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GLIMEPIRIDE TABLETS
1 mg, 2mg and 4mg

Rx only

DESCRIPTION
Glimepiride tablets are an oral-blood-glucose-lowering drug of the sulfonylurea class. 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 tablets contain the active ingredient glimepiride USP and the following inactive ingredients: carboxymethylcellulose calcium, lactose monohydrate, magnesium stearate and povidone. In addition, glimepiride 1-mg tablets contain Red 30 Iron Oxide, glimepiride 2-mg tablets contain FD&C Blue #2 Aluminum Lake and Yellow 10 Iron Oxide, and glimepiride 4-mg tablets contain FD&C Blue #2 Aluminum Lake.

Chemically, glimepiride is identified as 1-[[ρ-[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: C24H34N4O5S
Molecular Weight: 490.62
Glimepiride is practically insoluble in water.

CLINICAL PHARMACOLOGY

Pharmacokinetics

Special Populations

INDICATIONS AND USAGE
Glimepiride tablets are indicated as an adjunct to diet and exercise to lower the blood glucose in patients with noninsulin-dependent (Type 2) 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 tablets are 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.

In initiating treatment for noninsulin-dependent diabetes, diet and exercise should be emphasized as the primary form of treatment. Caloric restriction, weight loss, and exercise are essential in the obese diabetic patient. Proper dietary management and exercise alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. In addition to regular physical activity, cardiovascular risk factors should be identified and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of glimepiride tablets must be viewed by both the physician and patient as a treatment in addition to diet and exercise and not as a substitute for diet and exercise or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet and exercise alone may be transient, thus requiring only short-term administration of glimepiride tablets.

During maintenance programs, glimepiride monotherapy should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations. Secondary failures to glimepiride monotherapy can be treated with glimepiride-insulin combination therapy.

In considering the use of glimepiride tablets in asymptomatic patients, it should be recognized that blood glucose control in Type 2 diabetes has not definitely been established to be effective in preventing the long-term cardiovascular and neural complications of diabetes. However, the Diabetes Control and Complications Trial (DCCT) demonstrated that control of HbAlc and glucose was associated with a decrease in retinopathy, neuropathy, and nephropathy for insulin-dependent diabetic (IDDM) patients.

CONTRAINDICATIONS
Glimepiride tablets are contraindicated in patients with:

  • Known hypersensitivity to the drug.
  • Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

WARNINGS

PRECAUTIONS

General

Information for Patients
Patients should be informed of the potential risks and advantages of 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.

Laboratory Tests
Fasting blood glucose should be monitored periodically to determine therapeutic response. Glycosylated hemoglobin should also be monitored, usually every 3 to 6 months, to more precisely assess long-term glycemic control.

Carcinogenesis, Mutagenesis, and Impairment of Fertility
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 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 was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on surface area). 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).

Pregnancy

Nursing Mothers
In rat reproduction studies, significant concentrations of glimepiride were observed in the serum and breast milk of the dams, as well as in the serum of the pups. Although it is not known whether glimepiride is excreted in human milk, other sulfonylureas are excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, glimepiride should be discontinued in nursing mothers. If glimepiride is discontinued, and if diet and exercise alone are inadequate for controlling blood glucose, insulin therapy should be considered. (See Pregnancy, Nonteratogenic Effects. )

Pediatric Use
The safety and efficacy of 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 (n=135) was administered at 1 mg 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 < 7.0 mmol/L (< 126 mg/dl) was achieved. The active comparator metformin (n=137) was administered at 500 mg twice daily initially and titrated up to 1000 mg twice daily (mean last dose 1469 mg).

HbAlc (%)Naive Patients- Intent-to-treat population (glimepiride, n=127; metformin, n=126)Previously Treated Patients
MetforminGlimepirideMetforminGlimepiride
69725755
Baseline (mean)8.28.39.08.7
Change from baseline (mean)- Change from baseline means are least square means adjusting for baseline HbA1c and Tanner Stage-1.2-1.0-0.20.2
Adjusted Treatment Difference- Difference is glimepiride – metformin with positive differences favoring metformin0.20.4
(95% CI)(-0.3;0.7)(-0.4;1.2)

The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults.

Hypoglycemic events, as documented by blood glucose values <36 mg/dL, were observed in 4% of patients treated with glimepiride and in 1% of patients treated with metformin.

Weight(kg)Metformin- Safety population with on-treatment evaluation for weight (glimepiride, n=129; metformin, n=126)Glimepiride
Baseline (mean)67.366.5
Change from Baseline (mean)- Change from baseline means are least square means adjusting for baseline HbA1c and Tanner Stage0.72.0
Adjusted Treatment Difference- Difference is glimepiride – metformin with positive differences favoring metformin1.3
(95% CI)(0.3;2.3)

Geriatric Use
In US clinical studies of 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 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 pharmacokinetics between the two age groups (see CLINICAL PHARMACOLOGY, Special Populations, Geriatric).

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 CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency;PRECAUTIONS, General; and DOSING AND ADMINISTRATION, Specific Patient Population).

ADVERSE REACTIONS

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.

DOSAGE AND ADMINISTRATION
There is no fixed dosage regimen for the management of diabetes mellitus with glimepiride tablets or any other hypoglycemic agent. The patient's fasting blood glucose and HbAlc 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 tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet and exercise.

HOW SUPPLIED
Glimepiride tablets 1 mg are pink, round compressed tablets debossed cor above the bisect and 164 below the bisect on one side and other side is plain. They are supplied as follows:
           Bottles of 100                     (NDC 0781-5045-01)
           Bottles of 1000                   (NDC 0781-5045-10)

Glimepiride tablets 2 mg are light green, round compressed tablets debossed cor above the bisect and 165 below the bisect on one side and other side is plain. They are supplied as follows:
           Bottles of 100                     (NDC 0781-5046-01)
           Bottles of 1000                   (NDC 0781-5046-10)

Glimepiride tablets 4 mg are blue, round compressed tablets debossed cor above the bisect and 166 below the bisect on one side and other side is plain. They are supplied as follows:
           Bottles of 100                    (NDC 0781-5047-01)
           Bottles of 1000                  (NDC 0781-5047-10)

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Dispense in a light-resistant, tight container with child-resistant closure as defined in the USP.

Keep this and all drugs out of the reach of children.

ANIMAL TOXICOLOGY
Reduced serum glucose values and degranulation of the pancreatic beta cells were observed in beagle dogs exposed to 320 mg 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 was unlikely to exacerbate cataract formation. Evaluation of the co-cataractogenic potential of glimepiride in several diabetic and cataract rat models was negative and there was no adverse effect of glimepiride on bovine ocular lens metabolism in organ culture.

HUMAN OPTHAMOLOGY 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 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 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.

Rev. 07-2007
MF # 442-02


Manufactured by
Corepharma LLC
Middlesex, NJ 08846 for
Sandoz Inc.
Princeton,NJ 08540

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