Glimepiride
FDA Label NDC 42549-499

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 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 lowers blood glucose during long-term administration has not been clearly established.

Glimepiride is effective as initial drug therapy. In patients where monotherapy with glimepiride or metformin has not produced adequate glycemic control, the combination of 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.

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 (C_max) at 2 to 3 hours. When glimepiride was given with meals, the mean T_max (time to reach C_max) was slightly increased (12%) and the mean C_max 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.

When¹⁴C-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.

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:

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 C_max, AUC, and CL/f for glimepiride were 23%, 17%, and 15%, respectively, and the inter-individual variabilities were 25%, 29%, and 24%, respectively.

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), C_max (102.4±47.7 ng/mL) and T_1/2(3.1±1.7 hours) were comparable to those previously reported in adults (AUC_(0-last) 315.2±95.9 ng•hr/mL, C_max 103.2±34.3 ng/mL and T_1/2 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 glimepiride tablets in patients with Type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 536), blacks (n = 63), and Hispanics (n = 63).

 A single-dose, open-label study was conducted in 15 patients with renal impairment. Glimepiride (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). Glimepiride 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 (T_1/2) 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 glimepiride may be given to Type 2 diabetic patients with kidney disease, and the dose may be titrated based on fasting blood glucose levels.

 No studies were performed in patients with hepatic insufficiency.

 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 C_max and AUC. However, since neither C_max nor AUC values were normalized for body surface area, the lower values of C_max 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.

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory drugs, clarithromycin, disopyramide, fluoxetine, and quinolones 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.

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 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 closely for hypoglycemia.

Coadministration of aspirin (1 g tid) and glimepiride led to a 34% decrease in the mean glimepiride AUC and, therefore, a 34% increase in the mean CL/f. The mean C_max 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 glimepiride 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 glimepiride significantly increased C_max, AUC, and T_1/2 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 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. Glimepiride 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 glimepiride 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 glimepiride 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.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.

Hypoglycemia: 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 1 mg 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 glucoselowering drugs. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy, 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 drug is used. Combined use of glimepiride with insulin or metformin may increase the potential for hypoglycemia.

Loss of control of blood glucose: 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 glimepiride, in lowering blood glucose to a desired level decreases 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. This phenomenon is known as secondary failure, to distinguish it 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 combined glimepiride/metformin therapy, it may be necessary to initiate insulin therapy.

Hemolytic anemia: Treatment of patients with glucose 6-phosphate dehydrogenase (G6DP) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glimepiride belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

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.

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 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.

There are no adequate and well-controlled studies in pregnant women. On the basis of results from animal studies, 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 during pregnancy and lactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. Significant concentrations of 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.

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.

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.

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 patient’s blood glucose response. Long-term efficacy should be monitored by measurement of HbA_1c levels, for example, every 3 to 6 months.

If patients do not respond adequately to the maximal dose of glimepiride monotherapy, addition of metformin may be considered. Published clinical information exists for the use of other sulfonylureas including glyburide, glipizide, chlorpropamide, and tolbutamide in combination with metformin.

With concomitant glimepiride and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the minimum effective dose of each drug to achieve this goal. With concomitant glimepiride and metformin therapy, the risk of hypoglycemia associated with glimepiride therapy continues and may be increased. Appropriate precautions should be taken.

Combination therapy with glimepiride and insulin may also be used in secondary failure patients. The fasting glucose level for instituting combination therapy is in the range of >150 mg/dL in plasma or serum depending on the patient. The recommended glimepiride dose is 8 mg once daily administered with the first main meal. After starting with low-dose insulin, upward adjustments of insulin can be done approximately weekly as guided by frequent measurements of fasting blood glucose. Once stable, combination-therapy patients should monitor their capillary blood glucose on an ongoing basis, preferably daily. Periodic adjustments of insulin may also be necessary during maintenance as guided by glucose and HbA_1c levels.

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.