8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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 (seeClinical Considerations). Poorly controlled diabetes in pregnancy is also associated with risks to the mother and fetus (seeClinical Considerations). In animal studies (see Data), 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 HbA1c >7% and has been reported to be as high as 20% to 25% in women with a HbA1c >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.

Clinical Considerations

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 4 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 (see Fetal/Neonatal Adverse Reactions).

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.

8.2 Lactation

Risk Summary

Breastfed infants of lactating women using glimepiride tablets should be monitored for symptoms of hypoglycemia (seeClinical Considerations). It is not known whether glimepiride is excreted in human milk and there are no data on the effects of glimepiride on milk production. Glimepiride is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for glimepiride and any potential adverse effects on the breastfed child from glimepiride or from the underlying maternal condition.

Clinical Considerations

Monitoring for adverse reactions

Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

Data

During prenatal and postnatal studies in rats, significant concentrations of glimepiride were present in breast milk and the serum of the pups. Offspring of rats 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. These skeletal deformations were determined to be the result of nursing from mothers exposed to glimepiride.

8.4 Pediatric Use

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 10 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 HbA1Cand Body Weight in Pediatric Patients Taking Glimepiride****or Metformin
	Metformin	Glimepiride
Treatment-Naïve Patients*	N=69	N=72
HbA1C(%)
Baseline (mean)	8.2	8.3
Change from baseline (adjusted LS mean) †	-1.2	-1
Adjusted Treatment Difference ‡ (95%CI)	0.2 (-0.3; 0.6)
Previously Treated Patients*	N=57	N=55
HbA1C(%)
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)
Intent-to-treat population using last-observation-carried-forward for missing data (Glimepiride, n=127; metformin, n=126) † adjusted for baseline HbA 1c and Tanner Stage ‡ Difference is glimepiride – metformin with positive differences favoring metformin

The profile of adverse reactions in pediatric patients treated with glimepiride was similar to that observed in adults [seeAdverse Reactions ( 6)].

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).

8.5 Geriatric Use

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) [see Clinical Pharmacology (12.3)].

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 [see**Dosage and Administration (2.1)and ** Warnings and Precautions (5.1)]. Use caution when initiating glimepiride and increasing the dose of glimepiride tablets in this patient population.

8.6 Renal Impairment

To minimize the risk of hypoglycemia, the recommended starting dose of glimepiride tablets are 1 mg daily for all patients with type 2 diabetes and renal impairment [seeDosage and Administration (2.1)and Warnings and Precautions (5.1)].

A multiple-dose titration study was conducted in 16 patients with type 2 diabetes and renal impairment using doses ranging from 1 mg to 8 mg daily for 3 months. Baseline creatinine clearance ranged from 10 to 60 mL/min. The pharmacokinetics of glimepiride tablets were evaluated in the multiple-dose titration study and the results were consistent with those observed in patients enrolled in a single-dose study. In both studies, the relative total clearance of glimepiride increased when kidney function was impaired. Both studies also demonstrated that the elimination of the two major metabolites was reduced in patients with renal impairment [seeClinical Pharmacology ( 12.3)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Glimepiride primarily lowers blood glucose by stimulating the release of insulin from pancreatic beta cells. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin.

12.2 Pharmacodynamics

In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations) was approximately 2 to 3 hours after single oral doses of glimepiride tablets. The effects of glimepiride on HbA 1c, fasting plasma glucose, and postprandial glucose have been assessed in clinical trials [see Clinical Studies (14)].

12.3 Pharmacokinetics

Absorption

Studies with single oral doses of glimepiride in healthy subjects and with multiple oral doses in patients with type 2 diabetes showed peak drug concentrations (C max) 2 to 3 hours postdose. When glimepiride was given with meals, the mean C max and AUC (area under the curve) were decreased by 8% and 9%, respectively.

Glimepiride does not accumulate in serum following multiple dosing. The pharmacokinetics of glimepiride does not differ between healthy subjects and patients with type 2 diabetes. Clearance of glimepiride after oral administration does not change over the 1 mg to 8 mg dose range, indicating linear pharmacokinetics.

In healthy subjects, the intraindividual and interindividual variabilities of glimepiride pharmacokinetic parameters were 15% to 23% and 24% to29%, respectively.

Distribution

After intravenous dosing in healthy 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%.

Metabolism

Glimepiride is completely metabolized by oxidative biotransformation after either an intravenous or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M2 is inactive. In animals, M1 possesses about one-third of the pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically meaningful effects on blood glucose in humans.

Excretion

When 14C-glimepiride was given orally to 3 healthy male subjects, approximately 60% of the total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for 80% to 90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total radioactivity was recovered in feces. M1 and M2 accounted for about 70% (ratio of M1 to M2 was 1:3) of the radioactivity recovered in feces. No parent drug was recovered from urine or feces. After intravenous dosing in patients, no significant biliary excretion of glimepiride or its M1 metabolite was observed.

Specific Populations

Geriatric Patients

A comparison of glimepiride pharmacokinetics in patients with type 2 diabetes ≤65 years and those >65 years was evaluated in a multiple-dose study using glimepiride tablets 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 approximately 13% lower than that for the younger patients; the mean weight-adjusted clearance for the older patients was approximately 11% higher than that for the younger patients.

Gender

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

Race

No studies have been conducted to assess the effects of race on glimepiride pharmacokinetics but in placebo-controlled trials of glimepiride in patients with type 2 diabetes, the reduction in HbA 1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).

Renal Impairment

In a single-dose, open-label study, glimepiride tablets 3 mg was administered to patients with mild, moderate and severe renal impairment as estimated by creatinine clearance (CLcr): Group I consisted of 5 patients with mild renal impairment (CLcr > 50 mL/min), Group II consisted of 3 patients with moderate renal impairment (CLcr = 20 to 50 mL/min) and Group III consisted of 7 patients with severe renal impairment (CLcr < 20 mL/min). Although glimepiride serum concentrations decreased with decreasing renal function, Group III had a 2.3-fold higher mean AUC for M1 and an 8.6-fold higher mean AUC for M2 compared to corresponding mean AUCs in Group I. 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 a percentage of dose decreased from 44.4% for Group I to 21.9% for Group II and 9.3% for Group III.

Hepatic Impairment

It is unknown whether there is an effect of hepatic impairment on glimepiride pharmacokinetics because the pharmacokinetics of glimepiride has not been adequately evaluated in patients with hepatic impairment.

Obese Patients

The pharmacokinetics of glimepiride and its metabolites were measured in a single-dose study involving 28 patients with type 2 diabetes who either had normal body weight or were morbidly obese. While the t max, clearance and volume of distribution of glimepiride in the morbidly obese patients were similar to those in the normal weight group, the morbidly obese had lower C max and AUC than those of normal body weight. The mean C max, AUC 0-24, AUC 0-∞ values of glimepiride in normal vs. morbidly obese patients were 547 ± 218 ng/mL vs. 410 ± 124 ng/mL, 3210 ± 1030 hours·ng/mL vs. 2820 ± 1110 hours·ng/mL and 4000 ± 1320 hours·ng/mL vs. 3280 ± 1360 hours·ng/mL, respectively.

Drug Interactions

Aspirin

In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or aspirin 1 gram three times daily for a total treatment period of 5 days. On Day 4 of each study period, a single 1 mg dose of glimepiride tablets was administered. The glimepiride tablets doses were separated by a 14-day washout period. Coadministration of aspirin and glimepiride resulted in a 34% decrease in the mean glimepiride AUC and a 4% decrease in the mean glimepiride C max.

Colesevelam

Concomitant administration of colesevelam and glimepiride resulted in reductions in glimepiride AUC 0-∞ and C max of 18% and 8%, respectively. When glimepiride was administered 4 hours prior to colesevelam, there was no significant change in glimepiride AUC 0-∞ or C max, -6% and 3%, respectively [seeDosage and Administration**** (2.1)**** and Drug Interactions**** (7.4)].

Cimetidine and Ranitidine

In a randomized, open-label, 3-way crossover study, healthy subjects received either a single 4 mg dose of glimepiride tablets alone, glimepiride with ranitidine (150 mg twice daily for 4 days; glimepiride was administered on Day 3), or glimepiride with cimetidine (800 mg daily for 4 days; glimepiride was administered on Day 3). Co-administration of cimetidine or ranitidine with a single 4 mg oral dose of glimepiride tablets did not significantly alter the absorption and disposition of glimepiride.

Propranolol

In a randomized, double-blind, two-period, crossover study, healthy subjects were given either placebo or propranolol 40 mg three times daily for a total treatment period of 5 days. On Day 4 of each study period, a single 2 mg dose of glimepiride tablets was administered. The glimepiride tablets doses were separated by a 14-day washout period. Concomitant administration of propranolol and glimepiride significantly increased glimepiride C max, AUC, and T 1/2 by 23%, 22%, and 15%, respectively, and decreased glimepiride CL/f by 18%. The recovery of M1 and M2 from urine was not changed.

Warfarin

In an open-label, two-way, crossover study, healthy subjects received 4 mg of glimepiride tablets daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting glimepiride and on Day 4 of glimepiride administration. The concomitant administration of glimepiride did not alter the pharmacokinetics of R- and S-warfarin enantiomers. No changes were observed in warfarin plasma protein binding. Glimepiride resulted in a 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 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.

14 CLINICAL STUDIES

14.1 Monotherapy

A total of 304 patients with type 2 diabetes already treated with sulfonylurea therapy participated in a 14-week, multicenter, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of glimepiride monotherapy. Patients discontinued their sulfonylurea therapy then entered a 3-week placebo washout period followed by randomization into 1 of 4 treatment groups: placebo (n=74), glimepiride tablets 1 mg (n=78), glimepiride tablets 4 mg (n=76) and glimepiride tablets 8 mg (n=76). All patients randomized to glimepiride tablets started 1 mg daily. Patients randomized to glimepiride tablets 4 mg or 8 mg had blinded, forced titration of the glimepiride tablets dose at weekly intervals, first to 4 mg and then to 8 mg, as long as the dose was tolerated, until the randomized dose was reached. Patients randomized to the 4 mg dose reached the assigned dose at Week 2. Patients randomized to the 8 mg dose reached the assigned dose at Week 3. Once the randomized dose level was reached, patients were to be maintained at that dose until Week 14. Approximately 66% of the placebo-treated patients completed the trial compared to 81% of patients treated with glimepiride 1 mg and 92% of patients treated with glimepiride 4 mg or 8 mg. Compared to placebo, treatment with glimepiride tablets 1 mg, 4 mg, and 8 mg daily provided statistically significant improvements in HbA 1C compared to placebo (Table 3).

Table 3: 14-week Monotherapy Trial Comparing Glimepiride to Placebo in Patients Previously Treated With Sulfonylurea Therapya
	Placebo**(N=74)**	Glimepiride
1 mg**(N=78)**	4 mg**(N=76)**	8 mg**(N=76)**
HbA1C(%)
	n=59	n=65	n=65	n=68
Baseline (mean)	8	7.9	7.9	8
Change from Baseline (adjusted mean b)	1.5	0.3	-0.3	-0.4
Difference from Placebo (adjusted mean b) 95% confidence interval		-1.2* (-1.5, -0.8)	-1.8* (-2.1, -1.4)	-1.8* (-2.2, -1.5)
Mean Baseline Weight (kg)
	n=67	n=76	n=75	n=73
Baseline (mean)	85.7	84.3	86.1	85.5
Change from Baseline (adjusted mean b)	-2.3	-0.2	0.5	1
Difference from Placebo (adjusted mean b) 95% confidence interval		2* (1.4, 2.7)	2.8* (2.1, 3.5)	3.2* (2.5, 4)
aIntent-to-treat population using last observation on study bLeast squares mean adjusted for baseline value *p≤0.001

A total of 249 patients who were treatment-naïve or who had received limited treatment with antidiabetic therapy in the past were randomized to receive 22 weeks of treatment with either glimepiride (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-controlled, dose-titration trial. The starting dose of glimepiride tablets was 1 mg daily and was titrated upward or downward at 2-week intervals to a goal FPG of 90 to 150 mg/dL. Blood glucose levels for both FPG and PPG were analyzed in the laboratory. Following 10 weeks of dose adjustment, patients were maintained at their optimal dose (1, 2, 3, 4, 6, or 8 mg) for the remaining 12 weeks of the trial. Treatment with glimepiride provided statistically significant improvements in HbA 1C and FPG compared to placebo (Table 4).

Table 4: 22-Week Monotherapy Trial Comparing Glimepiride to Placebo in Patients Who Were Treatment-Naïve or Who Had No Recent Treatment with Antidiabetic Therapy****a
	Placebo**(N=126)**	Glimepiride**(N=123)**
HbA1C(%)	n=97	n=106
Baseline (mean)	9.1	9.3
Change from Baseline (adjusted mean b)	-1.1*	-2.2*
Difference from Placebo (adjusted mean b) 95% confidence interval	-1.1* (-1.5, -0.8)
Body Weight (kg)
	n=122	n=119
Baseline (mean)	86.5	87.1
Change from Baseline (adjusted mean b)	-0.9	1.8
Difference from Placebo (adjusted mean b) 95% confidence interval	2.7 (1.9, 3.6)
aIntent to treat population using last observation on study bLeast squares mean adjusted for baseline value *p≤0.0001