GLUCOTROL XL

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

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 1.1 Limitations of Use 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 ). 2.1 Recommended Dosing 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. 2.2 Use with Other Glucose Lowering Agents 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 ).

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 . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, 580 patients from 31 to 87 years of age received 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. Table 1: Incidence (%) of Adverse Reactions Reported in ≥3% of Patients Treated in Placebo-Controlled Clinical Trials and More Commonly in Patients Treated with GLUCOTROL XL (Excluding Hypoglycemia) GLUCOTROL XL (%) (N=278) Placebo (%) (N=69) Adverse Effect Dizziness 6.8 5.8 Diarrhea 5.4 0.0 Nervousness 3.6 2.9 Tremor 3.6 0.0 Flatulence 3.2 1.4 Hypoglycemia Of the 580 patients that received 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. 6.2 Postmarketing Experience 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.

▪ 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 ). 7.1 Drugs Affecting Glucose Metabolism 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. 7.2 Miconazole 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) ] . 7.3 Fluconazole 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) ] . 7.4 Colesevelam 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) ] .

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].