Glipizide XL

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 (5.2) ] Most common adverse reactions (incidence > 3%) are dizziness, diarrhea, nervousness, tremor, hypoglycemia and flatulence ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Greenstone LLC Professional Information Services at 1-800-438-1985 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. In clinical trials, 580 patients from 31 to 87 years of age received GLIPIZIDE XL in doses from 5 mg to 60 mg in both controlled and open trials. The dosages above 20 mg are not recommended dosages. In these trials, approximately 180 patients were treated with GLIPIZIDE XL for at least 6 months. Table 1 summarizes the incidence of adverse reactions, other than hypoglycemia, that were reported in pooled double-blind, placebo-controlled trials in ≥3% of GLIPIZIDE XL-treated patients and more commonly than in patients who received placebo. Table 1: Incidence (%) of Adverse Reactions Reported in ≥3% of Patients Treated in Placebo-Controlled Clinical Trials and More Commonly in Patients Treated with GLIPIZIDE XL (Excluding Hypoglycemia) GLIPIZIDE XL (%) (N=278) Placebo (%) (N=69) Adverse Effect Dizziness 6.8 5.8 Diarrhea 5.4 0.0 Nervousness 3.6 2.9 Tremor 3.6 0.0 Flatulence 3.2 1.4 Hypoglycemia Of the 580 patients that received GLIPIZIDE XL in clinical trials, 3.4% had hypoglycemia documented by a blood-glucose measurement <60 mg/dL and/or symptoms believed to be associated with hypoglycemia and 2.6% of patients discontinued for this reason. Hypoglycemia was not reported for any placebo patients. Gastrointestinal Reactions In clinical trials, the incidence of gastrointestinal (GI) side effects (nausea, vomiting, constipation, dyspepsia), occurred in less than 3% of GLIPIZIDE XL-treated patients and were more common in GLIPIZIDE XL-treated patients than those receiving placebo. Dermatologic Reactions In clinical trials, allergic skin reactions, i.e., urticaria occurred in less than 1.5% of treated patients and were more common in GLIPIZIDE XL treated patients than those receiving placebo. These may be transient and may disappear despite continued use of glipizide XL; if skin reactions persist, the drug should be discontinued. Laboratory Tests Mild to moderate elevations of ALT, LDH, alkaline phosphatase, BUN and creatinine have been noted. The relationship of these abnormalities to glipizide is uncertain. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of GLIPIZIDE XL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Abdominal pain • Cholestatic and hepatocellular forms of liver injury accompanied by jaundice • Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia [see Warnings and Precautions (5.2) ] , aplastic anemia, pancytopenia • Hepatic porphyria and disulfiram-like reactions • Hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion • Rash • There have been reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug with this non-dissolvable extended release formulation.

4 CONTRAINDICATIONS Glipizide is contraindicated in patients with: • Known hypersensitivity to glipizide or any of the product's ingredients. • Hypersensitivity to sulfonamide derivatives. ▪ Known hypersensitivity to glipizide or any of the product's ingredients ( 4 ). ▪ Hypersensitivity to sulfonamide derivatives ( 4 ).

11 DESCRIPTION GLIPIZIDE XL (glipizide) is an oral sulfonylurea. The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl] phenyl]sulfonyl]urea. The molecular formula is C 21 H 27 N 5 O 4 S; the molecular weight is 445.55; the structural formula is shown below: Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. Each tablet contains 2.75 mg glipizide to provide a 2.5 mg dose. Each tablet contains 5.49 mg glipizide to provide a 5 mg dose. Each tablet contains 10.98 mg glipizide to provide a 10 mg dose. Inert ingredients in the 2.5 mg, 5 mg and 10 mg formulations are: polyethylene oxide, hypromellose, magnesium stearate, sodium chloride, red ferric oxide, cellulose acetate, polyethylene glycol, Opadry ® blue (OY-LS-20921)(2.5 mg tablets), Opadry ® white (YS-2-7063)(5 mg and 10 mg tablet) and Opacode ® Black Ink (S-1-17823). System Components and Performance GLIPIZIDE XL Extended Release Tablet is similar in appearance to a conventional tablet. It consists, however, of an osmotically active drug core surrounded by a semipermeable membrane. The core itself is divided into two layers: an "active" layer containing the drug, and a "push" layer containing pharmacologically inert (but osmotically active) components. The membrane surrounding the tablet is permeable to water but not to drug or osmotic excipients. As water from the gastrointestinal tract enters the tablet, pressure increases in the osmotic layer and "pushes" against the drug layer, resulting in the release of drug through a small, laser-drilled orifice in the membrane on the drug side of the tablet. The function of the GLIPIZIDE XL Extended Release Tablet depends upon the existence of an osmotic gradient between the contents of the bi-layer core and fluid in the GI tract. The biologically inert components of the tablet remain intact during GI transit and are eliminated in the feces as an insoluble shell. Chemical Structure

2 DOSAGE AND ADMINISTRATION ▪ Recommended starting dose is 5 mg once daily. Dose adjustment can be made based on the patient's glycemic control. Maximum recommended dose is 20 mg once daily ( 2.1 ). ▪ Administer with breakfast or the first meal of the day ( 2.1 ). ▪ For combination therapy with other blood-glucose-lowering agents, initiate the agent at the lowest recommended dose, and observe patients for hypoglycemia ( 2.2 ). 2.1 Recommended Dosing GLIPIZIDE XL should be administered orally with breakfast or the first main meal of the day. The recommended starting dose of GLIPIZIDE XL is 5 mg once daily. Start patients at increased risk for hypoglycemia (e.g. the elderly or patients with hepatic insufficiency) at 2.5 mg [see Use in Specific Population (8.5 , 8.6) ] . Dosage adjustment can be made based on the patient's glycemic control. The maximum recommended dose is 20 mg once daily. Patients receiving immediate release glipizide may be switched to GLIPIZIDE XL once daily at the nearest equivalent total daily dose. 2.2 Use with Other Glucose Lowering Agents When adding GLIPIZIDE XL to other anti-diabetic drugs, initiate GLIPIZIDE XL at 5 mg once daily. Start patients at increased risk for hypoglycemia at a lower dose. When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, GLIPIZIDE XL should be administered at least 4 hours prior to colesevelam.

1 INDICATIONS AND USAGE GLIPIZIDE XL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. GLIPIZIDE XL is a sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. 1.1 Limitations of Use GLIPIZIDE XL is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

10 OVERDOSAGE Overdosage of sulfonylureas including GLIPIZIDE XL can produce severe hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated with oral glucose. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment are medical emergencies requiring immediate treatment. The patient should be treated with glucagon or intravenous glucose. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of glipizide from plasma may be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.

7 DRUG INTERACTIONS ▪ Certain medications may affect glucose metabolism, requiring GLIPIZIDE XL dose adjustment and close monitoring of blood glucose ( 7.1 ). ▪ Miconazole: Monitor patients closely. Severe hypoglycemia can occur when GLIPIZIDE and oral miconazole are used concomitantly ( 7.2 , 12.3 ). ▪ Fluconazole: Monitor patients closely. An increase in GLIPIZIDE AUC was seen after fluconazole administration ( 7.3 , 12.3 ). ▪ Colesevelam: GLIPIZIDE XL should be administered at least 4 hours prior to colesevelam ( 7.4 , 12.3 ). 7.1 Drugs Affecting Glucose Metabolism A number of medications affect glucose metabolism and may require GLIPIZIDE XL dose adjustment and close monitoring for hypoglycemia or worsening glycemic control. The following are examples of medication that may increase the glucose lowering effect of GLIPIZIDE XL, increase the susceptibility to and/or intensity of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), sulfonamide antibiotics, nonsteroidal anti-inflammatory agents, chloramphenicol, probenecid, coumarins, voriconazole, H2 receptor antagonists, and quinolones. When these medications are administered to a patient receiving GLIPIZIDE XL, monitor the patient closely for hypoglycemia. When these medications are discontinued from a patient receiving GLIPIZIDE XL, monitor the patient closely for worsening glycemic control. The following are examples of medication that may reduce the glucose-lowering effect of GLIPIZIDE XL, leading to worsening glycemic control: atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), thyroid hormones, phenytoin, nicotinic acid, and calcium channel blocking drugs. When such drugs are administered to patients receiving GLIPIZIDE XL, monitor the patients closely for worsening glycemic control. When these medications are discontinued from patients receiving GLIPIZIDE XL, monitor the patient closely for hypoglycemia. Alcohol, beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of the glucose-lowering effect. Increased frequency of monitoring may be required when GLIPIZIDE XL is co-administered with these drugs. The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine. Increased frequency of monitoring may be required when GLIPIZIDE XL is co-administered with these drugs. 7.2 Miconazole Monitor patients closely for hypoglycemia when Glipizide XL is co-administered with miconazole. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported [see Clinical Phamacology (12.3) ] . 7.3 Fluconazole Monitor patients closely for hypoglycemia when Glipizide XL is co-administered with fluconazole. Concomitant treatment with fluconazole increases plasma concentrations of glipizide, which may lead to hypoglycemia [see Clinical Pharmacology (12.3) ] . 7.4 Colesevelam GLIPIZIDE XL should be administered at least 4 hours prior to the administration of colesevelam. Colesevelam can reduce the maximum plasma concentration and total exposure of glipizide when the two are coadministered [see Clinical Pharmacology (12.3) ] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Glipizide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. 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. 12.2 Pharmacodynamics The insulinotropic response to a meal is enhanced with GLIPIZIDE XL administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. In two randomized, double-blind, dose-response studies comprising a total of 347 patients, there was no significant increase in fasting insulin in all GLIPIZIDE XL-treated patients combined compared to placebo, although minor elevations were observed at some doses. In studies of GLIPIZIDE XL in subjects with type 2 diabete mellitus, once daily administration produced reductions in hemoglobin A1c, fasting plasma glucose and postprandial glucose. The relationship between dose and reduction in hemoglobin A1c was not established, however subjects treated with 20 mg had a greater reduction in fasting plasma glucose compared to subjects treated with 5 mg. 12.3 Pharmacokinetics Absorption The absolute bioavailability of glipizide was 100% after single oral doses in patients with type 2 diabetes mellitus. Beginning 2 to 3 hours after administration of GLIPIZIDE XL, plasma drug concentrations gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of GLIPIZIDE XL, plasma glipizide concentrations are maintained throughout the 24 hour dosing interval with less peak to trough fluctuation than that observed with twice daily dosing of immediate release glipizide. The mean relative bioavailability of glipizide in 21 males with type 2 diabetes mellitus after administration of 20 mg GLIPIZIDE XL, compared to immediate release Glipizide (10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at least the fifth day of dosing with GLIPIZIDE XL in 21 males with type 2 diabetes mellitus and patients younger than 65 years. No accumulation of drug was observed in patients with type 2 diabetes mellitus during chronic dosing with GLIPIZIDE XL. Administration of GLIPIZIDE XL with food has no effect on the 2 to 3 hour lag time in drug absorption. In a single dose, food effect study in 21 healthy male subjects, the administration of GLIPIZIDE XL immediately before a high fat breakfast resulted in a 40% increase in the glipizide mean C max value, which was significant, but the effect on the AUC was not significant. There was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of the GLIPIZIDE XL tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and potentially result in lower plasma concentrations. In a multiple dose study in 26 males with type 2 diabetes mellitus, the pharmacokinetics of glipizide were linear with GLIPIZIDE XL in that the plasma drug concentrations increased proportionately with dose. In a single dose study in 24 healthy subjects, four 5-mg, two 10-mg, and one 20-mg GLIPIZIDE XL tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5-mg GLIPIZIDE XL tablets were bioequivalent to one 10-mg GLIPIZIDE XL tablet. Distribution The mean volume of distribution was approximately 10 liters after single intravenous doses in patients with type 2 diabetes mellitus. Glipizide is 98–99% bound to serum proteins, primarily to albumin. Metabolism The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite, an acetylamino-ethyl benzene derivative, which accounts for less than 2% of a dose, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound. Elimination Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%). The mean total body clearance of glipizide was approximately 3 liters per hour after single intravenous doses in patients with type 2 diabetes mellitus. The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus. Specific Populations Pediatric: Studies characterizing the pharmacokinetics of glipizide in pediatric patients have not been performed. Geriatric: There were no differences in the pharmacokinetics of glipizide after single dose administration to older diabetic subjects compared to younger healthy subjects [see Use in Specific Populations (8.5) ]. Renal Impairment: The pharmacokinetics of glipizide has not been evaluated in patients with varying degree of renal impairment. Limited data indicates that glipizide biotransformation products may remain in circulation for a longer time in subjects with renal impairment than that seen in subjects with normal renal function. Hepatic Impairment: The pharmacokinetics of glipizide has not been evaluated in patients with hepatic impairment. Drug-drug Interactions Miconazole A potential interaction between oral miconazole and oral glipizide leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known [see Drug Interactions (7.2) ] . Fluconazole Concomitant treatment with fluconazole increases plasma concentrations of glipizide. The effect of concomitant administration of Diflucan ® (fluconazole) and Glipizide has been demonstrated in a placebo controlled crossover study in healthy volunteers. All subjects received Glipizide alone and following treatment with 100 mg of Diflucan ® as a single daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%) [see Drug Interactions (7.3) ] . Colesevelam Colesevelam can reduce the maximum plasma concentration and total exposure of glipizide when the two are coadministered. In studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy volunteers, reductions in glipizide AUC 0–∞ and C max of 12% and 13%, respectively were observed when colesevelam was coadministered with glipizide ER. When glipizide ER was administered 4 hours prior to colesevelam, there was no significant change in glipizide AUC 0–∞ or C max , -4% and 0%, respectively [see Drug Interactions (7.4) ] .

12.1 Mechanism of Action Glipizide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. 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.

12.2 Pharmacodynamics The insulinotropic response to a meal is enhanced with GLIPIZIDE XL administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. In two randomized, double-blind, dose-response studies comprising a total of 347 patients, there was no significant increase in fasting insulin in all GLIPIZIDE XL-treated patients combined compared to placebo, although minor elevations were observed at some doses. In studies of GLIPIZIDE XL in subjects with type 2 diabete mellitus, once daily administration produced reductions in hemoglobin A1c, fasting plasma glucose and postprandial glucose. The relationship between dose and reduction in hemoglobin A1c was not established, however subjects treated with 20 mg had a greater reduction in fasting plasma glucose compared to subjects treated with 5 mg.

12.3 Pharmacokinetics Absorption The absolute bioavailability of glipizide was 100% after single oral doses in patients with type 2 diabetes mellitus. Beginning 2 to 3 hours after administration of GLIPIZIDE XL, plasma drug concentrations gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of GLIPIZIDE XL, plasma glipizide concentrations are maintained throughout the 24 hour dosing interval with less peak to trough fluctuation than that observed with twice daily dosing of immediate release glipizide. The mean relative bioavailability of glipizide in 21 males with type 2 diabetes mellitus after administration of 20 mg GLIPIZIDE XL, compared to immediate release Glipizide (10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at least the fifth day of dosing with GLIPIZIDE XL in 21 males with type 2 diabetes mellitus and patients younger than 65 years. No accumulation of drug was observed in patients with type 2 diabetes mellitus during chronic dosing with GLIPIZIDE XL. Administration of GLIPIZIDE XL with food has no effect on the 2 to 3 hour lag time in drug absorption. In a single dose, food effect study in 21 healthy male subjects, the administration of GLIPIZIDE XL immediately before a high fat breakfast resulted in a 40% increase in the glipizide mean C max value, which was significant, but the effect on the AUC was not significant. There was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of the GLIPIZIDE XL tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and potentially result in lower plasma concentrations. In a multiple dose study in 26 males with type 2 diabetes mellitus, the pharmacokinetics of glipizide were linear with GLIPIZIDE XL in that the plasma drug concentrations increased proportionately with dose. In a single dose study in 24 healthy subjects, four 5-mg, two 10-mg, and one 20-mg GLIPIZIDE XL tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5-mg GLIPIZIDE XL tablets were bioequivalent to one 10-mg GLIPIZIDE XL tablet. Distribution The mean volume of distribution was approximately 10 liters after single intravenous doses in patients with type 2 diabetes mellitus. Glipizide is 98–99% bound to serum proteins, primarily to albumin. Metabolism The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite, an acetylamino-ethyl benzene derivative, which accounts for less than 2% of a dose, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound. Elimination Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%). The mean total body clearance of glipizide was approximately 3 liters per hour after single intravenous doses in patients with type 2 diabetes mellitus. The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes mellitus. Specific Populations Pediatric: Studies characterizing the pharmacokinetics of glipizide in pediatric patients have not been performed. Geriatric: There were no differences in the pharmacokinetics of glipizide after single dose administration to older diabetic subjects compared to younger healthy subjects [see Use in Specific Populations (8.5) ]. Renal Impairment: The pharmacokinetics of glipizide has not been evaluated in patients with varying degree of renal impairment. Limited data indicates that glipizide biotransformation products may remain in circulation for a longer time in subjects with renal impairment than that seen in subjects with normal renal function. Hepatic Impairment: The pharmacokinetics of glipizide has not been evaluated in patients with hepatic impairment. Drug-drug Interactions Miconazole A potential interaction between oral miconazole and oral glipizide leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known [see Drug Interactions (7.2) ] . Fluconazole Concomitant treatment with fluconazole increases plasma concentrations of glipizide. The effect of concomitant administration of Diflucan ® (fluconazole) and Glipizide has been demonstrated in a placebo controlled crossover study in healthy volunteers. All subjects received Glipizide alone and following treatment with 100 mg of Diflucan ® as a single daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%) [see Drug Interactions (7.3) ] . Colesevelam Colesevelam can reduce the maximum plasma concentration and total exposure of glipizide when the two are coadministered. In studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy volunteers, reductions in glipizide AUC 0–∞ and C max of 12% and 13%, respectively were observed when colesevelam was coadministered with glipizide ER. When glipizide ER was administered 4 hours prior to colesevelam, there was no significant change in glipizide AUC 0–∞ or C max , -4% and 0%, respectively [see Drug Interactions (7.4) ] .

20230920

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3 DOSAGE FORMS AND STRENGTHS GLIPIZIDE XL (glipizide) Extended Release tablets: 2.5 mg, blue and imprinted with "GLIPIZIDE XL 2.5" or "GXL 2.5" on one side 5 mg, white and imprinted with "GLIPIZIDE XL 5" or "GXL 5" on one side 10 mg, white and imprinted with "GLIPIZIDE XL 10" or "GXL 10" on one side Tablets: 2.5 mg, 5 mg, 10 mg ( 3 ).

Glipizide XL glipizide GLIPIZIDE GLIPIZIDE POLYETHYLENE GLYCOL, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE SODIUM CHLORIDE FERRIC OXIDE RED CELLULOSE ACETATE GXL;2;5 Glipizide XL glipizide GLIPIZIDE GLIPIZIDE POLYETHYLENE GLYCOL, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE SODIUM CHLORIDE FERRIC OXIDE RED CELLULOSE ACETATE GXL;5 Glipizide XL glipizide GLIPIZIDE GLIPIZIDE POLYETHYLENE GLYCOL, UNSPECIFIED HYPROMELLOSE, UNSPECIFIED MAGNESIUM STEARATE SODIUM CHLORIDE FERRIC OXIDE RED CELLULOSE ACETATE GXL;10

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A twenty month study in rats and an eighteen month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 20 times the human dose based on body surface area, showed no effects on fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility A twenty month study in rats and an eighteen month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 20 times the human dose based on body surface area, showed no effects on fertility.

NDA020329

Glipizide XL

glipizide

59762-0542

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Bottle Label NDC 59762-0540-1 30 Tablets GREENSTONE ® BRAND Glipizide XL (glipizide) extended-release tablets 2.5 mg Rx only PRINCIPAL DISPLAY PANEL - 2.5 mg Tablet Bottle Label

For more information, go to www.greenstonellc.com or call 1-800-438-1985. LAB-0330-14.0 Logo

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Inform patients of the potential adverse reactions of GLIPIZIDE XL including hypoglycemia. Explain the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development to patients and responsible family members. Also inform patients about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing of glycemic control. Inform patients that GLIPIZIDE XL should be swallowed whole. Inform patients that they should not chew, divide or crush tablets and they may occasionally notice in their stool something that looks like a tablet. In the GLIPIZIDE XL tablet, the medication is contained within a non-dissolvable shell that has been specially designed to slowly release the drug so the body can absorb it. 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 GLIPIZIDE XL to monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, hypothermia, excessive sleepiness, poor feeding, seizures) [see Use in Specific Populations (8.2) ].

15 REFERENCES 1. Diabetes , 19, SUPP. 2: 747–830, 1970

8.5 Geriatric Use There were no overall differences in effectiveness or safety between younger and older patients, but greater sensitivity of some individuals cannot be ruled out. Elderly patients are particularly susceptible to the hypoglycemic action of anti-diabetic agents. Hypoglycemia may be difficult to recognize in these patients. Therefore, dosing should be conservative to avoid hypoglycemia [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] .

8.4. Pediatric Use Safety and effectiveness in children have not been established.

8.1. Pregnancy Risk Summary Available data from a small number of published studies and postmarketing experience with GLIPIZIDE XL use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glipizide) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, GLIPIZIDE XL 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, there were no effects on embryofetal development following administration of glipizide to pregnant rats and rabbits during organogenesis at doses 833 times and 8 times the human dose based on body surface area, respectively. However, increased pup mortality was observed in rats administered glipizide from gestation day 15 throughout lactation at doses 2 times the maximum human dose based on body surface area (see Data ) . The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20–25% in women with 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 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly-controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, miscarriage, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, 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 4–10 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, Glipizide XL should be discontinued at least two weeks before expected delivery (see Fetal/Neonatal Adverse Reactions ) . Data Animal Data In teratology studies in rats and rabbits, pregnant animals received daily oral doses of glipizide during the period of organogenesis at doses up to 2000 mg/kg/day and 10 mg/kg/day (approximately 833 and 8 times the human dose based on body surface area), respectively. There were no adverse effects on embryo-fetal development at any of the doses tested. In a peri- and postnatal study in pregnant rats, there was a reduced number of pups born alive following administration of glipizide from gestation day 15 throughout lactation through weaning at doses ≥5 mg/kg/day (about 2 times the recommended maximum human dose based on body surface area).

8 USE IN SPECIFIC POPULATIONS ▪ Geriatric, Hepatically Impaired Patients: At risk for hypoglycemia with GLIPIZIDE XL. 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 GLIPIZIDE XL use in pregnancy over decades have not identified any drug associated risks for major birth defects, miscarriage, or adverse maternal outcomes. However, sulfonylureas (including glipizide) cross the placenta and have been associated with neonatal adverse reactions such as hypoglycemia. Therefore, GLIPIZIDE XL 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, there were no effects on embryofetal development following administration of glipizide to pregnant rats and rabbits during organogenesis at doses 833 times and 8 times the human dose based on body surface area, respectively. However, increased pup mortality was observed in rats administered glipizide from gestation day 15 throughout lactation at doses 2 times the maximum human dose based on body surface area (see Data ) . The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20–25% in women with 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 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly-controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, miscarriage, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, 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 4–10 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, Glipizide XL should be discontinued at least two weeks before expected delivery (see Fetal/Neonatal Adverse Reactions ) . Data Animal Data In teratology studies in rats and rabbits, pregnant animals received daily oral doses of glipizide during the period of organogenesis at doses up to 2000 mg/kg/day and 10 mg/kg/day (approximately 833 and 8 times the human dose based on body surface area), respectively. There were no adverse effects on embryo-fetal development at any of the doses tested. In a peri- and postnatal study in pregnant rats, there was a reduced number of pups born alive following administration of glipizide from gestation day 15 throughout lactation through weaning at doses ≥5 mg/kg/day (about 2 times the recommended maximum human dose based on body surface area). 8.2. Lactation Risk Summary Breastfed infants of lactating women using GLIPIZIDE XL should be monitored for symptoms of hypoglycemia (see Clinical Considerations ) . Although glipizide was undetectable in human milk in one small clinical lactation study; this result is not conclusive because of the limitations of the assay used in the study. There are no data on the effects of glipizide on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for GLIPIZIDE XL and any potential adverse effects on the breastfed child from GLIPIZIDE XL 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). 8.4. Pediatric Use Safety and effectiveness in children have not been established. 8.5 Geriatric Use There were no overall differences in effectiveness or safety between younger and older patients, but greater sensitivity of some individuals cannot be ruled out. Elderly patients are particularly susceptible to the hypoglycemic action of anti-diabetic agents. Hypoglycemia may be difficult to recognize in these patients. Therefore, dosing should be conservative to avoid hypoglycemia [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 8.6 Hepatic Impairment There is no information regarding the effects of hepatic impairment on the disposition of glipizide. However, since glipizide is highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with hepatic impairment. If hypoglycemia occurs in such patients, it may be prolonged and appropriate management should be instituted [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING GLIPIZIDE XL (glipizide) Extended Release Tablets are supplied to provide 2.5 mg, 5 mg, and 10 mg round, biconvex tablets and imprinted with black ink as follows: Table 2. GLIPIZIDE XL Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings Package Size NDC Code 2.5 mg Blue Round Biconvex imprinted with "GXL 2.5" on one side Bottles of 30 NDC 59762-0540-1 5 mg White Round Biconvex imprinted with "GXL 5" on one side Bottles of 100 NDC 59762-0541-1 Bottles of 500 NDC 59762-0541-2 10 mg White Round Biconvex imprinted with "GXL 10" on one side Bottles of 100 NDC 59762-0542-1 Bottles of 500 NDC 59762-0542-2 Recommended Storage: The tablets should be protected from moisture and humidity. Store at 68–77°F (20–25°C); excursions permitted between 59°F and 86°F (15°C and 30°C) [see USP Controlled Room Temperature].

Recommended Storage: The tablets should be protected from moisture and humidity. Store at 68–77°F (20–25°C); excursions permitted between 59°F and 86°F (15°C and 30°C) [see USP Controlled Room Temperature].