Glipizide 5 mg Tablet, Extended Release, 100-count — NDC 59651-781-01 (Billing 59651-0781-01)

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 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 anti-diabetic drug ( 5.4 ).

5.1Hypoglycemia 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. 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.

5.2Hemolytic 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.

5.3Increased 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.

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6 ADVERSE REACTIONS The followingserious adverse reactions are discussedinmoredetail below and elsewhereinthe labeling: Hypoglycemia [see Warnings and Precautions (5.1) ] Hemolyticanemia [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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical 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 glipizide extended-release tablets 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 glipizide extended-release tablets 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 glipizide extended-release tablets-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 glipizide extended-release tablets (Excluding Hypoglycemia) Glipizide extended-release tablets (%) (N=278) Placebo (%) (N=69) Adverse Effect Dizziness 6.8

5.8Diarrhea 5.4

0.0Nervousness 3.6

2.9Tremor 3.6

0.0Flatulence 3.2

1.4Hypoglycemia Of the 580 patients that received glipizide extended-release tablets 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 glipizide extended-release tablets-treated patients and were more common in glipizide extended-release tablets-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 glipizide extended-release tablets 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 Mildtomoderateelevations of ALT, LDH, alkalinephosphatase, BUN andcreatininehave been noted.Therelationship of theseabnormalitiestoglipizideisuncertain.

6.2Postmarketing Experience The following adverse reactions have been identified during post approval use of glipizide extended-release tablets. 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 extended release formulation.

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 4 hours prior to colesevelam ( 7.4 , 12.3 ).

7.1Drugs Affecting Glucose Metabolism A 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 a patient receiving glipizide extended-release tablets, monitor the patient closely for hypoglycemia. When these medications are discontinued from a 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 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 glipizide extended-release tablets is co-administered with these drugs.

7.2Miconazole Monitor patients closely for hypoglycemia when glipizide extended-release tablets are co-administered with miconazole. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported [see Clinical Pharmacology (12.3) ] .

7.3Fluconazole Monitor patients closely for hypoglycemia when glipizide extended-release tablets are co-administered with fluconazole. Concomitant treatment with fluconazole increases plasma concentrations of glipizide, which may lead to hypoglycemia [see Clinical Pharmacology (12.3) ] .

7.4Colesevelam Glipizide extended-release tablets 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) ] .