Glimepiride

1 INDICATIONS AND USAGE 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 ) ]. Glimepiride tablets are a sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1.1 ). Important Limitations of Use: Not for treating type 1 diabetes mellitus or diabetic ketoacidosis ( 1.1 ). 1.1 Important 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.

2 DOSAGE & ADMINISTRATION • Recommended starting dose is 1 or 2 mg once daily. Increase in 1 or 2 mg increments no more frequently than every 1-2 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 ) 2.1 Recommended Dosing • 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 ) ]. • The maximum recommended dose is 8 mg once daily. • Patients being transferred to glimepiride tablets 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 tablets should be administered at least 4 hours prior to colesevelam.

3 DOSAGE FORMS AND STRENGTHS Glimepiride is formulated as tablets of: 1 mg (Light pink colored, flat capsule shaped uncoated tablets having breakline on both faces and GM and 1 on engraved on either side of breakline on one face.) 2 mg (Light green coloured, flat capsule shaped uncoated matt finished tablets having break line on both faces and GM and 2 engraved on either side of breakline on one face.) 3 mg (Pale yellow colored, flat capsule shaped uncoated tablets having breakline on both faces and GM and 3 engraved on either side of breakline on one face.) 4 mg (Light blue coloured, flat capsule shaped uncoated matt finished tablets having break line on both faces and GM and 4 engraved on either side of breakline on one face.) 6 mg (Brick red colored, flat capsule shaped uncoated tablets having breakline on both faces and GM and 6 engraved on either side of breakline on one face.) 8 mg (White to off white, flat capsule shaped uncoated tablets having breakline on both faces and GM and 8 engraved on either side of breakline on one face.) Tablets (scored): 1 mg, 2 mg, 3 mg, 4 mg, 6 mg and 8 mg ( 3 )

4 CONTRAINDICATIONS 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. Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea) [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )]. • Hypersensitivity to glimepiride or any of the product’s ingredients ( 4 ) • Hypersensitivity to sulfonamide derivatives ( 4 )

6 ADVERSE REACTIONS 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 FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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.In clinical trials, the most common adverse reactions with glimepiride were hypoglycemia, dizziness, asthenia, headache, and nausea. Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled placebo-controlled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of ≥5% among glimepiride-treated patients and more commonly than in patients who received placebo. 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* Glimepiride Placebo N=745 N=294 % % Headache 8.2 7.8 Accidental Injury † 5.8 3.4 Flu Syndrome 5.4 4.4 Nausea 5.0 3.4 Dizziness 5.0 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 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* Glimepiride Placebo N=745 N=294 % % Headache 8.2 7.8 Accidental Injury † 5.8 3.4 Flu Syndrome 5.4 4.4 Nausea 5.0 3.4 Dizziness 5.0 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 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 sulfonylurea …

7 DRUG INTERACTIONS • Certain medications may affect glucose metabolism, requiring glimepiride tablets dose adjustment and close monitoring of blood glucose. ( 7.1 ) • Miconazole: Severe hypoglycemia can occur when glimepiride tablets 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 tablets should be administered at least 4 hours prior to colesevelam. ( 2.1 , 7.4 ) 7.1 Drugs Affecting Glucose Metabolism 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, H 2 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 Interaction 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 …

8 USE IN SPECIFIC POPULATIONS • 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 ). 8.1 Pregnancy Risk Summary Available data from a small number of published studies and postmarketing experience with glimepiride use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glimepiride) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, glimepiride tablets should be discontinued at least two weeks before expected delivery (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 4,000 times and 60 times the maximum human dose based on body surface area, respectively. However, fetotoxicity was observed in rats and rabbits at doses 50 times and 0.1 times the maximum human dose, respectively. The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with a HbA1c >7% and has been reported to be as high as 20% to 25% in women with a HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo-fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia-related morbidity. Fetal/neonatal adverse reactions Neonates of women with gestational diabetes who are treated with sulfonylureas during pregnancy may be at increased risk for neonatal intensive care admission and may develop respiratory distress, hypoglycemia, birth injury, and be large for gestational age. Prolonged severe hypoglycemia, lasting 4 to 10 days, has been reported in neonates born to mothers receiving a sulfonylurea at the time of delivery and has been reported with the use of agents with a prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly. Dose adjustments during pregnancy and the postpartum period Due to reports of prolonged severe hypoglycemia in neonates born to mothers receiving a sulfonylurea at the time of delivery, glimepiride tablets should be discontinued at least two weeks before expected delivery (see Fetal/Neonatal Adverse Reactions ). Data Animal data In animal studies, there was no increase in congenital anomalies, but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) and 0.1 times (rabbits) the maximum recommended human dose (based on body surface area). This fetotoxicity was observed only at doses inducing maternal hypoglycemia and is believed to be directly related to the pharmacologic (hypoglycemic) action of glimepiride, as has been similarly noted with other sulfonylureas. 8.2 Lactation Risk Summary Breastfed infants of lactating women using glimepiride tablets should be monitored for symptoms of hypoglycemia (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 developmenta …

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

11 DESCRIPTION Glimepiride tablets USP, are an oral sulfonylurea that contains the active ingredient glimepiride USP. Chemically, glimepiride USP 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 24 H 34 N 4 O 5 S) with a molecular weight of 490.62. Glimepiride USP is a white to almost white powder, soluble in dimethyl formamide, sparingly soluble in methylene chloride, practically insoluble in water. The structural formula is: Glimepiride tablets meets USP drug release test 2. Glimepiride tablets USP, contain the active ingredient glimepiride USP and the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. In addition, glimepiride 1 mg tablets contain ferric oxide red, glimepiride 2 mg tablets contain lake blend green (contains D&C yellow # 10 aluminium lake and FD&C blue #1/ brilliant blue FCF aluminium lake) and glimepiride 4 mg tablets contain lake blend blue (contains D&C yellow # 10 aluminium lake and FD&C blue # 1/ brilliant blue FCF aluminium lake). Structural Formula

10 OVERDOSAGE An overdosage of glimepiride tablets, 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 ) ].

16 HOW SUPPLIED/STORAGE AND HANDLING Glimepiride Tablets USP are available in the following strengths and package sizes: 1 mg (Light pink colored, flat capsule shaped uncoated tablets having break line on both faces and GM and 1 on engraved on either side of breakline on one face.) Bottles of 100 (NDC 42571-100-01) Bottles of 500 (NDC 42571-100-05) 2 mg (Light green colored, flat capsule shaped uncoated matt finished tablets having break line on both faces and GM and 2 engraved on either side of breakline on one face.) Bottles of 100 (NDC 42571-101-01) Bottles of 500 (NDC 42571-101-05) 3 mg (Pale yellow colored, flat capsule shaped uncoated tablets having breakline on both faces and GM and 3 engraved on either side of breakline on one face.) Bottles of 100 (NDC 42571-102-01) Bottles of 500 (NDC 42571-102-05) 4 mg (Light blue colored, flat capsule shaped uncoated matt finished tablets having break line on both faces and GM and 4 engraved on either side of breakline on one face.) Bottles of 100 (NDC 42571-103-01) Bottles of 500 (NDC 42571-103-05) 6 mg (Brick red colored, flat capsule shaped uncoated tablets having breakline on both faces and GM and 6 engraved on either side of breakline on one face.) Bottles of 100 (NDC 42571-104-01) Bottles of 500 (NDC 42571-104-05) 8 mg (White to off white, flat capsule shaped uncoated tablets having breakline on both faces and GM and 8 engraved on either side of breakline on one face.) Bottles of 100 (NDC 42571-105-01) Bottles of 500 (NDC 42571-105-05) Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in well-closed containers with safety closures.