glipizide 2.5 MG Oral Tablet

INDICATIONS AND USAGE Glipizide extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Glipizide extended-release tablet 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 extended-release tablets are not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. 1.1 Limitations of Use Glipizide extended-release tablets are not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

DOSAGE AND ADMINISTRATION There is no fixed dosage regimen for the management of diabetes mellitus with glipizide or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy. Short-term administration of glipizide tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet. In general, glipizide tablets should be given approximately 30 minutes before a meal to achieve the greatest reduction in postprandial hyperglycemia. Initial Dose: The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver disease may be started on 2.5 mg. Titration: Dosage adjustments should ordinarily be in increments of 2.5–5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. If response to a single dose is not satisfactory, dividing that dose may prove effective. The maximum recommended once daily dose is 15 mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate caloric content. The maximum recommended total daily dose is 40 mg. Maintenance: Some patients may be effectively controlled on a once-a-day regimen, while others show better response with divided dosing. Total daily doses above 15 mg should ordinarily be divided. Total daily doses above 30 mg have been safely given on a b.i.d. basis to long-term patients. In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see Error! Hyperlink reference not valid. section). Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many stable non-insulin-dependent diabetic patients receiving insulin may be safely placed on Glipizide tablets. When transferring patients from insulin to glipizide tablets, the following general guidelines should be considered: • For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide therapy may begin at usual dosages. Several days should elapse between glipizide titration steps. • For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between glipizide titration steps. During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period. Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide. Patients should be observed carefully (1–2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide due to potential overlapping of drug effect. When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, glipizide tablets should be administered at least 4 hours prior to colesevelam.

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 a 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 antidiabetic drug ( 5.4 ). 5.1 Hypoglycemia All sulfonylurea drugs, including glipizide, 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. A 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 patient’s ability to concentrate and react may be impaired as a 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 a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. 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), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with type 2 diabetes mellitus. The study involved 823 patients who were randomly assigned to one of four treatment groups. UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of 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 a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. 5.4 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). 5.1 Hypoglycemia All sulfonylurea drugs, including glipizide, 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. A 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 patient’s ability to concentrate and react may be impaired as a 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 a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. 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), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with type 2 diabetes mellitus. The study involved 823 patients who were randomly assigned to one of four treatment groups. UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortalit

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 ).

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 extended-release tablets 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 extended-release tablets-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 2 diabetes 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 extended-release tablets, plasma drug concentrations gradually rise reaching maximum concentrations within 6 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 2 diabetes mellitus after administration of 20 mg glipizide extended-release tablets, compared to immediate release glipizide tablets (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 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 extended-release tablets. Administration of glipizide extended-release tablets 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 extended-release tablets 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 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 a multiple dose study in 26 males with type 2 diabetes mellitus, the pharmacokinetics of glipizide were linear with glipizide extended-release tablets 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 extended-release tablets were bioequivalent. In a 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. 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 tablets has been demonstrated in a placebo controlled crossover study in healthy volunteers. All subjects received glipizide tablets 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 extended-release tablets 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 extended-release tablets-tre