%. In the subgroups treated with insulin with or without concomitant metformin, the placebo-adjusted mean reduction in HbA1c was -0.63% and -0.84%, respectively. The incidence of hypoglycemia in the overall population was 8.4% and 7.2% in the vildagliptin and placebo groups, respectively. Changes in weight were +0.2 kg and -0.7 kg in the vildagliptin and placebo groups, respectively.
A 24-week randomized, double-blind, placebo-controlled study was conducted in 318 patients to evaluate the efficacy and safety of vildagliptin (50 mg twice daily) in combination with metformin (≥1,500 mg daily) and glimepiride (≥4 mg daily). Vildagliptin in combination with metformin and glimepiride significantly decreased HbA1c compared with placebo: the placebo-adjusted mean reduction from a mean baseline HbA1c 8.8% was -0.76%.
Vildagliptin: More than 15,000 patients with type 2 diabetes participated in double-blind, placebo- or active-controlled clinical studies of up to more than 2 years treatment duration. In these studies, vildagliptin was administered to more than 9,000 patients at daily doses of 50 mg once daily, 50 mg twice daily or 100 mg once daily. More than 5,000 male and more than 4,000 female patients received vildagliptin 50 mg once daily or 100 mg daily. More than 1,900 patients receiving vildagliptin 50 mg once daily or 100 mg daily were ≥65 years of age. In these studies, vildagliptin was administered as monotherapy in drug-naïve patients with type 2 diabetes or in combination in patients not adequately controlled by other antidiabetic medicinal products.
Overall, vildagliptin improved glycemic control when given as monotherapy or when used in combination with metformin hydrochloride, as measured by clinically relevant reductions in HbA_1c and fasting plasma glucose from baseline at study endpoint. When given as monotherapy or in combination with metformin hydrochloride in studies of up to 52 weeks duration, these improvements in glucose homeostasis were durable.
A 52-week multi-center, randomized, double-blind study was conducted in patients with type 2 diabetes and congestive heart failure (NYHA class I-III) to evaluate the effect of vildagliptin 50 mg bid (N=128) compared to placebo (N=126) on left ventricular ejection fraction (LVEF). Vildagliptin was not associated with a change in left-ventricular function or worsening of pre-existing CHF. Adjudicated cardiovascular events were overall balanced. There were slightly more cardiac events in vildagliptin treated patients with NYHA class III heart failure compared to placebo. However there were imbalances in baseline CV risk favoring placebo and the number of events was low, precluding firm conclusions. Vildagliptin significantly decreased HbA_1c compared with placebo (difference of 0.6%) from a mean baseline of 7.8%. The incidence of hypoglycemia in the overall population was 4.7% and 5.6% in the vildagliptin and placebo groups, respectively.
Cardiovascular risk: A meta-analysis of independently and prospectively adjudicated cardiovascular events from 37 phase III and IV monotherapy and combination therapy clinical studies of up to more than 2 years in duration was performed. It involved 9,599 patients with type 2 diabetes treated with vildagliptin 50 mg qd or 50 mg bid and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk. The composite endpoint of adjudicated major adverse cardio-vascular events (MACE) including acute myocardial infarction, stroke or CV death was similar for vildagliptin versus combined active and placebo comparators [Mantel–Haenszel risk ratio (M-H RR) 0.82 (95% confidence interval 0.61-1.11)] supporting the cardiovascular safety of vildagliptin. A MACE occurred in 83 out of 9,599 (0.86%) vildagliptin-treated patients and in 85 out of 7,102 (1.20%) comparator treated patients. Assessment of each individual MACE components showed no increased risk (similar M-H RR). Confirmed HF events defined as HF requiring hospitalization or new onset of HF were reported in 41 (0.43%) vildagliptin-treated patients and 32 (0.45%) comparator-treated patients, with M-H RR 1.08 (95% CI 0.68-1.70) showing no increased risk of HF in vildagliptin treated patients.
Metformin hydrochloride: The prospective randomized (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with metformin hydrochloride after failure of diet alone showed: A significant reduction of the absolute risk of any diabetes-related complication in the metformin hydrochloride group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034.
A significant reduction of the absolute risk of diabetes-related mortality: metformin hydrochloride 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017.
A significant reduction of the absolute risk of overall mortality: metformin hydrochloride 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021).
A significant reduction in the absolute risk of myocardial infarction: metformin hydrochloride 11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years (p=0.01).
Pharmacokinetics: Absorption: Vildagliptin/Metformin: In the bioequivalence studies at three dose strengths (50 mg/500 mg, 50 mg/850 mg and 50 mg/1,000 mg), versus free combination of vildagliptin and metformin hydrochloride tablets at the corresponding doses, the area under the curve (AUC) and maximum concentration (C_max) of both the vildagliptin component and the metformin hydrochloride component were demonstrated to be bioequivalent to that of free combination tablets.
Food does not affect the extent and rate of absorption of vildagliptin component. The C_max and AUC of the metformin hydrochloride component were decreased by 26% and 7% respectively when given with food. The absorption of metformin hydrochloride was also delayed as reflected by the T_max (2.0 to 4.0 hrs) when given with food. These changes in C_max and AUC are consistent but lower than those observed when metformin hydrochloride was given alone under fed conditions. The effects of food on the pharmacokinetics of both the vildagliptin component and metformin hydrochloride component were similar to the pharmacokinetics of vildagliptin and metformin hydrochloride when given alone with food.
Vildagliptin: Following oral administration in the fasting state, vildagliptin is rapidly absorbed with peak plasma concentrations observed at 1.75 hours. Co-administration 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).
Metformin Hydrochloride: The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin hydrochloride, as shown by approximately a 40% lower mean peak plasma concentration (C_max), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (T_max) following administration of a single 850 mg tablet of metformin hydrochloride with food, compared to the same tablet strength administered under fasting conditions. The clinical relevance of these decreases is unknown.
Distribution: Vildagliptin: 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 litres, suggesting extravascular distribution.
Metformin Hydrochloride: The apparent volume of distribution (V/F) of metformin hydrochloride following single oral doses of 850 mg averaged 654±358 litres. Metformin hydrochloride is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin hydrochloride partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride, steady state plasma concentrations of metformin hydrochloride are reached within 24 to 48 hours and are generally <1 microgram/mL. During controlled clinical studies of metformin hydrochloride, maximum metformin hydrochloride plasma levels did not exceed 5 micrograms/mL, even at maximum doses.
Biotransformation/Metabolism: Vildagliptin: 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 the 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.
Metformin Hydrochloride: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Vildagliptin: 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 the unchanged vildagliptin accounts for 23% of the dose after oral administration. After an intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 litres/hour and 13 litres/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.
Metformin Hydrochloride: Intravenous single-dose studies in normal subjects demonstrate that metformin hydrochloride is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
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: Vildagliptin: 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.
Metformin Hydrochloride: Metformin hydrochloride pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride was comparable in males and females.
Obesity: Vildagliptin: BMI does not show any impact on the pharmacokinetic parameters of vildagliptin. DPP-4 inhibition by vildagliptin was unaffected by BMI.
Hepatic impairment: Vildagliptin: 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 to vildagliptin 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.
The use of vildagliptin is not recommended in patients with hepatic impairment including patients with a pre-treatment ALT or AST >2.5x the ULN.
Metformin Hydrochloride: No pharmacokinetic studies of metformin hydrochloride have been conducted in subjects with hepatic impairment.
Renal impairment: Vildagliptin: 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. The AUC of the metabolites LAY151 increased 1.6, 3.2 and 7.3-fold and that of BQS867 increased on average about 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 2-3-fold higher than in patients with severe renal impairment.
Vildagliptin was removed by hemodialysis to a limited extent (3% over a 3-4 hour haemodialysis session starting 4 hours post dose).
Metformin Hydrochloride: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin hydrochloride is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance.
Geriatric patients (65 years or above): Vildagliptin: 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.
Metformin Hydrochloride: Limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin hydrochloride is decreased, the half-life is prolonged, and C_max is increased, compared to healthy young subjects. From these data, it appears that the change in metformin hydrochloride pharmacokinetics with aging is primarily accounted for by a change in renal function.
Treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
Pediatric patients (below 18 years): No pharmacokinetic data available.
Ethnic Group: Vildagliptin: There was no evidence that ethnicity affects the pharmacokinetics of vildagliptin.
Metformin Hydrochloride: No studies of metformin hydrochloride pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin hydrochloride in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51) and Hispanics (n=24).
Toxicology: Non-Clinical Safety Data: Animal studies of up to 13-weeks in duration have been conducted with the combined active substances in the product. No new toxicities associated with the combination were identified. The following data are findings from studies performed with vildagliptin or metformin individually.
Vildagliptin: Carcinogenicity and mutagenicity: A two-year carcinogenicity study was conducted in rats at oral doses of up to 900 mg/kg (approximately 200 times the human exposure at the maximum recommended dose). No increases in tumor incidence attributable to vildagliptin were observed. A two-year carcinogenicity study was conducted in mice at oral doses of up to 1,000 mg/kg (up to 240 times the human exposure at the maximum recommended dose). Mammary tumor incidence was increased in female mice at approximately 150 times the maximum anticipated human exposure to vildagliptin; it did not increase at approximately 60 times the maximum human exposure. The incidence of hemangiosarcoma increased in male mice treated at 42 to 240 times the maximum human exposure to vildagliptin and in female mice at 150 times the maximum human exposure. No significant increases in hemangiosarcoma incidences were observed at approximately 16 times the maximum human exposure to vildagliptin in males and approximately 60 times the maximum human exposure in females.
Vildagliptin was not mutagenic in a variety of mutagenicity tests including a bacterial reverse mutation Ames assay and a human lymphocyte chromosomal aberration assay. Oral bone marrow micronucleus tests in both rats and mice did not reveal clastogenic or aneugenic potential up to 2,000 mg/kg or approximately 400 times the maximum human exposure. An in vivo mouse liver comet assay using the same dose was also negative.
Safety pharmacology and repeat dose toxicity: In a 13-week toxicology study in cynomolgus monkeys, skin lesions have been recorded at doses ≥5 mg/kg/day. These were consistently located on the extremities (hands, feet, ears and tail). At 5 mg/kg/day (approximately equivalent to human AUC exposure at the 100 mg dose), only blisters were observed. They were reversible despite continued treatment and were not associated with histopathological abnormalities. Flaking skin, peeling skin, scabs and tail sores with correlating histopathological changes were noted at doses ≥20 mg/kg/day (approximately 3 times human AUC exposure at the 100 mg dose). Necrotic lesions of the tail were observed at ≥80 mg/kg/day. It should be noted that vildagliptin exhibits a significantly higher pharmacological potency in monkeys compared with humans. Skin lesions were not reversible in the monkeys treated at 160 mg/kg/day during a 4-week recovery period. Skin lesions have not been observed in other animal species or in humans treated with vildagliptin.
Metformin Hydrochloride: Preclinical data on metformin reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.
Carcinogenicity: Long-term carcinogenicity studies with metformin hydrochloride have been performed in rats (dosing duration 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately four times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin hydrochloride was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin hydrochloride in male rats.
Reproductive toxicity: There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. This is a frequent spontaneous reproductive tract lesion in rats and its relevance in terms of toxicological and carcinogenicity study outcomes for humans is uncertain.
Mutagenicity: There was no evidence of mutagenic potential of metformin hydrochloride in the following in vitro tests: Ames test (S. typhimurium), and gene mutation test (mouse lymphoma cells) or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.