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TL;DR â Quick Summary
Key facts from the full medication guide below
đŠēWhat it's for
Glimepiride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies ( 14.1)]. Limitations of Use Glimepiride tablets should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.
đHow to take it
Recommended starting dose is 1 or 2 mg once daily. Increase in 1 or 2 mg increments no more frequently than every 1 to 2 weeks based on glycemic response. Maximum recommended dose is 8 mg once daily. ( 2.1) Administer with breakfast or first meal of the day. ( 2.1) Use 1 mg starting dose and titrate slowly in patients at increased risk for hypoglycemia (e.g., elderly, patients with renal impairment).
âšī¸Common side effects
The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions ( 5.1)] Hemolytic anemia [see Warnings and Precautions ( 5.3)] Common 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 Accord Healthcare Inc.
â ī¸Serious risks
Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications ( 5.1). Hypersensitivity Reactions: Postmarketing reports include anaphylaxis, angioedema and Stevens-Johnson Syndrome. If a reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes. ( 5.2).
đInteractions & cautions
Certain medications may affect glucose metabolism, requiring glimepiride dose adjustment and close monitoring of blood glucose. ( 7.1). Miconazole: Severe hypoglycemia can occur when glimepiride and oral miconazole are used concomitantly ( 7.2). Cytochrome P450 2C9 interactions: Inhibitors and inducers of cytochrome P450 2C9 may affect glycemic control by altering glimepiride plasma concentrations. ( 7.3).
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Recommended starting dose is 1 or 2 mg once daily. Increase in 1 or 2 mg increments no more frequently than every 1 to 2 weeks based on glycemic response. Maximum recommended dose is 8 mg once daily. ( 2.1) Administer with breakfast or first meal of the day. ( 2.1) Use 1 mg starting dose and titrate slowly in patients at increased risk for hypoglycemia (e.g., elderly, patients with renal impairment). ( 2.1)
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 1 mg (n=78), glimepiride 4 mg (n=76) and glimepiride 8 mg (n=76). All patients randomized to glimepiride started 1 mg daily. Patients randomized to glimepiride 4 mg or 8 mg had blinded, forced titration of the glimepiride 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 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 Glimepiride to Placebo in Patients Previously Treated With Sulfonylurea Therapy a Placebo (N=74) Glimepiride 1 mg (N=78) 4 mg (N=76) 8 mg (N=76) HbA 1C (%) n=59 n=65 n=65 n=68 Baseline (mean) 8.0 7.9 7.9 8.0 Change from Baseline (adjusted mean b) 1.5 0.3 -0.3 -0.4 Difference from Placebo (adjusted mean b) -1.2* (-1.5, -0.8) -1.8* (-2.1, -1.4) -1.8* (-2.2, -1.5) Mean Baseline Weight 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 1.0 Difference from Placebo (adjusted mean b) 2.0* (1.4, 2.7) 2.8* (2.1, 3.5) 3.2* (2.5, 4.0) 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-na ve 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 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 HbA1C and FPG compared to placebo (Table 4). Table 4: 22-Week Monotherapy Trial Comparing Glimepiride to Placebo in Patients Who Were Treatment-Na ve or Who Had No Recent Treatment with Antidiabetic Therapy a Placebo (N=126) Glimepiride (N=123) HbA 1C (%) 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 b Least squares mean adjusted for baseline value * p 0.0001
Glimepiride tablets, USP are formulated as tablets of: 1 mg tablets (pink coloured, oval shaped, biconvex, uncoated tablets debossed with AHI 1 on one side and break line on the other) 2 mg tablets (green coloured, oval shaped, biconvex, uncoated tablets debossed with AHI 2 on one side and break line on the other) 4 mg tablets (blue coloured, oval shaped, biconvex, uncoated tablets debossed with AHI 4 on one side and break line on the other) Tablets (scored): 1 mg, 2 mg, 4 mg ( 3)
Glimepiride tablet is contraindicated in patients with a history of a hypersensitivity reaction to: Glimepiride or any of the product s ingredients [see Warnings and Precautions ( 5.2)]. 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 ( 4) Hypersensitivity to sulfonamide derivatives ( 4)
Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications ( 5.1). Hypersensitivity Reactions: Postmarketing reports include anaphylaxis, angioedema and Stevens-Johnson Syndrome. If a reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes. ( 5.2). Hemolytic Anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider a non-sulfonylurea alternative. ( 5.3). Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives. ( 5.4). Macrovascular Outcomes: No clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug ( 5.5).
The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions ( 5.1)] Hemolytic anemia [see Warnings and Precautions ( 5.3)] Common 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 Accord Healthcare Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Certain medications may affect glucose metabolism, requiring glimepiride dose adjustment and close monitoring of blood glucose. ( 7.1). Miconazole: Severe hypoglycemia can occur when glimepiride and oral miconazole are used concomitantly ( 7.2). Cytochrome P450 2C9 interactions: Inhibitors and inducers of cytochrome P450 2C9 may affect glycemic control by altering glimepiride plasma concentrations. ( 7.3). Colesevelam: Coadministration may reduce glimepiride absorption.Glimepiride should be administered at least 4 hours prior to colesevelam ( 2.1, 7.4).
Pediatric Patients: Not recommended because of adverse effects on body weight and hypoglycemia ( 8.4). Geriatric or Renally Impaired Patients: At risk for hypoglycemia with glimepiride. Use caution in dose selection and titration, and monitor closely ( 8.5, 8.6).
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 should be discontinued at least two weeks before expected delivery (see Clinical Considerations). Poorly controlled diabetes in pregnancy is also associated with risks to the mother and fetus (see Clinical 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 4000 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 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.
Risk Summary Breastfed infants of lactating women using glimepiride should be monitored for symptoms of hypoglycemia (see Clinical 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.
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-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-na ve 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 HbA1c 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 HbA1c with glimepiride compared to metformin. Table 2: Change from Baseline in HbA1C and Body Weight in Pediatric Patients Taking Glimepiride or Metformin Metformin Glimepiride Treatment-Na ve Patients Intent-to-treat population using last-observation-carried-forward for missing data (Glimepiride, n=127; metformin, n=126) N=69 N=72 HbA1C (%) Baseline (mean) 8.2 8.3 Change from baseline (adjusted LS mean) adjusted for baseline HbA 1c and Tanner Stage -1.2 -1.0 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 HbA1C (%) Baseline (mean) 9.0 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 2.0 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 [see Adverse 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).
To minimize the risk of hypoglycemia, the recommended starting dose of glimepiride is 1 mg daily for all patients with type 2 diabetes and renal impairment [see Dosage 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 was 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 [see Clinical Pharmacology ( 12.3)].
An overdosage of glimepiride, as with other sulfonylureas, can produce severe hypoglycemia. Mild episodes of hypoglycemia can be treated with oral glucose. Severe hypoglycemic reactions constitute medical emergencies requiring immediate treatment. Severe hypoglycemia with coma, seizure, or neurological impairment can be treated with glucagon or intravenous glucose. Continued observation and additional carbohydrate intake may be necessary because hypoglycemia may recur after apparent clinical recovery [see Warnings and Precautions ( 5.1) ]
Glimepiride is an oral sulfonylurea that contains the active ingredient glimepiride. Chemically, glimepiride is identified as 1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1 carboxamido) ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea (C 24H 34N 4O 5S) with a molecular weight of 490.62. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder and is practically insoluble in water. The structural formula is: Glimepiride tablets, USP contain the active ingredient glimepiride and the following inactive ingredients: lactose monohydrate, sodium starch glycolate, povidone, and magnesium stearate. In addition, glimepiride tablets, USP 1 mg contain ferric oxide red, glimepiride tablets, USP 2 mg contain ferric oxide yellow and FD &C blue #2 aluminum lake, and glimepiride tablets, USP 4 mg contain FD&C blue #2 aluminum lake.
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.
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. The effects of glimepiride 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 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% 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 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 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 (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 was administered. The glimepiride 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 [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 glimepiride 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 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 was administered. The glimepiride 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 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.
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 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).
Glimepiride tablets, USP are available in the following strengths and package sizes: 1 mg tablets (pink coloured, oval shaped, biconvex, uncoated tablets debossed with AHI 1 on one side and break line on the other) in bottles of 100 (NDC 16729-001-01), 500 (NDC 16729-001-16) and 1,000 (NDC 16729-001-17) 2 mg tablets (green coloured, oval shaped, biconvex, uncoated tablets debossed with AHI 2 on one side and break line on the other) in bottles of 100 (NDC 16729-002-01), 500 (NDC 16729-002-16) and 1,000 (NDC 16729-002-17) 4 mg tablets (blue coloured, oval shaped, biconvex, uncoated tablets debossed with AHI 4 on one side and break line on the other) in bottles of 100 (NDC 16729-003-01), 500 (NDC 16729-003-16) and 1,000 (NDC 16729-003-17) Store at 25 C (77 F); excursions permitted to 20 C to 25 C (68 F to 77 F) (see USP Controlled Room Temperature). Dispense in well-closed containers with safety closures.
Hypoglycemia Explain the symptoms and treatment of hypoglycemia as well as conditions that predispose to hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia and that this may present a risk in situations where these abilities are especially important, such as driving or operating other machinery [see Warnings and Precautions (5.1)]. Hypersensitivity Reactions Inform patients that hypersensitivity reactions may occur with glimepiride and that if a reaction occurs to seek medical treatment and discontinue glimepiride [see Warnings and Precautions (5.2)]. Pregnancy Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise breastfeeding women taking glimepiride to monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures) [see Use in Specific Populations (8.2)]. Manufactured For: Accord Healthcare, Inc., 1009 Slater Road, Suite 210-B, Durham, NC 27703, USA. Manufactured By: Intas Pharmaceuticals Limited, Ahmedabad -380 054, India. 10 1677 2 693003 Issued February 2019
PRINCIPAL DISPLAY PANEL 1 mg : 100 Tablets 2 mg : 100 Tablets 4 mg : 100 Tablets
