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 when these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for worsening glycemic control.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 when these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for hypoglycemia.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. both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of glimepiride in an unpredictable fashion. the signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine. 7.2 miconazole a potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. whether this interaction also occurs with other dosage forms of miconazole is not known. 7.3 cytochrome p450 2c9 interactions there may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of cytochrome p450 2c9. fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control. 7.4 concomitant administration of colesevelam colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are coadministered. however, absorption is not reduced when glimepiride is administered 4 hours prior to colesevelam. therefore, glimepiride should be administered at least 4 hours prior to colesevelam.

nylureas, 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. patients must be educated to recognize and manage hypoglycemia. use caution when initiating and increasing glimepiride doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti- diabetic medications). debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested. early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. these situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia. 5.2 hypersensitivity reactions there have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angioedema, and stevens- johnson syndrome [ see adverse reactions ( 6.2 )]. if a hypersensitivity reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes. 5.3 hemolytic anemia sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (g6pd) deficiency. because glimepiride is a sulfonylurea, use caution in patients with g6pd deficiency and consider the use of a non-sulfonylurea alternative. there are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known g6pd deficiency [see adverse reactions ( 6.2 )]. 5.4 increased risk of cardiovascular mortality with sulfonylureas 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. ugdp reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2 and a half times that of patients treated with diet alone. a significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. despite controversy regarding the interpretation of these results, the findings of the ugdp study provide an adequate basis for this warning. the patient should be informed of the potential risks and advantages of glimepiride and of alternative modes of therapy. although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. 5.5 macrovascular outcomes there have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.

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 )]. the maximum recommended dose is 8 mg once daily. patients being transferred to glimepiride from longer half-life sulfonylureas (e.g., chlorpropamide) may have overlapping drug effect for 1 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 should be administered at least 4 hours prior to colesevelam.

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. both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of glimepiride in an unpredictable fashion. the signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine. 7.2 miconazole a potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. whether this interaction also occurs with other dosage forms of miconazole is not known. 7.3 cytochrome p450 2c9 interactions there may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of cytochrome p450 2c9. fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control. 7.4 concomitant administration of colesevelam colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are coadministered. however, absorption is not reduced when glimepiride is administered 4 hours prior to colesevelam. therefore, glimepiride should be administered at least 4 hours prior to colesevelam.

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.

cise 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-naïve 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).

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.

n. 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.

mals 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).

/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).

eeding, 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

ific 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