Amaryl Information
Amaryl () Description
Amaryl () (glimepiride tablets) is 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. Amaryl () tablets contain the active ingredient glimepiride and the following inactive ingredients: lactose (hydrous), sodium starch glycolate, povidone, microcrystalline cellulose, and magnesium stearate. In addition, Amaryl () 1-mg tablets contain Ferric Oxide Red, Amaryl () 2-mg tablets contain Ferric Oxide Yellow and FD&C Blue #2 Aluminum Lake, and Amaryl () 4-mg tablets contain FD&C Blue #2 Aluminum Lake.
Chemically, 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:
Amaryl () Clinical Pharmacology
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. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which Amaryl () 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 lowers blood glucose during long-term administration has not been clearly established.
Amaryl () is effective as initial drug therapy. In patients where monotherapy with Amaryl () or metformin has not produced adequate glycemic control, the combination of Amaryl () 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 (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 HbA were found to respond in a dose-dependent manner over the range of 1 to 4 mg/day of Amaryl () . Some patients, particularly those with higher fasting plasma glucose (FPG) levels, may benefit from doses of Amaryl () up to 8 mg once daily. No difference in response was found when Amaryl () was administered once or twice daily.
In two 14-week, placebo-controlled studies in 720 subjects, the average net reduction in HbA for Amaryl () (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, Amaryl () 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 Amaryl () therapy.
Combination therapy with Amaryl () 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 Amaryl () /insulin therapy group used approximately 38% less insulin.
Amaryl () therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for Type 2 diabetes.
Amaryl () Indications And Usage
Amaryl () is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (See section).
Amaryl () Contraindications
Amaryl () is contraindicated in patients with
Amaryl () Precautions
Patients should be informed of the potential risks and advantages of Amaryl () 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 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 and 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).
The safety and efficacy of Amaryl () 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. Amaryl () (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
The profile of adverse reactions in pediatric patients treated with Amaryl () was similar to that observed in adults.
Hypoglycemic events, as documented by blood glucose values
In US clinical studies of Amaryl () , 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 ).
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 ).
Amaryl () Adverse Reactions
The incidence of hypoglycemia with Amaryl () , as documented by blood glucose values
Amaryl () 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 Amaryl () are shown below.
Amaryl () Overdosage
Overdosage of sulfonylureas, including Amaryl () , 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.
Amaryl () Dosage And Administration
There is no fixed dosage regimen for the management of diabetes mellitus with Amaryl () 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 Amaryl () may be sufficient during periods of transient loss of control in patients usually controlled well on diet and exercise.
Amaryl () How Supplied
Amaryl () tablets are available in the following strengths and package sizes:
1 mg (pink, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on one side) Bottles of 100 (NDC 0039-0221-10)
2 mg (green, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on one side) Bottles of 100 (NDC 0039-0222-10)
4 mg (blue, flat-faced, oblong with notched sides at double bisect, imprinted with "AMA RYL" on one side) Bottles of 100 (NDC 0039-0223-10)
Amaryl () 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.
Amaryl () 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 Amaryl () 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 Amaryl () 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.
Amaryl ()
Amaryl () Principal Display Panel - Mg Tablet Bottle Label
NDC 0039-0221-10
ONCE A DAY
Amaryl () Principal Display Panel - Mg Tablet Bottle Label
NDC 0039-0222-10
ONCE A DAY
Amaryl () Principal Display Panel - Mg Tablet Bottle Label
NDC 0039-0223-10
ONCE A DAY
