Glipizide 10 mg Tablet, 30-count

WARNINGS SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY 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 non-insulin-dependent diabetes.

The study involved 823 patients who were randomly assigned to one of four treatment groups ( Diabetes , 19, supp. 2:747-830, 1970). 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.

ADVERSE REACTIONS In U.S. and foreign controlled studies, the frequency of serious adverse reactions reported was very low. Of 702 patients, 11.8% reported adverse reactions and in only 1.5% was glipizide discontinued. Hypoglycemia See PRECAUTIONS and OVERDOSAGE sections.

Gastrointestinal Gastrointestinal disturbances are the most common reactions. Gastrointestinal complaints were reported with the following approximate incidence: nausea and diarrhea, one in seventy; constipation and gastralgia, one in one hundred. They appear to be dose-related and may disappear on division or reduction of dosage.

Cholestatic jaundice may occur rarely with sulfonylureas: glipizide should be discontinued if this occurs. Dermatologic Allergic skin reactions including erythema, morbilliform or maculopapular eruptions, urticaria, pruritus, and eczema have been reported in about one in seventy patients. These may be transient and may disappear despite continued use of glipizide; if skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas. Hematologic Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS ), aplastic anemia, and pancytopenia have been reported with sulfonylureas. Metabolic Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas.

In the mouse, glipizide pretreatment did not cause an accumulation of acetaldehyde after ethanol administration. Clinical experience to date has shown that glipizide has an extremely low incidence of disulfiram-like alcohol reactions. Endocrine Reactions Cases of hyponatremia and the syndrome of inappropriate anti-diuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas.

Miscellaneous Dizziness, drowsiness, and headache have each been reported in about one in fifty patients treated with glipizide. They are usually transient and seldom require discontinuance of therapy. Laboratory Tests The pattern of laboratory test abnormalities observed with glipizide was similar to that for other sulfonylureas.

Occasional mild to moderate elevations of SGOT, LDH, alkaline phosphatase, BUN, and creatinine were noted. One case of jaundice was reported. The relationship of these abnormalities to glipizide is uncertain, and they have rarely been associated with clinical symptoms.

Post-Marketing Experience The following adverse events have been reported in post-marketing surveillance: Hepatobiliary Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with glipizide; glipizide should be discontinued if this occurs. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including non-steroidal anti-inflammatory agents, some azoles, and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, quinolones and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving glipizide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss of control.

In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of glipizide with these drugs. Certain drugs tend to produce hyperglycemia and may lead to loss of control.

These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glipizide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for hypoglycemia.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or vaginal preparations of miconazole is not known. The effect of concomitant administration of DIFLUCAN ® (fluconazole) and glipizide has been demonstrated in a placebo-controlled crossover study in normal volunteers.

All subjects received glipizide 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). 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 co-administered 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. Therefore, glipizide should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of glipizide.