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Amaryl (Glimepiride) - Description and Clinical Pharmacology



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:


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. 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 [Tmin]) 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 HbA1c 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 HbA1c 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 HbA1c. 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 HbA1c 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.



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 Type 2 diabetes 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).


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%.


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 2C9 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.


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 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.

Pharmacokinetic Parameters

The pharmacokinetic parameters of glimepiride obtained from a single-dose, crossover, dose-proportionality (1, 2, 4, and 8 mg) study in normal subjects and from a single- and multiple-dose, parallel, dose-proportionality (4 and 8 mg) study in patients with Type 2 diabetes are summarized below:

VolunteersPatients with Type 2 diabetes
Single Dose
Single Dose (Day 1)
Multiple Dose (Day 10)
() = No. of subjects
CL/f=Total body clearance after oral dosing
Vd/f=Volume of distribution calculated after oral dosing
Cmax (ng/mL)
1 mg103 ± 34 (12)
2 mg177 ± 44 (12)
4 mg308 ± 69 (12)352 ± 222 (12)309 ± 134 (12)
8 mg551 ± 152 (12)591 ± 232 (14)578 ± 265 (11)
Tmax (h)2.4 ± 0.8 (48)2.5 ± 1.2 (26)2.8 ± 2.2 (23)
CL/f (mL/min)52.1 ± 16.0 (48)48.5 ± 29.3 (26)52.7 ± 40.3 (23)
Vd/f (L)21.8 ± 13.9 (48)19.8 ± 12.7 (26)37.1 ± 18.2 (23)
T1/2 (h)5.3 ± 4.1 (48)5.0 ± 2.5 (26)9.2 ± 3.6 (23)

These data indicate that glimepiride did not accumulate in serum, and the pharmacokinetics of glimepiride were not different in healthy volunteers and in Type 2 diabetic patients. Oral clearance of glimepiride did not change over the 1–8-mg dose range, indicating linear pharmacokinetics.


In normal healthy volunteers, the intra-individual variabilities of Cmax, AUC, and CL/f for glimepiride were 23%, 17%, and 15%, respectively, and the inter-individual variabilities were 25%, 29%, and 24%, respectively.

Special Populations


Comparison of glimepiride pharmacokinetics in Type 2 diabetic patients ≤65 years and those >65 years 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. The mean AUC at steady state for the older patients was about 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was about 11% higher than that for the younger patients.


The pharmacokinetics of glimepiride (1 mg) were evaluated in a single dose study conducted in 30 Type 2 diabetic patients (Male = 7; Female = 23) between ages 10 and 17 years. The mean AUC(0–last)(338.8±203.1 ng∙hr/mL), Cmax (102.4±47.7 ng/mL) and T1/2(3.1±1.7 hours) were comparable to those previously reported in adults (AUC(0–last) 315.2±95.9 ng∙hr/mL, Cmax 103.2±34.3 ng/mL and T1/2 5.3±4.1 hours).


There were no differences between males and females in the pharmacokinetics of glimepiride when adjustment was made for differences in body weight.


No pharmacokinetic studies to assess the effects of race have been performed, but in placebo-controlled studies of AMARYL (glimepiride tablets) in patients with Type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 536), blacks (n = 63), and Hispanics (n = 63).

Renal Insufficiency

A single-dose, open-label study was conducted in 15 patients with renal impairment. AMARYL (3 mg) was administered to 3 groups of patients with different levels of mean creatinine clearance (CLcr); (Group I, CLcr = 77.7 mL/min, n = 5), (Group II, CLcr = 27.7 mL/min, n = 3), and (Group III, CLcr = 9.4 mL/min, n = 7). AMARYL was found to be well tolerated in all 3 groups. The results showed that glimepiride serum levels decreased as renal function decreased. However, M1 and M2 serum levels (mean AUC values) increased 2.3 and 8.6 times from Group I to Group III. The apparent terminal half-life (T1/2) for glimepiride did not change, while the half-lives for M1 and M2 increased as renal function decreased. Mean urinary excretion of M1 plus M2 as percent of dose, however, decreased (44.4%, 21.9%, and 9.3% for Groups I to III).

A multiple-dose titration study was also conducted in 16 Type 2 diabetic patients with renal impairment using doses ranging from 1–8 mg daily for 3 months. The results were consistent with those observed after single doses. All patients with a CLcr less than 22 mL/min had adequate control of their glucose levels with a dosage regimen of only 1 mg daily. The results from this study suggested that a starting dose of 1 mg AMARYL may be given to Type 2 diabetic patients with kidney disease, and the dose may be titrated based on fasting blood glucose levels.

Hepatic Insufficiency

No studies were performed in patients with hepatic insufficiency.

Other Populations

There were no important differences in glimepiride metabolism in subjects identified as phenotypically different drug-metabolizers by their metabolism of sparteine. The pharmacokinetics of glimepiride in morbidly obese patients were similar to those in the normal weight group, except for a lower Cmax and AUC. However, since neither Cmax nor AUC values were normalized for body surface area, the lower values of Cmax and AUC for the obese patients were likely the result of their excess weight and not due to a difference in the kinetics of glimepiride.

Drug Interactions

The hypoglycemic action of sulfonylureas 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, beta adrenergic blocking agents, disopyramide, fluoxetine, quinolones, and clarithromycin. When these drugs are administered to a patient receiving AMARYL, the patient should be observed closely for hypoglycemia. When these drugs are withdrawn from a patient receiving AMARYL, the patient should be observed closely for loss of glycemic control.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known.

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 AMARYL, the patient should be closely observed for loss of control. When these drugs are withdrawn from a patient receiving AMARYL, the patient should be observed closely for hypoglycemia.

Coadministration of aspirin (1 g tid) and AMARYL led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean Cmax had a decrease of 4%. Blood glucose and serum C-peptide concentrations were unaffected and no hypoglycemic symptoms were reported. Pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of aspirin and other salicylates.

Coadministration of either cimetidine (800 mg once daily) or ranitidine (150 mg bid) with a single 4-mg oral dose of AMARYL did not significantly alter the absorption and disposition of glimepiride, and no differences were seen in hypoglycemic symptomatology. Pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of H2-receptor antagonists.

Concomitant administration of propranolol (40 mg tid) and AMARYL significantly increased Cmax, AUC, and T1/2 of glimepiride by 23%, 22%, and 15%, respectively, and it decreased CL/f by 18%. The recovery of M1 and M2 from urine, however, did not change. The pharmacodynamic responses to glimepiride were nearly identical in normal subjects receiving propranolol and placebo. Pooled data from clinical trials in patients with Type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of beta-blockers. However, if beta-blockers are used, caution should be exercised and patients should be warned about the potential for hypoglycemia.

Concomitant administration of AMARYL (glimepiride tablets) (4 mg once daily) did not alter the pharmacokinetic characteristics of R-and S-warfarin enantiomers following administration of a single dose (25 mg) of racemic warfarin to healthy subjects. No changes were observed in warfarin plasma protein binding. AMARYL treatment did result in a slight, but statistically significant, decrease in the pharmacodynamic response to warfarin. The reductions in mean area under the prothrombin time (PT) curve and maximum PT values during AMARYL treatment were very small (3.3% and 9.9%, respectively) and are unlikely to be clinically important.

The responses of serum glucose, insulin, C-peptide, and plasma glucagon to 2 mg AMARYL were unaffected by coadministration of ramipril (an ACE inhibitor) 5 mg once daily in normal subjects. No hypoglycemic symptoms were reported. Pooled data from clinical trials in patients with Type 2 diabetes showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of ACE inhibitors.

There is a potential interaction of glimepiride with inhibitors (e.g. fluconazole) and inducers (e.g. rifampicin) of cytochrome P450 2C9.

Although no specific interaction studies were performed, pooled data from clinical trials showed no evidence of clinically significant adverse interactions with uncontrolled concurrent administration of calcium-channel blockers, estrogens, fibrates, NSAIDS, HMG CoA reductase inhibitors, sulfonamides, or thyroid hormone.


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.


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.

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