GLIMEPIRIDE - glimepiride tablet
Micro Labs Limited
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use glimepiride safely and effectively. See full prescribing information for glimepiride.
GLIMEPIRIDE TABLETS USP Initial U.S. Approval: 1995 INDICATIONS AND USAGEDOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHSTablets (scored): 1 mg, 2 mg, 3 mg, 4 mg, 6 mg and 8 mg (3) CONTRAINDICATIONSWARNINGS AND PRECAUTIONS
ADVERSE REACTIONSCommon adverse reactions in clinical trials (≥5% and more common than with placebo) include hypoglycemia, headache, nausea, and dizziness (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-875-7814 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION. Revised: 10/2012 |
Glimepiride Tablets should be administered with breakfast or the first main meal of the day.
The recommended starting dose of glimepiride tablets is 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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].
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 1 to 2 weeks. A conservative titration scheme is recommended for patients at increased risk for hypoglycemia [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5,8.6)].
All sulfonylureas, including glimepiride, can cause severe hypoglycemia [see Adverse Reactions (6.1)]. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.
The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups.
In clinical trials, the most common adverse reactions with glimepiride were hypoglycemia, dizziness, asthenia, headache, and nausea.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year.
Table 1. Eleven Pooled Placebo-Controlled Trials ranging from 13 weeks to 12 months: Adverse Events (Excluding Hypoglycemia) Occurring in ≥5% of Glimepiride-treated Patients and at a Greater Incidence than with Placebo*
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| Glimepiride N=745 %
| Placebo N=294 %
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Headache | 8.2 | 7.8 |
Accidental Injury†
| 5.8 | 3.4 |
Flu Syndrome | 5.4 | 4.4 |
Nausea | 5 | 3.4 |
Dizziness | 5 | 2.4 |
*Glimepiride doses ranged from 1 to 16 mg administered daily † Insufficient information to determine whether any of the accidental injury events were associated with hypoglycemia |
In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated [see Clinical Studies (14.1)]. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo. All of these events were self-treated.
In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90 to 150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6 or 8 mg [see Clinical Studies (14.1)]. The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride vs. placebo was 19.7% vs. 3.2%. All of these events were self-treated.
Weight gain: Glimepiride, like all sulfonylureas, can cause weight gain [see Clinical Studies (14.1)].
Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride-treated patients. These may resolve despite continued treatment with glimepiride. There are postmarketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock) [see Warnings and Precautions (5.2)].
A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control.
The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for worsening glycemic control.
The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including glimepiride, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid. When these medications are administered to a patient receiving glimepiride, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for hypoglycemia.
Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of glimepiride’s glucose-lowering effect.
Pregnancy Category C
The pharmacokinetics, efficacy and safety of glimepiride have been evaluated in pediatric patients with type 2 diabetes as described below. Glimepiride is 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 to last) (339±203 ng•hr/mL), Cmax (102±48 ng/mL) and t1/2 (3.1±1.7 hours) for glimepiride were comparable to historical data from adults (AUC (0 to last) 315±96 ng•hr/mL, Cmax 103±34 ng/mL and t1/2 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).
Table 2. Change from Baseline in HbA1C and Body Weight in Pediatric Patients Taking Glimepiride or Metformin
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| Metformin
| Glimepiride
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Treatment-Naïve Patients*
| N=69 | N=72 |
HbA1C (%)
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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) |
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Previously Treated Patients*
| N=57 | N=55 |
HbA1C (%)
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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) |
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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) |
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* Intent-to-treat population using last-observation-carried-forward for missing data (glimepiride, n=127; metformin, n=126) + adjusted for baseline HbA1c and Tanner Stage **Difference is glimepiride – metformin with positive differences favoring metformin |
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.
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 (Cmax) 2 to 3 hours post-dose. When glimepiride was given with meals, the mean Cmax 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 intra- and inter-individual variabilities of glimepiride pharmacokinetic parameters were 15 to 23% and 24 to 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 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 approximately 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.
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 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 HbA1C was comparable in Caucasians (n = 536), blacks (n = 63), and Hispanics (n = 63).
Renal Impairment: In a single-dose, open-label study glimepiride 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 (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 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 tmax, 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 Cmax and AUC than those of normal body weight. The mean Cmax, AUC0 to 24, AUC0 to ∞ 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.
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 to 54 mg/kg body weight/day. This is about 35 times the maximum human recommended dose of 8 mg once daily based on surface area.
Table 3. 14-week Monotherapy Trial Comparing glimepiride to Placebo in Patients Previously Treated With Sulfonylurea Therapya |
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Placebo (N=74) |
GLIMEPIRIDE |
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1 mg (N=78) |
4 mg (N=76) |
8 mg (N=76) |
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HbA1C (%) |
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n=59 |
n=65 |
n=65 |
n=68 |
Baseline (mean) |
8 |
7.9 |
7.9 |
8 |
Change from Baseline (adjusted meanb) |
1.5 |
0.3 |
-0.3 |
-0.4 |
Difference from Placebo (adjusted meanb) 95% confidence interval |
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-1.2* (-1.5, -0.8) |
-1.8* (-2.1, -1.4) |
1.8* (-2.2, -1.5) |
Mean Baseline Weight (kg) |
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n=67 |
n=76 |
n=75 |
n=73 |
Baseline (mean) |
85.7 |
84.3 |
86.1 |
85.5 |
Change from Baseline (adjusted meanb) |
-2.3 |
-0.2 |
0.5 |
1 |
Difference from Placebo (adjusted meanb) 95% confidence interval |
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2* (1.4, 2.7) |
2.8* (2.1, 3.5) |
3.2* (2.5, 4) |
a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value *p≤0.001 |
Table 4. 22-Week Monotherapy Trial Comparing Glimepiride to Placebo in Patients Who Were Treatment-Naïve or Who Had No Recent Treatment with Antidiabetic Therapya
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| Placebo (N=126)
| GLIMEPIRIDE (N=123)
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HbA1C (%)
| n=97 | n=106 |
Baseline (mean) | 9.1 | 9.3 |
Change from Baseline (adjusted mean b) | -1.1*
| -2.2*
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Difference from Placebo (adjusted meanb) 95% confidence interval | -1.1* (-1.5, -0.8) |
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Body Weight (kg)
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| n=122 | n=119 |
Baseline (mean) | 86.5 | 87.1 |
Change from Baseline (adjusted meanb) | -0.9 | 1.8 |
Difference from Placebo (adjusted meanb) 95% confidence interval | 2.7 (1.9, 3.6) |
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a Intent to treat population using last observation on study b Least squares mean adjusted for baseline value * p≤0.0001 |
GLIMEPIRIDE
glimepiride tablet |
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GLIMEPIRIDE
glimepiride tablet |
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GLIMEPIRIDE
glimepiride tablet |
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GLIMEPIRIDE
glimepiride tablet |
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GLIMEPIRIDE
glimepiride tablet |
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GLIMEPIRIDE
glimepiride tablet |
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Labeler - Micro Labs Limited (862174955) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
Micro Labs Limited, Goa | 915793658 | MANUFACTURE(42571-100, 42571-101, 42571-102, 42571-103, 42571-104, 42571-105) |