Glimepiride Information
Glimepiride (Glimepiride) Description
Glimepiride (Glimepiride) tablets USP, are an oral blood-glucose-lowering drug of the sulfonylurea class. Glimepiride (Glimepiride) is a white to yellowish-white, crystalline, odorless to practically odorless powder formulated into tablets of 1 mg, 2 mg, and 4 mg strengths for oral administration. Glimepiride (Glimepiride) tablets contain the active ingredient Glimepiride (Glimepiride) and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. In addition, Glimepiride (Glimepiride) 1 mg tablets contain ferric oxide red, Glimepiride (Glimepiride) 2 mg tablets contain lake blend green (contains D&C yellow # 10 aluminium lake and FD&C blue #1/ brilliant blue FCF aluminium lake) and Glimepiride (Glimepiride) 4 mg tablets contain lake blend blue (contains D&C yellow # 10 aluminium lake and FD&C blue # 1/ brilliant blue FCF aluminium lake).
Chemically, Glimepiride (Glimepiride) is identified as 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1- carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.
The CAS Registry Number is 93479-97-1
The structural formula is:
Molecular Formula: CHNOS
Molecular Weight: 490.62
Glimepiride (Glimepiride) is practically insoluble in water.
Glimepiride (Glimepiride) Clinical Pharmacology
The primary mechanism of action of Glimepiride (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 (Glimepiride) . This is supported by both preclinical and clinical studies demonstrating that Glimepiride (Glimepiride) administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which Glimepiride (Glimepiride) therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which Glimepiride (Glimepiride) lowers blood glucose during long-term administration has not been clearly established.
Glimepiride (Glimepiride) is effective as initial drug therapy. In patients where monotherapy with Glimepiride (Glimepiride) or metformin has not produced adequate glycemic control, the combination of Glimepiride (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 appeared 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 [T]) was about 2 to 3 hours. In noninsulin-dependent (Type 2) diabetes mellitus (NIDDM) patients, both fasting and 2-hour postprandial glucose levels were significantly lower with Glimepiride (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 HbAwere found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of Glimepiride (Glimepiride) . Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of Glimepiride (Glimepiride) up to 8 mg once daily. No difference in response was found when Glimepiride (Glimepiride) was administered once or twice daily
In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in HbA for Glimepiride (Glimepiride) tablets patients treated with 8 mg once daily was 2.0% in absolute units compared with placebo-treated patients. In a long-term, randomized, placebo-controlled study of Type 2 diabetic patients unresponsive to dietary management, Glimepiride (Glimepiride) therapy improved postprandial insulin/C-peptide responses, and 75% of patients achieved and maintained control of blood glucose and HbA. Efficacy results were not affected by age, gender, weight, or race.
In long-term extension trials with previously-treated patients, no meaningful deterioration in mean fasting blood glucose (FBG) or HbA levels was seen after 2 1/2 years of Glimepiride (Glimepiride) therapy.
Combination therapy with Glimepiride (Glimepiride) and insulin (70% NPH/30% regular) was compared to placebo/insulin in secondary failure patients whose body weight was >130% of their ideal body weight. Initially, 5-10 units of insulin were administered with the main evening meal and titrated upward weekly to achieve predefined FPG values. Both groups in this double-blind study achieved similar reductions in FPG levels but the Glimepiride (Glimepiride) /insulin therapy group used approximately 38% less insulin.
Glimepiride (Glimepiride) therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for Type 2 diabetes.
Glimepiride (Glimepiride) Indications And Usage
Glimepiride (Glimepiride) tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (See section).
Glimepiride (Glimepiride) Contraindications
Glimepiride (Glimepiride) tablets are contraindicated in patients with
1. Known hypersensitivity to the drug.
2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
Glimepiride (Glimepiride) Precautions
Patients should be informed of the potential risks and advantages of Glimepiride (Glimepiride) and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. The potential for primary and secondary failure should also be explained.
Studies in rats at doses of up to 5000 ppm in complete feed (approximately 340 times the maximum recommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis. In mice, administration of Glimepiride (Glimepiride) for 24 months resulted in an increase in benign pancreatic adenoma formation which was dose related and is thought to be the result of chronic pancreatic stimulation. The no-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46-54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.
Glimepiride (Glimepiride) was non-mutagenic in a battery of and mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test).
There was no effect of Glimepiride (Glimepiride) on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>l,700 times the maximum recommended human dose based on surface area). Glimepiride (Glimepiride) had no effect on the fertility of male and female rats administered up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area).
Glimepiride (Glimepiride) did not produce teratogenic effects in rats exposed orally up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended human dose based on surface area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times the maximum recommended human dose based on surface area). Glimepiride (Glimepiride) has been shown to be associated with intrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surface area and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. This fetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with other sulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action of Glimepiride (Glimepiride) .
There are no adequate and well-controlled studies in pregnant women. On the basis of results from animal studies, Glimepiride (Glimepiride) tablets should not be used during pregnancy. Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain glucose levels as close to normal as possible.
In some studies in rats, offspring of dams exposed to high levels of Glimepiride (Glimepiride) during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of Glimepiride (Glimepiride) were observed in the serum and breast milk of the dams as well as in the serum of the pups. These skeletal deformations were determined to be the result of nursing from mothers exposed to Glimepiride (Glimepiride) .
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.
The safety and efficacy of Glimepiride (Glimepiride) were evaluated in an active-controlled, single-blind (patients only), 24-week trial involving 272 pediatric patients, ranging from 8 to 17 years of age, with Type 2 diabetes. Glimepiride (Glimepiride) (n=135) was administered at 1mg initially, and then titrated up to 2, 4 or 8 mg (mean last dose 4 mg) until the therapeutic goal of self-monitored fasting blood glucose
* - Intent-to-treat population (Glimepiride (Glimepiride) , n=127; metformin, n=126)
+ - Change from baseline means are least square means adjusting for baseline HbA and Tanner Stage
** - Difference is Glimepiride (Glimepiride) – metformin with positive differences favoring metformin
The profile of adverse reactions in pediatric patients treated with Glimepiride (Glimepiride) was similar to that observed in adults.
Hypoglycemic events, as documented by blood glucose values
* - Safety population with on-treatment evaluation for weight (Glimepiride (Glimepiride) , n=129; metformin, n=126)
+ - Change from baseline means are least square means adjusting for baseline HbA and Tanner Stage
** - Difference is Glimepiride (Glimepiride) – metformin with positive differences favoring metformin
In US clinical studies of Glimepiride (Glimepiride) , 608 of 1986 patients were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Comparison of Glimepiride (Glimepiride) pharmacokinetics in Type 2 diabetic patients £65 years (n=49) and those >65 years (n=42) was performed in a study using a dosing regimen of 6 mg daily. There were no significant differences in Glimepiride (Glimepiride) pharmacokinetics between the two age groups (see ).
The drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Elderly patients are particularly susceptible to hypoglycemic action of glucose-lowering drugs. In elderly, debilitated, or malnourished patients, or in patients with renal and hepatic insufficiency, the initial dosing, dose increments, and maintenance dosage should be conservative based upon blood glucose levels prior to and after initiation of treatment to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs or other sympatholytic agents (see ; ; and ).
Glimepiride (Glimepiride) Adverse Reactions
The incidence of hypoglycemia with Glimepiride (Glimepiride) , as documented by blood glucose values
Glimepiride (Glimepiride) has been evaluated for safety in 2,013 patients in US controlled trials, and in 1,551 patients in foreign controlled trials. More than 1,650 of these patients were treated for at least 1 year.
Adverse events, other than hypoglycemia, considered to be possibly or probably related to study drug that occurred in US placebo-controlled trials in more than 1% of patients treated with Glimepiride (Glimepiride) are shown below.
Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in less than 1% of treated patients. These may be transient and may disappear despite continued use of Glimepiride (Glimepiride) . If those hypersensitivity reactions persist or worsen, (e.g., dyspnea, fall in blood pressure, shock), the drug should be discontinued.
Porphyria cutanea tarda, photosensitivity reactions, and allergic vasculitis have been reported with sulfonylureas, including Glimepiride (Glimepiride) .
Glimepiride (Glimepiride) Overdosage
Overdosage of sulfonylureas, including Glimepiride (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.
Glimepiride (Glimepiride) Dosage And Administration
There is no fixed dosage regimen for the management of diabetes mellitus with Glimepiride (Glimepiride) or any other hypoglycemic agent. The patient’s fasting blood glucose and HbA 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 (Glimepiride) may be sufficient during periods of transient loss of control in patients usually controlled well on diet and exercise.
Glimepiride (Glimepiride) How Supplied
Glimepiride (Glimepiride) tablets USP, 2 mg are green, oval, flat bevelled edged, uncoated tablets embossed "ROY" on one side and "321" separating "3" and "21" with bisect line scoring on the other side and are supplied in unit dose package of 100 (10 x 10).
Unit dose package of 100 (10 x 10) NDC 68084-326-01
Glimepiride (Glimepiride) tablets USP, 4 mg are blue, oval, flat bevelled edged, uncoated tablets embossed "ROY" on one side and "322" separating "3" and "22" with bisect line scoring on the other side and are supplied in unit dose package of 100 (10 x 10).
Unit dose package of 100 (10 x 10) NDC 68084·327-01
Store at 20'-25'C (68'·77'F) [see USP Controlled Room Temperature].
Glimepiride (Glimepiride) animal Toxicology
Reduced serum glucose values and degranulation of the pancreatic beta cells were observed in beagle dogs exposed to 320 mg Glimepiride (Glimepiride) /kg/day for 12 months (approximately 1,000 times the recommended human dose based on surface area). No evidence of tumor formation was observed in any organ. One female and one male dog developed bilateral subcapsular cataracts. Non-GLP studies indicated that Glimepiride (Glimepiride) was unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic potential of Glimepiride (Glimepiride) in several diabetic and cataract rat models was negative and there was no adverse effect of Glimepiride (Glimepiride) on bovine ocular lens metabolism in organ culture.
Glimepiride (Glimepiride) Human Ophthalmology Data
Ophthalmic examinations were carried out in over 500 subjects during long-term studies using the methodology of Taylor and West and Laties et al. No significant differences were seen between Glimepiride (Glimepiride) and glyburide in the number of subjects with clinically important changes in visual acuity, intra-ocular tension, or in any of the five lens-related variables examined.
Ophthalmic examinations were carried out during long-term studies using the method of Chylack et al. No significant or clinically meaningful differences were seen between Glimepiride (Glimepiride) and glipizide with respect to cataract progression by subjective LOCS II grading and objective image analysis systems, visual acuity, intraocular pressure, and general ophthalmic examination.
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Manufactured by: Bachepalli – 502 325 INDIA
Repackaged by: Columbus, Ohio 43217
Glimepiride (Glimepiride) Package Label.principal Display Panel
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