AMARYL Tablet Ref.[10536] Active ingredients: Glimepiride

In healthy subjects, the time to reach maximal effect (minimum blood glucose concentrations) was approximately 2–3 hours after single oral doses of AMARYL. The effects of AMARYL on HbA1c, fasting plasma glucose, and postprandial glucose have been assessed in clinical trials [see Clinical Studies (14)].

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 post dose. 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%–23% and 24%–29%, 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%–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 AMARYL 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 AMARYL in patients with type 2 diabetes, the reduction in HbA1c was comparable in Caucasians (n=536), blacks (n=63), and Hispanics (n=63).

Renal impairment

In a single-dose, open-label study, AMARYL 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=20–50 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 AMARYL pharmacokinetics because the pharmacokinetics of AMARYL 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 AMARYL was administered. The AMARYL doses were separated by a 14-day washout period. Coadministration of aspirin and AMARYL 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 [see Dosage 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 AMARYL alone, AMARYL with ranitidine (150 mg twice daily for 4 days; AMARYL was administered on Day 3), or AMARYL with cimetidine (800 mg daily for 4 days; AMARYL was administered on Day 3). Coadministration of cimetidine or ranitidine with a single 4 mg oral dose of AMARYL 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 AMARYL was administered. The AMARYL doses were separated by a 14-day washout period. Concomitant administration of propranolol and AMARYL 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 AMARYL daily for 10 days. Single 25 mg doses of warfarin were administered 6 days before starting AMARYL and on Day 4 of AMARYL administration. The concomitant administration of AMARYL did not alter the pharmacokinetics of R-and S-warfarin enantiomers. No changes were observed in warfarin plasma protein binding. AMARYL 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 AMARYL treatment were 3.3% and 9.9%, respectively, and are unlikely to be clinically relevant.

Studies in rats at doses of up to 5000 parts per million (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 that was dose-related and was thought to be the result of chronic pancreatic stimulation. No adenoma formation in mice was observed at a dose of 320 ppm in complete feed, or 46–54 mg/kg body weight/day. This is at least 28 times the maximum human recommended dose of 8 mg once daily based on surface area.

Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test, somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, and mouse micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg body weight (>1,500 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).

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 AMARYL 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), AMARYL 1 mg (n=78), AMARYL 4 mg (n=76), and AMARYL 8 mg (n=76). All patients randomized to AMARYL started 1 mg daily. Patients randomized to AMARYL 4 mg or 8 mg had blinded, forced titration of the AMARYL 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 AMARYL 1 mg, 4 mg, and 8 mg daily provided statistically significant improvements in HbA1c compared to placebo (Table 3).

Table 3. 14-Week Monotherapy Trial Comparing AMARYL to Placebo in Patients Previously Treated With Sulfonylurea Therapy^*:

^* Intent-to-treat population using last observation on study
^† Least squares mean adjusted for baseline value
^‡ p≤0.001

A total of 249 patients who were treatment-naive or who had received limited treatment with antidiabetic therapy in the past were randomized to receive 22 weeks of treatment with either AMARYL (n=123) or placebo (n=126) in a multicenter, randomized, double-blind, placebo-controlled, dose-titration trial. The starting dose of AMARYL was 1 mg daily and was titrated upward or downward at 2-week intervals to a goal FPG of 90–150 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 AMARYL provided statistically significant improvements in HbA1c and FPG compared to placebo (Table 4).

Table 4. 22-Week Monotherapy Trial Comparing AMARYL to Placebo in Patients Who Were Treatment-Naive or Who Had No Recent Treatment with Antidiabetic Therapy^*:

^* Intent-to-treat population using last observation on study
^† Least squares mean adjusted for baseline value
^‡ p≤0.0001