About us

Services
Registration Dossiers
SPC
Preclinical Expert Report
Clinical Expert Report
Package Inserts
Patient Leaflets
Medical Writing

Contact us

For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory

Glimepiride Tablets

Composition

Each tablet contains :
Glimepiride 1, 2 or 4 mg

Therapeutic Category: Antidiabetic Agent

Pharmacology

Pharmacodynamics

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. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. However, as with other sulfonylureas, the mechanism by which glimepiride lowers blood glucose during long-term administration has not been clearly established. 

Glimepiride is effective as initial drug therapy. In patients where monotherapy with glimepiride or metformin has not produced adequate glycemic control, the combination of glimepiride and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different primary mechanisms of action. This complementary effect has been observed with metformin and other sulfonylureas, in multiple studies. 

A mild glucose-lowering effect first appears following single oral doses as low as 0.5-0.6 mg in healthy subjects. The time required to reach the maximum effect (i.e., minimum blood glucose level [Tmin]) was about 2 to 3 hours. In noninsulin-dependent (Type II) diabetes mellitus (NIDDM) patients, both fasting and 2-hour postprandial glucose levels were significantly lowered with glimepiride (1, 2, 4, and 8 mg once daily) than with placebo after 14 days of oral dosing. The glucose-lowering effect in all active treatment groups was maintained over 24 hours. 

In larger dose-ranging studies, blood glucose and HbA1c were found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of glimepiride. Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of glimepiride up to 8 mg once daily. No difference in response was found when glimepiride was administered once or twice daily. 

Pharmacokinetics

Absorption

After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with NIDDM have shown significant absorption of glimepiride within 1 hour after administration and peak drug levels (Cmax) at 2 to 3 hours. When glimepiride was given with meals, the mean Tmax (time to reach Cmax) was slightly increased (12%) and the mean Cmax and AUC (area under the curve) were slightly decreased (8% and 9%, respectively). 

Distribution

After intravenous (IV) dosing in normal 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 IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 II C9 has been shown to be involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear. 

Excretion

When 14 C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that 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. 

Glimepiride may be given in a starting dose of 1 mg to NIDDM patients with kidney disease and the dose may be titrated based on fasting blood glucose levels.

Indications

Glimepiride is indicated as an adjunct to diet and exercise to lower the blood glucose in patients with noninsulin-dependent (Type II) diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled by diet and exercise alone. Glimepiride may be used concomitantly with metformin when diet, exercise, and glimepiride or metformin alone do not result in adequate glycemic control. 

Glimepiride is also indicated for use in combination with insulin to lower blood glucose in patients whose hyperglycemia cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent. Combined use of glimepiride and insulin may increase the potential for hypoglycemia. 

Contraindications

Glimepiride is contraindicated in patients with known hypersensitivity to the drug and diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. 

Side effects/Adverse reactions

The incidence of hypoglycemia with glimepiride, as documented by blood glucose values <60 mg/dL, ranged from 0.9-1.7% in clinical studies.

Besides hypoglycemia, dizziness, asthenia, headache and nausea are the common adverse effects with glimepiride. Vomiting, gastrointestinal pain and diarrhea have been reported, but the incidence in placebo-controlled trials was less than 1%. In rare cases, there may be an elevation of liver enzyme levels. In isolated instances, impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, have been reported with sulfonylureas, including glimepiride. 

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in some patients. These may be transient and may disappear with continued use of glimepiride. If these hypersensitivity reactions persist or worsen, the drug should be discontinued.

Changes in accommodation and/or blurred vision may occur with the use of glimepiride. This is thought to be due to changes in blood glucose, and may be more pronounced when treatment is initiated. This condition is also seen in untreated diabetic patients, and may actually be reduced by treatment. 

Precautions and Warnings

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection, dosage and instructions are important to avoid hypoglycemic episodes. Patients with impaired renal function may be more sensitive to the glucose-lowering effect of glimepiride. A starting dose of 1 mg once daily followed by appropriate dose titration is recommended in these patients. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. Combined use of glimepiride with insulin or metformin may increase the potential for hypoglycemia.

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to add insulin in combination with glimepiride or even use insulin monotherapy. The effectiveness of any oral hypoglycemic drug, including glimepiride, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Should secondary failure occur with glimepiride monotherapy, combined therapy with glimepiride and metformin or glimepiride and insulin may result in a response. 

Dosage and Administration

There is no fixed dosage regimen for the management of diabetes mellitus with glimepiride or any other hypoglycemic agent. The patient's fasting blood glucose and HbA1c must be measured periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels should be performed to monitor the patient's response to therapy. 

Short-term administration of glimepiride may be sufficient during periods of transient loss of control in patients usually controlled well on diet and exercise. 

Usual Starting Dose 

The usual starting dose of glimepiride as initial therapy is 1-2 mg once daily, administered with breakfast or the first main meal. Patients who are more sensitive to hypoglycemic drugs should be started at 1 mg once daily, and should be titrated carefully. 

No exact dosage relationship exists between glimepiride and the other oral hypoglycemic agents. The maximum starting dose of glimepiride should be no more than 2 mg. 

Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy. 

Usual Maintenance Dose 

The usual maintenance dose is 1 to 4 mg once daily. The maximum recommended dose is 8 mg once daily. After reaching a dose of 2 mg, dosage increases should be made in increments of no more than 2 mg at 1-2 week intervals based upon the patient's blood glucose response. Long-term efficacy should be monitored by measurement of HbA1c levels, for example, every 3 to 6 months. 

Specific Patient Populations 

Glimepiride is not recommended for use in pregnancy, nursing mothers, or children. In elderly, debilitated, or malnourished patients, or in patients with renal or hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions 

Patients Receiving Other Oral Hypoglycemic Agents 

As with other sulfonylurea hypoglycemic agents, no transition period is necessary when transferring patients to glimepiride. Patients should be observed carefully(1-2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glimepiride due to potential overlapping of drug effect. 

Symptoms and treatment of overdosage

Overdosage of sulfonylureas, including glimepiride, can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent clinical recovery. 

Storage conditions, user instructions and pharmaceutical precautions

Storage condition :
Expiry :

Presentation

Blister pack of 10 tablets