Vilatin M

Dosage Form & Strength

Combination may be initiated at either the 50 mg/500 mg or 50mg/850mg or 50mg/1000mg tablet strength twice daily, one tablet in the morning and the other in the evening. The recommended daily dose is 100mg vildagliptin plus 2000mg metformin hydrochloride.

Dosage in Special Population

A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3 to 6 months. The maximum daily dose of metformin should preferably be divided into 2 to 3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin-containing products in patients with GFR<60 ml/min. Combination is contraindicated in patients with GFR <30 ml/min because of its metformin component

Indications

Vilatin M is indicated for the treatment of type 2 diabetes

Adverse Effects

Vildagliptin Common side effects noted during trials were headache, dizziness, constipation, cough, nasopharyngitis and sweating. Some of the studies also reported a feeling of hypertension amongst the patients. Vildagliptin can also lead to weight gain. Metformin Commonly reported side effects of metformin include: lactic acidosis, diarrhea, nausea, nausea and vomiting, vomiting, and flatulence. Other side effects include: asthenia, and decreased vitamin b12 serum concentrate. See below for a comprehensive list of adverse effects.

Drug Interactions

Metformin: Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake Vildagliptin: 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. 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; There may be an increased risk of angioedema in patients concomitantly taking ACE-inhibitors; As with other oral antidiabetic medicinal products the hypoglycaemic effect of vildagliptin may be reduced by certain active substances, including thiazides, corticosteroids, thyroid products and sympathomimetics

Mechanism of Action

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 (glucosedependent insulinotropic polypeptide). 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 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 glycaemic) 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 hyperglycaemia due to increased incretin hormone levels results in a decrease in fasting and postprandial hepatic glucose production, leading to reduced glycaemia. The known effect of increased GLP-1 levels delaying gastric emptying is not observed with vildagliptin treatment. Metformin: Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation and delay of intestinal glucose absorption. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT)

Pharmacokinetics

Metformin Absorption After an oral dose of the prolonged release tablet, metformin absorption is significantly delayed compared to the immediate release tablet with a Tmax at 7 hours (Tmax for the immediate release tablet is 2.5 hours). Metformin absorption from the prolonged release formulation is not altered by meal composition. Distribution Plasma protein binding is negligible. Metformin partitions into erythrocytes. Metabolism Metformin is excreted unchanged in the urine. No metabolites have been identified in humans. Elimination Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. Vildagliptin 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 Cmax (19%). However, the magnitude of change is not clinically significant, so that vildagliptin can be given with or 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 (Vss) 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. DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent. Elimination Following oral administration of vildagliptin, approximately 85% of the dose was excreted into the urine and 15% of the dose is recovered in the faeces. 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.

Absorption, Distribution, Metabolism & Excretion

Metformin Absorption After an oral dose of the prolonged release tablet, metformin absorption is significantly delayed compared to the immediate release tablet with a Tmax at 7 hours (Tmax for the immediate release tablet is 2.5 hours). Metformin absorption from the prolonged release formulation is not altered by meal composition. Distribution Plasma protein binding is negligible. Metformin partitions into erythrocytes. Metabolism Metformin is excreted unchanged in the urine. No metabolites have been identified in humans. Elimination Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. Vildagliptin 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 Cmax (19%). However, the magnitude of change is not clinically significant, so that vildagliptin can be given with or 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 (Vss) 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. DPP-4 contributes partially to the hydrolysis of vildagliptin based on an in vivo study using DPP-4 deficient rats. Vildagliptin is not metabolised by CYP 450 enzymes to any quantifiable extent. Elimination Following oral administration of vildagliptin, approximately 85% of the dose was excreted into the urine and 15% of the dose is recovered in the faeces. 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.

Drug Use in Pregnancy

Pregnancy: There is insufficient experience with Vilatin M in pregnant women. Vilatin M should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Lactation Studies in animals have shown excretion of both metformin and vildagliptin in milk. No studies have been conducted with the combined components of Vilatin M. Metformin is excreted into human breast milk. It is not known whether vildagliptin is excreted in human milk or not. Vilatin M should not be administered to breast-feeding women.

Drug Use in Renal Impairment

Renal Impairement: A GFR should be assessed before initiation of treatment with metformin-containing products (such as Vilatin-M) and at least annually thereafter. In patients at increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3 to 6 months. The maximum daily dose of metformin should preferably be divided into 2 to 3 daily doses. Factors that may increase the risk of lactic acidosis should be reviewed before considering initiation of metformin-containing products (such as Vilatin-M) in patients with GFR<60 ml/min. Vilatin-M is contraindicated in patients with GFR <30 ml/min because of its metformin component . The following dosing recommendations apply to metformin and Vildagliptin, used separately or in combination, in patients with renal impairment. If no adequate strength of Vilatin-M is available, individual components should be used instead of the fixed dose combination.

Drug Use in Hepatic Impairment

Vilatin M is not recommended in patients with clinical or laboratory evidence of hepatic impairment including patients with a pre-treatment ALT or AST >2.5X the upper limit of normal

Drug Use in Pediatric Population

The safety and effectiveness of Vilatin M in pediatric patients have not been established. Therefore, Vilatin M is not recommended for use in children below 18 years of age.

Drug Use in Geriatric Population

Geriatric patients (65 years or above) As metformin is excreted via the kidneys, and elderly patients tend to exhibit decreased renal function, elderly patients taking metformin-containing products (such as Vilatin-M) should have their renal function monitored regularly.