PIRAMYL

First introduced in 1995, glimepiride is a member of the second-generation sulfonylurea (SU) drug class used for the management of type 2 diabetes mellitus (T2DM) to improve glycemic control.

Type 2 diabetes is a metabolic disorder with increasing prevalences worldwide; it is characterized by insulin resistance in accordance with progressive β cell failure and long-term microvascular and macrovascular complications that lead to co-morbidities and mortalities.

Sulfonylureas are one of the insulin secretagogues widely used for the management of type 2 diabetes to lower blood glucose levels.

The main effect of

SUs is thought to be effective when residual pancreatic β-cells are present, 3 as they work by stimulating the release of insulin from the pancreatic beta cells and they are also thought to exert extra-pancreatic effects, such as increasing the insulin-mediated peripheral glucose uptake.

Glimepiride works by stimulating the secretion of insulin granules from pancreatic islet beta cells by blocking ATP-sensitive potassium channels (K ATP channels) and causing depolarization of the beta cells.

Compared to glipizide, another second SU drug, glimepiride has a longer duration of action.

It is sometimes classified as a third-generation SU because it has larger substitutions than other second-generation SUs.

Compared to other

SUs, glimepiride was associated with a lower risk of developing hypoglycemia and weight gain in clinical trials as well as fewer cardiovascular effects than other SUs due to minimal effects on ischemic preconditioning of cardiac myocytes.

It is effective in reducing fasting plasma glucose, postprandial glucose, and glycosylated hemoglobin levels and is considered to be a useful, cost-effective treatment option for managing type 2 diabetes mellitus.

Glimepiride was approved by the Food and Drug Administration (FDA) in the United States in for the treatment of T2DM.

It is commonly marketed under the brand name Amaryl as oral tablets and is typically administered once daily.

Glimepiride is indicated for the management of type 2 diabetes in adults as an adjunct to diet and exercise to improve glycemic control as monotherapy.

It may also be indicated for use in combination with metformin or insulin to lower blood glucose in patients with type 2 diabetes whose high blood sugar levels cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic (a drug used to lower blood sugar levels) agent alone.

Glimepiride stimulates the secretion of insulin granules from the pancreatic beta cells and improves the sensitivity of peripheral tissues to insulin to increase peripheral glucose uptake, thus reducing plasma blood glucose levels and glycated hemoglobin (HbA1C) levels.

A multi-center, randomized, placebo-controlled clinical trial evaluated the efficacy of glimepiride (1–8 mg) as monotherapy titrated over 10 weeks compared with placebo in T2DM subjects who were not controlled by diet alone.

In this study, there was a reduction in fasting plasma glucose (FPG) by 46 mg/dL, post-prandial glucose (PPG) by 72 mg/dL, and HbA1c by 1.4% more than the placebo.

In another randomized study comprising of patients with T2DM receiving either placebo or one of the three doses (1, 4, or 8 mg) of glimepiride during a 14-week study period, all glimepiride regimens significantly reduced FPG, PPG, and HbA1c values (P < 0.001) compared to placebo by the end of the study period.

The 4.

• and 8-mg doses of glimepiride were more effective than the 1-mg dose; however, the 4-mg dose provided a nearly maximal antihyperglycemic effect.

ATP-sensitive inward rectifier potassium channel 11 Inhibitor ATP-sensitive inward rectifier potassium channel 1 Inhibitor ATP-binding cassette sub-family C member 8 Inducer.

Glimepiride is completely absorbed after oral administration within 1 hour of administration with a linear pharmacokinetics profile.

Following administration of a single oral dose of glimepiride in healthy subjects and with multiple oral doses with type 2 diabetes, the peak plasma concentrations (Cmax) were reached after 2-3 hours post-dose.

Accumulation does not occur after multiple doses.

When glimepiride was given with meals, the time to reach Cmax was increased by 12% while the mean and AUC (area under the curve) were decreased by 8-9%, respectively.

In a pharmacokinetic study of Japanese patients with T2DM, Cmax value in once-daily dose was higher than those in twice-daily doses.

The absolute bioavailability of glimepiride is reported to be complete following oral administration.

Following intravenous dosing in healthy subjects, the volume of distribution was 8.8 L (113 mL/kg).

Glimepiride is reported to undergo hepatic metabolism.

Following either an intravenous or oral dose, glimepiride undergoes oxidative biotransformation mediated by CYP2C9 enzyme to form a major metabolite, cyclohexyl hydroxymethyl derivative (M1), that is pharmacologically active.

M1 can be further metabolized to the inactive metabolite carboxyl derivative (M2) by one or several cytosolic enzymes.

M1 retained approximately one third of the pharmacologic activity of its parent in an animal model, with a half-life of 3-6 hours.

However, whether the glucose-lowering effect of M1 is clinically significant is not clear.

Hover over products below to view reaction partners Glimepiride Cyclohexyl hydroxymethyl glimepiride Cyclohexyl carboxyl glimepiride.

Following oral administration of glimepiride in healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days, with M1 and M2 accounting for 80-90% of the total radioactivity recovered in the urine.

The ratio of

M1 to M2 was approximately 3:2 in two subjects and 4:1 in one subject.

Approximately 40% of the total radioactivity was recovered in feces where M1 and M2 accounted for about 70% of the radioactivity and a ratio of M1 to M2 being 1:3.

No parent drug was recovered from urine or feces.

The elimination half-life of glimepiride is approximately 5-8 hours, 3 which can increase up to 9 hours following multiple doses.

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 (T2D) were performed.

In these studies, the total body clearance was 52.1 +/.

• 16.0 mL/min, 48.5 +/.

• 29.3 mL/min in patients with T2D given a single oral dose, and 52.7 +/.

• 40.3 mL/min in patients with T2D given multiple oral doses.

Following intravenous dosing in healthy subjects, the total body clearance was 47.8 mL/min.

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The oral

LD50 value in rats is > 10000 mg/kg.

Although glimepiride is reported to have fewer risks of hypoglycemia compared to other sulfonylureas such as glyburide, overdosage of glimepiride may result in severe hypoglycemia with coma, seizure, or other neurological impairment may occur.

This can be treated with glucagon or intravenous glucose.

Continued observation and additional carbohydrate intake may be necessary since hypoglycemia may recur after apparent clinical recovery.

In a study of rats given doses of up to 5000 parts per million (ppm) in complete feed for 30 months, there were no signs of carcinogenesis.

Meanwhile, the administration of glimepiride at a dose much higher than the maximum human recommended dose for 24 months in mice resulted in an increase in benign pancreatic adenoma formation in a dose-related manner, which was thought to be the result of chronic pancreatic stimulation.

Glimepiride was non-mutagenic in in vitro and in vivo mutagenicity studies.

In male and female rat studies, glimepiride was shown to have no effects on fertility.

Glimepiride tablets are contraindicated in patients with a history of a hypersensitivity reaction to: Glimepiride or any of the product’s ingredients.

Sulfonamide derivatives

Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to glimepiride.

Do not use glimepiride in patients who have a history of an allergic reaction to sulfonamide derivatives.

Hypersensitivity to glimepiride or any of the product’s ingredients Hypersensitivity to sulfonamide derivatives.

Recommended starting dose is 1 or 2 mg once daily.

Increase in 1 or 2 mg increments no more frequently than every to 2 weeks based on glycemic response.

Maximum recommended dose is 8 mg once daily.

Administer with breakfast or first meal of the day.

Use 1 mg starting dose and titrate slowly in patients at increased risk for hypoglycemia (e.g., elderly, patients with renal impairment) . 2.1 Recommended Dosing Glimepiride tablets should be administered with breakfast or the first main meal of the day. The recommended starting dose of glimepiride tablets are 1 mg or 2 mg once daily.

Patients at increased risk for hypoglycemia (e.g., the elderly or patients with renal impairment) should be started on 1 mg once daily.

After reaching a daily dose of 2 mg, further dose increases can be made in increments of 1 mg or 2 mg based upon the patient’s glycemic response.

Uptitration should not occur more frequently than every to 2 weeks.

A conservative titration scheme is recommended for patients at increased risk for hypoglycemia.

The maximum recommended dose is 8 mg once daily.

Patients being transferred to glimepiride tablets from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for to 2 weeks and should be appropriately monitored for hypoglycemia.

When colesevelam is coadministered with glimepiride, maximum plasma concentration and total exposure to glimepiride is reduced.

Therefore, glimepiride tablets should be administered at least 4 hours prior to colesevelam.

Glimepiride tablets

USP, are available in the following strengths and package sizes: Glimepiride tablets USP, 1 mg are peach, oval, flat beveled edged, uncoated tablets debossed “RDY” on one side and “320” separating “3” and “20” with bisect line scoring on the other side and are supplied in: Unit dose packages of 30 (5 x 6) NDC 68084-788-25 Glimepiride tablets USP, 2 mg are green, oval, flat beveled edged, uncoated tablets debossed “RDY” on one side and “321” separating “3” and “21” with bisect line scoring on the other side and are supplied in: Unit dose packages of 100 (10 x 10) NDC 68084-326-01 Glimepiride tablets USP, 4 mg are blue, oval, flat beveled edged, uncoated tablets debossed “RDY” on one side and “322” separating “3” and “22” with bisect line scoring on the other side and are supplied in: Unit dose packages of 100 (10 x 10) NDC 68084-327-01 Store at 20°-25°C (68°-77°F) .

Do not use if blister is torn or broken.

Available data from a small number of published studies and postmarketing experience with glimepiride use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes.

However, sulfonylureas (including glimepiride) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia.

Therefore, glimepiride tablets should be discontinued at least two weeks before expected delivery.

Poorly controlled diabetes in pregnancy is also associated with risks to the mother and fetus.

In animal studies, there were no effects on embryo-fetal development following administration of glimepiride to pregnant rats and rabbits at oral doses approximately 4,000 times and 60 times the maximum human dose based on body surface area, respectively.

However, fetotoxicity was observed in rats and rabbits at doses 50 times and 0.1 times the maximum human dose, respectively.

The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a HbA 1c >7% and has been reported to be as high as 20% to 25% in women with a HbA 1c >10%.

The estimated background risk of miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Disease-associated maternal and/or embryo-fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia-related morbidity.

Fetal/neonatal adverse reactions Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age.

Prolonged severe hypoglycemia, lasting to 10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life.

Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.

Dose adjustments during pregnancy and the postpartum period Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, glimepiride tablets should be discontinued at least two weeks before expected delivery.

Data Animal data

In animal studies, there was no increase in congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum recommended human dose (based on body surface area).

This fetotoxicity was observed only at doses inducing maternal hypoglycemia and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride, as has been similarly noted with other sulfonylureas.

The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below.

Glimepiride tablets are not recommended in pediatric patients because of its adverse effects on body weight and hypoglycemia.

The pharmacokinetics of a 1 mg single dose of glimepiride was evaluated in 30 patients with type 2 diabetes (male = 7; female = 23) between ages and 17 years.

The mean (± SD) AUC (0-last) (339±203 ng•hr/mL), C max (102±48 ng/mL) and t 1/2 (3.1±1.7 hours) for glimepiride were comparable to historical data from adults (AUC (0-last) 315±96 ng•hr/mL, C max 103±34 ng/mL and t 1/2 5.3±4.1 hours).

The safety and efficacy of glimepiride in pediatric patients was evaluated in a single-blind, 24-week trial that randomized 272 patients (8 to 17 years of age) with type 2 diabetes to glimepiride (n=135) or metformin (n=137).

Both treatment-naïve patients (those treated with only diet and exercise for at least 2 weeks prior to randomization) and previously treated patients (those previously treated or currently treated with other oral antidiabetic medications for at least 3 months) were eligible to participate.

Patients who were receiving oral antidiabetic agents at the time of study entry discontinued these medications before randomization without a washout period.

Glimepiride was initiated at 1 mg, and then titrated up to 2, 4 or 8 mg (mean last dose 4 mg) through Week 12, targeting a self-monitored fasting fingerstick blood glucose < 126 mg/dL.

Metformin was initiated at 500 mg twice daily and titrated at Week 12 up to 1000 mg twice daily (mean last dose 1365 mg).

After 24 weeks, the overall mean treatment difference in HbA 1c between glimepiride and metformin was 0.2%, favoring metformin (95% confidence interval -0.3% to +0.6%).

Based on these results, the trial did not meet its primary objective of showing a similar reduction in HbA 1c with glimepiride compared to metformin.

Table 2.

Change from Baseline in

HbA 1C and Body Weight in Pediatric Patients Taking Glimepiride or Metformin Metformin Glimepiride Treatment-Naïve Patients Intent-to-treat population using last-observation-carried-forward for missing data (Glimepiride, n=127; metformin, n=126) N=69 N=72 HbA 1C (%) Baseline (mean) 8.2 8.3 Change from baseline (adjusted LS mean) adjusted for baseline HbA1c and Tanner Stage -1.2 -1 Adjusted Treatment Difference Difference is glimepiride – metformin with positive differences favoring metformin (95% CI) 0.2 (-0.3; 0.6) Previously Treated Patients N=57 N=55 HbA 1C (%) Baseline (mean) 9 8.7 Change from baseline (adjusted LS mean) -0.2 0.2 Adjusted Treatment Difference (95% CI) 0.4 (-0.4; 1.2) Body Weight (kg) N=126 N=129 Baseline (mean) 67.3 66.5 Change from baseline (adjusted LS mean) 0.7 2 Adjusted Treatment Difference (95% CI) 1.3 (0.3; 2.3) The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults.

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

One patient in each treatment group experienced a severe hypoglycemic episode (severity was determined by the investigator based on observed signs and symptoms).

In clinical trials of glimepiride, 1053 of 3491 patients (30%) were >65 years of age.

No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

There were no significant differences in glimepiride pharmacokinetics between patients with type 2 diabetes ≤65 years (n=49) and those >65 years (n=42) .

Glimepiride is substantially excreted by the kidney.

Elderly patients are more likely to have renal impairment.

In addition, hypoglycemia may be difficult to recognize in the elderly.

Use caution when initiating glimepiride and increasing the dose of glimepiride tablets in this patient population.