Sunday, June 2, 2013


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Drug Category: Oral Hypoglycemic (Sulfonylurea group)

Glimepiride is an oral blood-glucose-lowering drug of the sulfonylurea class. Chemically, Glimepiride is identified as 1-[{p[2-(3-ethyl-4-methyl-2-oxo-3-pyrolline-1-carboxamido)ethyl]phenyl]-sulfonyl-3-(trans-4-methylcyclhexyl)urea. Its molecular formula is C24H34N4O5S and its molecular weight is 490.62.

Mechanism of Action:
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.

After oral administration, glimepiride is completely (100%) absorbed from the GI tract. Peak levels (Cmax) occur 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 curve) were slightly decreased (8% and 9%, respectively). Protein binding was greater than 99.5%. Glimepiride is completely metabolized by oxidative biotransformation. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxy 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 no 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 clinical meaningful is not clear. When 14C-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 the 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.

Glimepiride is indicated as an adjunct to diet and exercise to lower the blood glucose in patients with non-insulin-dependent (Type II) diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled by diet and exercise alone.

Glimepiride is not suitable for the treatment of type I diabetes mellitus (eg for the treatment of diabetics with history of ketoacidosis), of diabetic ketoacidosis, or of diabetic precoma or coma.
Glimepiride is contraindicated in patients with known hypersensitivity to glimepiride, other sulfonylureas, other sulfonamides or any of the excipients.
There is insufficient data concerning the use of Glimaryl in patients with severe renal or hepatic impairment. A changeover to insulin is indicated.

Precautions and Warnings:
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. The patient should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy.

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 1mg once daily followed by appropriate dose titration is recommended in those 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 drugs 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 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. The phenomenon is known as secondary failure to distinguish if from primary failure in which the drug is ineffective in an individual patient when first given. Should secondary failure occur with glimepiride or metformin monotherapy, combined therapy with glimepiride and metformin or glimepiride and insulin may result in a response. Should secondary failure occur with glimepiride/metformin therapy, it may be necessary to initiate insulin therapy.

Usage in pregnancy, lactation and children:
There are no adequate and well-controlled studies in pregnant women. On basis of results from animal studies, Glimepiride should not be used during pregnancy. Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. Patients who are planning a pregnancy should consult their physician, and it is recommended that they change over to insulin for the entire course of pregnancy and lactation.

Because of the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, glimepiride should be discontinued in nursing mothers. Safety and effectiveness of the drug in pediatric patients have not been established.

Adverse Reactions:
The incidence of hypoglycemia with glimepiride, as documented by blood glucose values ,60mg/dhl, has ranged from 0.9-1.7% in most of the clinical trials carried out with the drug. Adverse events, other than hypoglycemia, considered to be possible or probably related to study drug that occurred in more than 1% patients treated with glimepiride are dizziness, asthenia, headache and nausea.

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 enzymes levels. In isolated instances impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may also lead to liver failure have been reported with sulfonylureas including glimepiride.

Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbiliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of glimepiride. If these hypersensitivity reactions persist, the drug should be discontinued. Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis have been reported with sulfonylurea.

Drug Interactions:
The hypoglycemic action of sulfonylurea may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When these drugs are administered to a patient receiving glimepiride, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed closely for loss of glycemic control.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics and isoniazid. When these drugs are administered to a patient receiving glimepiride, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving glimepiride, the patient should be observed for hypoglycemia.

Dosage and Administration:
The usual starting dose of glimepiride as initial therapy is 1-2mg once daily, administered with breakfast of the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1 mg once daily, and should be titrated carefully. The maximum starting dose of glimepiride should be no more than 2mg.

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 patients blood glucose response.

If patients do not respond adequately to the maximal dose of glimepiride monotherapy, addition of metformin may be considered. Combination therapy with glimepiride and insulin may also be used in secondary failure patients.

Glimepiride is not recommended for use in pregnancy, nursing mother, 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.

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. Or as prescribed by a physician.

Overdosage of sulfonylureas, including glimepiride, can produce hypoglycemia. Mild hypoglycemia 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 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 lever above 100mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparent recovery.

Storage condition:
Store at temperatures not exceeding 30oC. Protect from moisture. Store away from heat and direct light.

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