ADVERSE REACTIONS SECTION.

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)] 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 Par Pharmaceutical at 1-800-828-9393 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 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 extended-release tablets in doses from 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 extended-release tablets for at least months.Table summarizes the incidence of adverse reactions, other than hypoglycemia, that were reported in pooled double-blind, placebo-controlled trials in >=3% of glipizide extended-release tablet-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 GlipizideExtended-Release Tablets (Excluding Hypoglycemia)Glipizide Extended-Release Tablets (%)Placebo (%)(N=278)(N=69)Adverse EffectDizziness6.85.8Diarrhea5.40.0Nervousness3.62.9Tremor3.60.0Flatulence3.21.4HypoglycemiaOf the 580 patients that received glipizide extended-release tablets in clinical trials, 3.4% had hypoglycemia documented by 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 ReactionsIn clinical trials, the incidence of gastrointestinal (GI) side effects (nausea, vomiting, constipation, dyspepsia), occurred in less than 3% of glipizide extended-release tablet-treated patients and were more common in glipizide extended-release tablet-treated patients than those receiving placebo.Dermatologic ReactionsIn clinical trials, allergic skin reactions, i.e., urticaria occurred in less than 1.5% of treated patients and were more common in glipizide extended-release tablet-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 extended-release tablets. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Abdominal painCholestatic and hepatocellular forms of liver injury accompanied by jaundiceLeukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia [see Warnings and Precautions (5.2)], aplastic anemia, pancytopeniaHepatic porphyria and disulfiram-like reactionsHyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretionRashThere have been reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug with this non-dissolvable extended release formulation.. 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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.

CLINICAL PHARMACOLOGY SECTION.

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 meal is enhanced with glipizide extended-release tablets administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least months of treatment. In two randomized, double-blind, dose-response studies comprising total of 347 patients, there was no significant increase in fasting insulin in all glipizide extended-release tablet-treated patients combined compared to placebo, although minor elevations were observed at some doses.In studies of glipizide extended-release tablets in subjects with type 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 greater reduction in fasting plasma glucose compared to subjects treated with mg.. 12.3 Pharmacokinetics. AbsorptionThe absolute bioavailability of glipizide was 100% after single oral doses in patients with type diabetes mellitus. Beginning to hours after administration of glipizide extended-release tablets, plasma drug concentrations gradually rise reaching maximum concentrations within to 12 hours after dosing. With subsequent once daily dosing of glipizide extended-release tablets, 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 diabetes mellitus after administration of 20 mg glipizide extended-release tablets, 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 extended-release tablets in 21 males with type diabetes mellitus and patients younger than 65 years. No accumulation of drug was observed in patients with type diabetes mellitus during chronic dosing with glipizide extended-release tablets.Administration of glipizide extended-release tablets with food has no effect on the to hour lag time in drug absorption. In single dose, food effect study in 21 healthy male subjects, the administration of glipizide extended-release tablets immediately before high fat breakfast resulted in 40% increase in the glipizide mean Cmax 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 extended-release 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 multiple dose study in 26 males with type diabetes mellitus, the pharmacokinetics of glipizide were linear with glipizide extended-release tablets in that the plasma drug concentrations increased proportionately with dose. In single dose study in 24 healthy subjects, four mg, two 10 mg, and one 20 mg glipizide extended-release tablets were bioequivalent. In separate single dose study in 36 healthy subjects, four 2.5-mg glipizide extended-release tablets were bioequivalent to one 10 mg glipizide extended-release tablets.DistributionThe mean volume of distribution was approximately 10 liters after single intravenous doses in patients with type diabetes mellitus. Glipizide is 98 to 99% bound to serum proteins, primarily to albumin.MetabolismThe major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. minor metabolite, an acetylamino-ethyl benzene derivative, which accounts for less than 2% of dose, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound.EliminationGlipizide is eliminated primarily by hepatic biotransformation: less than 10% of dose is excreted as unchanged drug in urine and feces; approximately 90% of dose is excreted as biotransformation products in urine (80%) and feces (10%).The mean total body clearance of glipizide was approximately liters per hour after single intravenous doses in patients with type diabetes mellitus. The mean terminal elimination half-life of glipizide ranged from to hours after single or multiple doses in patients with type diabetes mellitus.Specific PopulationsPediatric: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 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 InteractionsMiconazoleA 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)]. FluconazoleConcomitant treatment with fluconazole increases plasma concentrations of glipizide. The effect of concomitant administration of Diflucan(R) (fluconazole) and glipizide has been demonstrated in placebo controlled crossover study in healthy volunteers. All subjects received glipizide alone and following treatment with 100 mg of Diflucan(R) as single daily oral dose for days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%) [see Drug Interactions (7.3)]. ColesevelamColesevelam 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 AUC0- and Cmax of 12% and 13%, respectively were observed when colesevelam was coadministered with glipizide ER. When glipizide ER was administered hours prior to colesevelam, there was no significant change in glipizide AUC0- or Cmax, -4% and 0%, respectively [see Drug Interactions (7.4)].

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Glipizide extended-release tablets are 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 C21 H27 N5 O4 S; the molecular weight is 445.55; the structural formula is shown below:Molecular StructureGlipizide, USP is whitish, odorless powder with pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 NaOH; it is freely soluble in dimethylformamide.Inert ingredients in the mg and 10 mg formulations are: anhydrous lactose, butylated hydroxytoluene, cellulose acetate, colloidal silicon dioxide, glyceryl monostearate, hypromellose, magnesium stearate, methacrylic acid copolymer (Type Powder), polyethylene glycol, polyethylene oxide, polysorbate 80, propylene glycol, sodium chloride, sodium starch glycolate (Type A), iron oxide black, titanium dioxide and triacetin. Additionally, the mg strength also contains FD&C yellow aluminum lake and FD&C red 40 aluminum lake.System Components and PerformanceGlipizide extended-release tablets are similar in appearance to conventional tablet. It consists, however, of an osmotically active drug core surrounded by semipermeable membrane. The core itself is divided into two layers: an active layer containing the drug, and 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 small, laser-drilled orifice in the membrane on the drug side of the tablet.The function of the glipizide extended-release tablets 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.. Molecular Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended starting dose is mg once daily. Dose adjustment can be made based on the patients 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).. Recommended starting dose is mg once daily. Dose adjustment can be made based on the patients 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 extended-release tablets should be administered orally with breakfast or the first main meal of the day.The recommended starting dose of glipizide extended-release tablets is 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 patients glycemic control. The maximum recommended dose is 20 mg once daily. Patients receiving immediate release glipizide may be switched to glipizide extended-release tablets once daily at the nearest equivalent total daily dose.. 2.2 Use with Other Glucose Lowering Agents. When adding glipizide extended-release tablets to other anti-diabetic drugs, initiate glipizide extended-release tablets at mg once daily. Start patients at increased risk for hypoglycemia at lower dose.When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, glipizide extended-release tablets should be administered at least hours prior to colesevelam.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Glipizide Extended-Release Tablets:5 mg, pink, film-coated, round tablets, with an indentation hole on one side, with C and 745 in black on one side and plain on the other side.10 mg, white, film-coated, round tablets, with an indentation hole on one side, with C and 746 in black on one side and plain on the other side.. Tablets: mg, 10 mg (3).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdosage of sulfonylureas including glipizide 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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL. NDC 10370-745-01 GlipiZIDEExtended-Release Tablets5 mg100-count and 500-countRx Onlybottle-label-5mg. bottle-label-5mg.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Certain medications may affect glucose metabolism, requiring glipizide extended-release tablets 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 extended-release tablets should be administered at least hours prior to colesevelam (7.4, 12.3).. Certain medications may affect glucose metabolism, requiring glipizide extended-release tablets 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 extended-release tablets should be administered at least hours prior to colesevelam (7.4, 12.3).. 7.1 Drugs Affecting Glucose Metabolism. number of medications affect glucose metabolism and may require glipizide extended-release tablets 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 extended-release tablets, 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 patient receiving glipizide extended-release tablets, monitor the patient closely for hypoglycemia. When these medications are discontinued from patient receiving glipizide extended-release tablets, monitor the patient closely for worsening glycemic control.The following are examples of medication that may reduce the glucose-lowering effect of glipizide extended-release tablets, 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 extended-release tablets, monitor the patients closely for worsening glycemic control. When these medications are discontinued from patients receiving glipizide extended-release tablets, 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 extended-release tablets is coadministered 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 extended-release tablets is coadministered with these drugs.. 7.2 Miconazole. Monitor patients closely for hypoglycemia when glipizide extended-release tablets are coadministered with miconazole. potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported [see Clinical Pharmacology (12.3)].. 7.3 Fluconazole. Monitor patients closely for hypoglycemia when glipizide extended-release tablets are coadministered 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 extended-release tablets should be administered at least 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)].

GERIATRIC USE SECTION.

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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Glipizide Extended-Release Tablets are supplied as mg and 10 mg film-coated, round tablets and imprinted in black as follows:Table 2. Glipizide Extended-Release Tablets PresentationsTablet StrengthTablet Color/ ShapeTablet MarkingsPackage SizeNDC Code5 mgPink, Film-coated, RoundIndentation hole on one side, with C and 745 in black on one side and plain on the other sideBottles of 100NDC 10370-745-01Bottles of 500NDC 10370-745-0510 mgWhite, Film-coated, RoundIndentation hole on one side, with C and 746 in black on one side and plain on the other sideBottles of 100NDC 10370-746-01Bottles of 500NDC 10370-746-05Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature]. PROTECT FROM MOISTURE AND HUMIDITY. Dispense in tight, light-resistant container as defined in the USP. Do not crush.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Glipizide extended-release tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.. Glipizide extended-release tablets are sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus.Limitations of Use: Not for treatment of type diabetes or diabetic ketoacidosis.. 1.1 Limitations of Use. Glipizide extended-release tablets are not recommended for the treatment of type diabetes mellitus or diabetic ketoacidosis.

INFORMATION FOR PATIENTS SECTION.

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 extended-release tablets 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 regular exercise program, and of regular testing of glycemic control.Inform patients that glipizide extended-release tablets 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 tablet. In the glipizide extended-release tablets, the medication is contained within non-dissolvable shell that has been specially designed to slowly release the drug so the body can absorb it.PregnancyAdvise females of reproductive potential to inform their prescriber of known or suspected pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise breastfeeding women taking glipizide extended-release tablets 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)].This products label may have been updated. For full prescribing information, please contact Par Pharmaceutical at 1-800-828-9393 or visit www.parpharm.com.

MECHANISM OF ACTION SECTION.

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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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.

NURSING MOTHERS SECTION.

8.2 Lactation. Risk SummaryBreastfed infants of lactating women using glipizide extended-release tablets 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 mothers clinical need for glipizide extended-release tablets and any potential adverse effects on the breastfed child from glipizide extended-release tablets or from the underlying maternal condition.Clinical ConsiderationsMonitoring for adverse reactions Monitor breastfed infants for signs of hypoglycemia (e.g., jitters, cyanosis, apnea, hypothermia, excessive sleepiness, poor feeding, seizures).

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The insulinotropic response to meal is enhanced with glipizide extended-release tablets administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least months of treatment. In two randomized, double-blind, dose-response studies comprising total of 347 patients, there was no significant increase in fasting insulin in all glipizide extended-release tablet-treated patients combined compared to placebo, although minor elevations were observed at some doses.In studies of glipizide extended-release tablets in subjects with type 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 greater reduction in fasting plasma glucose compared to subjects treated with mg.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe absolute bioavailability of glipizide was 100% after single oral doses in patients with type diabetes mellitus. Beginning to hours after administration of glipizide extended-release tablets, plasma drug concentrations gradually rise reaching maximum concentrations within to 12 hours after dosing. With subsequent once daily dosing of glipizide extended-release tablets, 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 diabetes mellitus after administration of 20 mg glipizide extended-release tablets, 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 extended-release tablets in 21 males with type diabetes mellitus and patients younger than 65 years. No accumulation of drug was observed in patients with type diabetes mellitus during chronic dosing with glipizide extended-release tablets.Administration of glipizide extended-release tablets with food has no effect on the to hour lag time in drug absorption. In single dose, food effect study in 21 healthy male subjects, the administration of glipizide extended-release tablets immediately before high fat breakfast resulted in 40% increase in the glipizide mean Cmax 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 extended-release 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 multiple dose study in 26 males with type diabetes mellitus, the pharmacokinetics of glipizide were linear with glipizide extended-release tablets in that the plasma drug concentrations increased proportionately with dose. In single dose study in 24 healthy subjects, four mg, two 10 mg, and one 20 mg glipizide extended-release tablets were bioequivalent. In separate single dose study in 36 healthy subjects, four 2.5-mg glipizide extended-release tablets were bioequivalent to one 10 mg glipizide extended-release tablets.DistributionThe mean volume of distribution was approximately 10 liters after single intravenous doses in patients with type diabetes mellitus. Glipizide is 98 to 99% bound to serum proteins, primarily to albumin.MetabolismThe major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. minor metabolite, an acetylamino-ethyl benzene derivative, which accounts for less than 2% of dose, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound.EliminationGlipizide is eliminated primarily by hepatic biotransformation: less than 10% of dose is excreted as unchanged drug in urine and feces; approximately 90% of dose is excreted as biotransformation products in urine (80%) and feces (10%).The mean total body clearance of glipizide was approximately liters per hour after single intravenous doses in patients with type diabetes mellitus. The mean terminal elimination half-life of glipizide ranged from to hours after single or multiple doses in patients with type diabetes mellitus.Specific PopulationsPediatric: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 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 InteractionsMiconazoleA 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)]. FluconazoleConcomitant treatment with fluconazole increases plasma concentrations of glipizide. The effect of concomitant administration of Diflucan(R) (fluconazole) and glipizide has been demonstrated in placebo controlled crossover study in healthy volunteers. All subjects received glipizide alone and following treatment with 100 mg of Diflucan(R) as single daily oral dose for days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%) [see Drug Interactions (7.3)]. ColesevelamColesevelam 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 AUC0- and Cmax of 12% and 13%, respectively were observed when colesevelam was coadministered with glipizide ER. When glipizide ER was administered hours prior to colesevelam, there was no significant change in glipizide AUC0- or Cmax, -4% and 0%, respectively [see Drug Interactions (7.4)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from small number of published studies and postmarketing experience with glipizide extended-release tablets 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 extended-release 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, there were no effects on embryofetal development following administration of glipizide to pregnant rats and rabbits during organogenesis at doses 833 times and 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 times the maximum human dose based on body surface area (see Data). The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20 to 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPoorly-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 ReactionsNeonates 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 to 10 days, has been reported in neonates born to mothers receiving sulfonylurea at the time of delivery and has been reported with the use of agents with prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.Dose adjustments during pregnancy and the postpartum periodDue to reports of prolonged severe hypoglycemia in neonates born to mothers receiving sulfonylurea at the time of delivery, glipizide extended-release tablets should be discontinued at least two weeks before expected delivery (see Fetal/Neonatal Adverse Reactions). DataAnimal 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 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 peri- and postnatal study in pregnant rats, there was 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 times the recommended maximum human dose based on body surface area).

REFERENCES SECTION.

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

SPL UNCLASSIFIED SECTION.

1.1 Limitations of Use. Glipizide extended-release tablets are not recommended for the treatment of type diabetes mellitus or diabetic ketoacidosis.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Geriatric, Hepatically Impaired Patients: At risk for hypoglycemia with glipizide extended-release tablets. Use caution in dose selection and titration, and monitor closely (8.5, 8.6).. Geriatric, Hepatically Impaired Patients: At risk for hypoglycemia with glipizide extended-release tablets. Use caution in dose selection and titration, and monitor closely (8.5, 8.6).. 8.1 Pregnancy. Risk SummaryAvailable data from small number of published studies and postmarketing experience with glipizide extended-release tablets 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 extended-release 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, there were no effects on embryofetal development following administration of glipizide to pregnant rats and rabbits during organogenesis at doses 833 times and 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 times the maximum human dose based on body surface area (see Data). The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20 to 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 to 4% and 15 to 20%, respectively.Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPoorly-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 ReactionsNeonates 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 to 10 days, has been reported in neonates born to mothers receiving sulfonylurea at the time of delivery and has been reported with the use of agents with prolonged half-life. Observe newborns for symptoms of hypoglycemia and respiratory distress and manage accordingly.Dose adjustments during pregnancy and the postpartum periodDue to reports of prolonged severe hypoglycemia in neonates born to mothers receiving sulfonylurea at the time of delivery, glipizide extended-release tablets should be discontinued at least two weeks before expected delivery (see Fetal/Neonatal Adverse Reactions). DataAnimal 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 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 peri- and postnatal study in pregnant rats, there was 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 times the recommended maximum human dose based on body surface area).. 8.2 Lactation. Risk SummaryBreastfed infants of lactating women using glipizide extended-release tablets 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 mothers clinical need for glipizide extended-release tablets and any potential adverse effects on the breastfed child from glipizide extended-release tablets or from the underlying maternal condition.Clinical ConsiderationsMonitoring 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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).Hemolytic Anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider non-sulfonylurea alternative (5.2).Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives (5.3).Macrovascular Outcomes: No clinical studies have established conclusive evidence of macrovascular risk reduction with glipizide extended-release tablets or any other anti-diabetic drug (5.4).. 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).. Hemolytic Anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider non-sulfonylurea alternative (5.2).. Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives (5.3).. Macrovascular Outcomes: No clinical studies have established conclusive evidence of macrovascular risk reduction with glipizide extended-release tablets or any other anti-diabetic drug (5.4).. 5.1 Hypoglycemia. All sulfonylurea drugs, including glipizide extended-release tablets, are capable of producing severe hypoglycemia [see ADVERSE REACTIONS (6)].Concomitant use of glipizide extended-release tablets with other anti-diabetic medication can increase the risk of hypoglycemia. lower dose of glipizide extended-release tablets may be required to minimize the risk of hypoglycemia when combining it with other anti-diabetic medications.Educate patients to recognize and manage hypoglycemia. When initiating and increasing glipizide extended-release tablets in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications) start at 2.5 mg. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of anti-diabetic medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested.The patients ability to concentrate and react may be impaired as result of hypoglycemia. 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.These impairments may present 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.. 5.2 Hemolytic Anemia. Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including glipizide extended-release tablets, can lead to hemolytic anemia. Avoid use of glipizide extended-release tablets in patients with G6PD deficiency. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.. 5.3 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), long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with type diabetes mellitus. The study involved 823 patients who were randomly assigned to one of four treatment groups.UGDP reported that patients treated for to years with diet plus fixed dose of tolbutamide (1.5 grams per day) had rate of cardiovascular mortality approximately 1/2 times that of patients treated with diet alone. 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 glipizide and of alternative modes of therapy.Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from 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.. 5.4 Macrovascular Outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glipizide extended-release tablets or any other anti-diabetic drug.. 5.5 Gastrointestinal Obstruction. There have been reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug with this non-dissolvable extended release formulation. Avoid use of glipizide extended-release tablets in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic).