This medication contains two oral anti-hyperglycaemic drugs glimepiride and metformin hydrochloride sustained release used in the management of type 2 diabetes (NIDDM). The primary mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Hence, the combination of glimepiride and metformin sustained release complement each other and provide better glycaemic control in management of type 2 diabetes and probably in the prevention of its associated macrovascular and microvascular complications.
Mechanism Of Action
Glimepiride:Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.
In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations) was approximately 2-3 hours after single oral doses of glimepiride.
Metformin:Metformin is an oral antihyperglycaemic drug used in the management of type 2 diabetes. It improves glucose tolerance in patients with type 2 diabetes (NIDDM), lowering both basal and postprandial plasma glucose. Metformin is not chemically or pharmacologically related to sulphonylureas, thiazolidinediones, or α-glucosidase inhibitors. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Glimepiride:Absorption: Studies with single oral doses of glimepiride in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours post-dose. When glimepiride was given with meals, the mean Cmax and AUC (area under the curve) were decreased by 8% and 9%, respectively.
Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range, indicating linear pharmacokinetics. In healthy subjects, the intra- and inter-individual variabilities of glimepiride pharmacokinetic parameters were 15-23% and 24-29%, respectively.
Distribution: After intravenous (IV) dosing in healthy subjects, the volume of distribution (Vd) was 8.8 l (113 ml/Kg), and the total body clearance (CL) was 47.8 ml/min. Protein binding was greater than 99.5%.
Metabolism: Glimepiride is completely metabolized by oxidative biotransformation after either an intravenous (IV) or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 C9 is involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M2 is inactive. In animals, M1 possesses about one-third of the pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically meaningful effects on blood glucose in humans.
Excretion: When 14 C-glimepiride was given orally to 3 healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 and M2 accounted for 80-90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. M1 and M2 accounted for approximately 70% (ratio of M1 to M2 was 1:3) of the radioactivity recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite has been observed.
Metformin SR:Absorption: The absolute bioavailability of a metformin 500-mg tablet given under fasting conditions is approximately 50-60%. Following a single oral dose of metformin sustained release; Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin immediate release, however, the extent of absorption (as measured by AUC) is similar to immediate release.
Although the extent of metformin absorption (as measured by AUC) from the sustained release tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of sustained release. Distribution: Distribution studies with metformin sustained release have not been conducted. However, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulphonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of immediate-release metformin, steady state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 μg/mL. During controlled clinical trials of immediate-release metformin, maximum metformin plasma levels did not exceed 5 μg/mL, even at maximum doses.
Metabolism: Metabolism studies with metformin sustained release have not been conducted. However, intravenous single-dose studies in normal subjects demonstrate that metformin immediate release is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Excretion: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance of metformin is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin 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.
Hypoglycemia, dizziness, asthenia, headache, nausea, vomiting, diarrhea
- Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females] or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicaemia.
- Known hypersensitivity to metformin, glimepiride or any of the components of this product.
- Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
- Patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.
- Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to this medicine. Do not use this in patients who have a history of an allergic reaction to sulfonamide derivatives.
Fertility, Pregnancy And Lactation
Pregnancy:Category C: There are no adequate and well-controlled studies of glimepiride in pregnant women. Glimepiride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because data suggest that abnormal blood glucose during pregnancy is associated with a higher incidence of congenital abnormalities, diabetes treatment during pregnancy should maintain the blood glucose levels as close to normal as possible. The use of glimepiride and metformin combination is not recommended for use in pregnancy.
Lactation:Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted on nursing mothers. Glimepiride should not be used by breast-feeding mothers. Hence, the use of glimepiride and metformin combination is not recommeneded for use in lactating mothers, and if the diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Paediatric use:Glimepiride is not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia. Safety and effectiveness of metformin sustained release in paediatric patients have not been established.
Geriatric use:Metformin is known to be excreted by the kidneys, and because risk of serious adverse reactions to the drug is greater in patients with impaired renal function, hence glimepiride and metformin should be used only in patients with normal renal function. Because aging is associated with reduced renal function the use of glimepiride and metformin combination should be with caution as age increases. Care should be taken in the dose selection of this combination and regular renal function should be monitored.
- Concomitant administration with propranolol increases Cmax, AUC, and T1/2 of glimepiride.
- Aspirin increases the mean AUC of glimepiride.
- Furosemide increases the Cmax of metformin.
- Potentially Fatal: NSAIDS, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, MAOs, and beta blockers potentiate the hypoglycemic action of glimepiride.
- Reduced plasma concentration with colesevelam.
- Renal and hepatic impairment
- Avoid alcohol consumption
- Hypoglycaemic episodes
Glimepiride:An overdosage of glimepiride, as with other sulfonylureas, can produce severe hypoglycemia. Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma, seizure, or neurological impairment can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary because hypoglycemia may recur after apparent clinical recovery.
Metformin SR :Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycaemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, haemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.