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

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

Limitations of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis

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

• ▪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 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.

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.

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).

• ▪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).

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.

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 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.

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

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).

The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling:

• •Hypoglycemia [see Warnings and Precautions (5.1)]
• •Hemolytic anemia [see Warnings and Precautions (5.2)]

Most common adverse reactions (incidence > 3%) are dizziness, diarrhea, nervousness, tremor, hypoglycemia and flatulence (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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.

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.

Gastrointestinal Reactions

In clinical trials, the incidence of gastrointestinal (GI) side effects (nausea, vomiting, constipation, dyspepsia), occurred in less than 3% of GLUCOTROL XL-treated patients and were more common in GLUCOTROL XL-treated patients than those receiving placebo.

Dermatologic Reactions

In clinical trials, allergic skin reactions, i.e., urticaria occurred in less than 1.5% of treated patients and were more common in GLUCOTROL XL treated patients than those receiving placebo. These may be transient and may disappear despite continued use of glipizide XL; if skin reactions persist, the drug should be discontinued.

Laboratory Tests

Mild to moderate elevations of ALT, LDH, alkaline phosphatase, BUN and creatinine have been noted. The relationship of these abnormalities to glipizide is uncertain.

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.