These Highlights Do Not Include All The Information Needed To Use Glucotrol Xl Safely And Effectively. See Full Prescribing Information For Glucotrol Xl.

Hypoglycemia

Of the 580 patients that received GLUCOTROL 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.

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].

Overdosage of sulfonylureas including GLUCOTROL 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.

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

GLUCOTROL 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 C₂₁H₂₇N₅O₄S; 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).

Monitor patients closely for hypoglycemia when Glucotrol 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)].

Monitor patients closely for hypoglycemia when Glucotrol 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)].

GLUCOTROL 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)].

All sulfonylurea drugs, including GLUCOTROL XL, are capable of producing severe hypoglycemia [see Adverse Reactions (6)]. Concomitant use of GLUCOTROL XL with other anti-diabetic medication can increase the risk of hypoglycemia. A lower dose of GLUCOTROL XL 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 GLUCOTROL XL 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.

Safety and effectiveness in children have not been established.

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)].

Glipizide is contraindicated in patients with:

• •
  Known hypersensitivity to glipizide or any of the product's ingredients.
• •
  Hypersensitivity to sulfonamide derivatives.

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)]

• ▪
  Certain medications may affect glucose metabolism, requiring GLUCOTROL XL dose adjustment and close monitoring of blood glucose (7.1).
• ▪
  Miconazole: Monitor patients closely. Severe hypoglycemia can occur when GLUCOTROL and oral miconazole are used concomitantly (7.2, 12.3).
• ▪
  Fluconazole: Monitor patients closely. An increase in GLUCOTROL AUC was seen after fluconazole administration (7.3, 12.3).
• ▪
  Colesevelam: GLUCOTROL XL should be administered at least 4 hours prior to colesevelam (7.4, 12.3).

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including GLUCOTROL XL, can lead to hemolytic anemia. Avoid use of GLUCOTROL XL in patients with G6PD deficiency. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

The insulinotropic response to a meal is enhanced with GLUCOTROL 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 GLUCOTROL XL-treated patients combined compared to placebo, although minor elevations were observed at some doses.

In studies of GLUCOTROL 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.

GLUCOTROL XL is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

GLUCOTROL XL should be administered orally with breakfast or the first main meal of the day.

The recommended starting dose of GLUCOTROL 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 GLUCOTROL XL once daily at the nearest equivalent total daily dose.

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)].

GLUCOTROL XL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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.

• ▪
  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 GLUCOTROL XL or any other anti-diabetic drug (5.4).

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOTROL XL or any other anti-diabetic drug.

• ▪
  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).

GLUCOTROL XL (glipizide) Extended Release tablets:

2.5 mg, blue and imprinted with "GLUCOTROL XL 2.5" or "GXL 2.5" on one side

5 mg, white and imprinted with "GLUCOTROL XL 5" or "GXL 5" on one side

10 mg, white and imprinted with "GLUCOTROL XL 10" or "GXL 10" on one side

The following adverse reactions have been identified during post approval use of GLUCOTROL 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.

• ▪
  Geriatric, Hepatically Impaired Patients: At risk for hypoglycemia with GLUCOTROL XL. Use caution in dose selection and titration, and monitor closely (8.5, 8.6).

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 GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL XL-treated patients and more commonly than in patients who received placebo.

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 GLUCOTROL XL in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic).

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Inform patients of the potential adverse reactions of GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL 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.

GLUCOTROL 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:

A number of medications affect glucose metabolism and may require GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL XL, monitor the patient closely for hypoglycemia. When these medications are discontinued from a patient receiving GLUCOTROL XL, monitor the patient closely for worsening glycemic control.

The following are examples of medication that may reduce the glucose-lowering effect of GLUCOTROL 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 GLUCOTROL XL, monitor the patients closely for worsening glycemic control. When these medications are discontinued from patients receiving GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL XL is co-administered with these drugs.

When adding GLUCOTROL XL to other anti-diabetic drugs, initiate GLUCOTROL 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, GLUCOTROL XL should be administered at least 4 hours prior to colesevelam.

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.

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.

Pfizer

NDC 0049-0174-02

Glucotrol XL ^®

(glipizide) extended release

Tablets

5 mg

GITS

100 Tablets

Rx only

Pfizer

NDC 0049-0178-07

Glucotrol XL ^®

(glipizide) extended release

Tablets

10 mg

GITS

100 Tablets

Rx only

Pfizer

NDC 0049-0170-01

Glucotrol XL ^®

(glipizide) extended release

Tablets

2.5 mg

GITS

30 Tablets

Rx only

Hypoglycemia

Of the 580 patients that received GLUCOTROL 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.

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].

Overdosage of sulfonylureas including GLUCOTROL 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.

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

GLUCOTROL 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 C₂₁H₂₇N₅O₄S; 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).

Monitor patients closely for hypoglycemia when Glucotrol 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)].

Monitor patients closely for hypoglycemia when Glucotrol 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)].

GLUCOTROL 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)].

All sulfonylurea drugs, including GLUCOTROL XL, are capable of producing severe hypoglycemia [see Adverse Reactions (6)]. Concomitant use of GLUCOTROL XL with other anti-diabetic medication can increase the risk of hypoglycemia. A lower dose of GLUCOTROL XL 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 GLUCOTROL XL 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.

Safety and effectiveness in children have not been established.

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)].

Glipizide is contraindicated in patients with:

• •
  Known hypersensitivity to glipizide or any of the product's ingredients.
• •
  Hypersensitivity to sulfonamide derivatives.

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)]

• ▪
  Certain medications may affect glucose metabolism, requiring GLUCOTROL XL dose adjustment and close monitoring of blood glucose (7.1).
• ▪
  Miconazole: Monitor patients closely. Severe hypoglycemia can occur when GLUCOTROL and oral miconazole are used concomitantly (7.2, 12.3).
• ▪
  Fluconazole: Monitor patients closely. An increase in GLUCOTROL AUC was seen after fluconazole administration (7.3, 12.3).
• ▪
  Colesevelam: GLUCOTROL XL should be administered at least 4 hours prior to colesevelam (7.4, 12.3).

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including GLUCOTROL XL, can lead to hemolytic anemia. Avoid use of GLUCOTROL XL in patients with G6PD deficiency. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

The insulinotropic response to a meal is enhanced with GLUCOTROL 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 GLUCOTROL XL-treated patients combined compared to placebo, although minor elevations were observed at some doses.

In studies of GLUCOTROL 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.

GLUCOTROL XL is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

GLUCOTROL XL should be administered orally with breakfast or the first main meal of the day.

The recommended starting dose of GLUCOTROL 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 GLUCOTROL XL once daily at the nearest equivalent total daily dose.

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)].

GLUCOTROL XL is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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.

• ▪
  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 GLUCOTROL XL or any other anti-diabetic drug (5.4).

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with GLUCOTROL XL or any other anti-diabetic drug.

• ▪
  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).

GLUCOTROL XL (glipizide) Extended Release tablets:

2.5 mg, blue and imprinted with "GLUCOTROL XL 2.5" or "GXL 2.5" on one side

5 mg, white and imprinted with "GLUCOTROL XL 5" or "GXL 5" on one side

10 mg, white and imprinted with "GLUCOTROL XL 10" or "GXL 10" on one side

The following adverse reactions have been identified during post approval use of GLUCOTROL 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.

• ▪
  Geriatric, Hepatically Impaired Patients: At risk for hypoglycemia with GLUCOTROL XL. Use caution in dose selection and titration, and monitor closely (8.5, 8.6).

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 GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL XL-treated patients and more commonly than in patients who received placebo.

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 GLUCOTROL XL in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic).

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Inform patients of the potential adverse reactions of GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL 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.

GLUCOTROL 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:

A number of medications affect glucose metabolism and may require GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL XL, monitor the patient closely for hypoglycemia. When these medications are discontinued from a patient receiving GLUCOTROL XL, monitor the patient closely for worsening glycemic control.

The following are examples of medication that may reduce the glucose-lowering effect of GLUCOTROL 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 GLUCOTROL XL, monitor the patients closely for worsening glycemic control. When these medications are discontinued from patients receiving GLUCOTROL 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 GLUCOTROL 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 GLUCOTROL XL is co-administered with these drugs.

When adding GLUCOTROL XL to other anti-diabetic drugs, initiate GLUCOTROL 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, GLUCOTROL XL should be administered at least 4 hours prior to colesevelam.

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.

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.

Pfizer

NDC 0049-0174-02

Glucotrol XL ^®

(glipizide) extended release

Tablets

5 mg

GITS

100 Tablets

Rx only

Pfizer

NDC 0049-0178-07

Glucotrol XL ^®

(glipizide) extended release

Tablets

10 mg

GITS

100 Tablets

Rx only

Pfizer

NDC 0049-0170-01

Glucotrol XL ^®

(glipizide) extended release

Tablets

2.5 mg

GITS

30 Tablets

Rx only