Source: Health Products Regulatory Authority (ZA) Revision Year: 2022 Publisher: Novartis South Africa (Pty) Ltd., Magwa Crescent West, Waterfall City, Jukskei View, Johannesburg, 2090
Pharmacological Classification: A 21.2. Oral hypoglycaemics
JALRAMET combines two antihyperglycaemic agents with different mechanisms of action to improve glycaemic control in patients with type 2 diabetes: vildagliptin, a member of the DPP-4 (dipeptidylpeptidase-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 (DPP4) inhibitor that improves glycaemic control.
The administration of vildagliptin results in inhibition of DPP-4 activity. In patients with type 2 diabetes, administration of vildagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. Vildagliptin inhibition of DPP-4 results in increased fasting and postprandial endogenous levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic polypeptide).
By increasing the endogenous levels of these incretin hormones, vildagliptin enhances the sensitivity of 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 nondiabetic (normal glycaemic) 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 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 to delay gastric emptying is not observed with vildagliptin treatment. In addition, a reduction in postprandial lipaemia that is not associated with vildagliptin’s incretin mediated effect to improve islet function, has been observed.
Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation. With metformin hydrochloride therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
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 GLUT4).
In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or longterm clinical studies: metformin hydrochloride reduces total cholesterol, LDLc and triglyceride levels.
In the bioequivalence studies of JALRAMET at two dose strengths (50 mg/850 mg and 50 mg/1000 mg), versus free combination of vildagliptin and metformin hydrochloride tablets at the corresponding doses, the area under the curve (AUC) and maximum concentration (Cmax) of both the vildagliptin component and the metformin hydrochloride component of the JALRAMET tablets were demonstrated to be bioequivalent to that of free combination tablets.
Food does not affect the extent and rate of absorption of vildagliptin from JALRAMET. The Cmax and AUC of the metformin hydrochloride component from JALRAMET were decreased by 26% and 7% respectively when given with food. The absorption of metformin hydrochloride was also delayed as reflected by the Tmax (2,0 to 4,0 hours) when given with food. These changes in Cmax 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 of JALRAMET were similar to the pharmacokinetics of vildagliptin and metformin hydrochloride when given alone with food.
Following oral administration in the fasting state, vildagliptin is well absorbed with peak plasma concentrations observed at 1,75 hours. Co-administration with food slightly decreases the rate of absorption of vildagliptin, as characterised 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).
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 1500 mg, and 850 mg to 2550 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 (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) 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.
Vildagliptin is well 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.
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 L, suggesting extravascular distribution.
The apparent volume of distribution (V/F) of metformin hydrochloride following single oral doses of 850 mg averaged 654 ± 358 L. 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 µgram/mL. During controlled clinical studies of metformin hydrochloride, maximum metformin hydrochloride plasma levels did not exceed 5 µgram/mL, even at maximum doses.
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 metabolised by cytochrome P450 enzymes to any quantifiable extent. In-vitro studies demonstrated that vildagliptin does not inhibit or induce cytochrome P450 enzymes.
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
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 faeces. 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 dose.
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 medicine 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.
BMI does not show any impact on the pharmacokinetic parameters of vildagliptin. DPP-4 inhibition by vildagliptin was unaffected by BMI.
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 >2,5 x the ULN (upper limit of normal).
No pharmacokinetic studies of metformin hydrochloride have been conducted in subjects with hepatic impairment.
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 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- 3-fold higher than in patients with severe renal impairment.
Vildagliptin was removed by haemodialysis to a limited extent (3% over a 3-4 hour haemodialysis session starting 4 hours post dose).
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.
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.
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 Cmax 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.
JALRAMET treatment should not be initiated in patients 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.
No pharmacokinetic data available.
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