iscontinued 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.

poglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used. loss of control of blood glucose: when a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. at such times, it may be necessary to discontinue glipizide and administer insulin. the effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. this phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. hemolytic anemia: treatment of patients with glucose 6-phosphate dehydrogenase (g6pd) deficiency with sulfonylurea agents can lead to hemolytic anemia. because glipizide belongs to the class of sulfonylurea agents, caution should be used in patients with g6pd deficiency and a non-sulfonylurea alternative should be considered. in postmarketing reports, hemolytic anemia has also been reported in patients who did not have known g6pd deficiency.

ing dose is 5 mg, given before breakfast. geriatric patients or those with liver disease may be started on 2.5 mg. titration: dosage adjustments should ordinarily be in increments of 2.5 to 5 mg, as determined by blood glucose response. at least several days should elapse between titration steps. if response to a single dose is not satisfactory, dividing that dose may prove effective. the maximum recommended once daily dose is 15 mg. doses above 15 mg should ordinarily be divided and given before meals of adequate caloric content. the maximum recommended total daily dose is 40 mg. maintenance: some patients may be effectively controlled on a once-a-day regimen, while others show better response with divided dosing. total daily doses above 15 mg should ordinarily be divided. total daily doses above 30 mg have been safely given on a b.i.d. basis to long-term patients. in elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see precautions section). patients receiving insulin: as with other sulfonylurea-class hypoglycemics, many stable non-insulin- dependent diabetic patients receiving insulin may be safely placed on glipizide. when transferring patients from insulin to glipizide, the following general guidelines should be considered: for patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide therapy may begin at usual dosages. several days should elapse between glipizide titration steps. for patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide therapy may begin at usual dosages. subsequent reductions in insulin dosage should depend on individual patient response. several days should elapse between glipizide titration steps. during the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. patients should be instructed to contact the prescriber immediately if these tests are abnormal. in some cases, especially when patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period. patients receiving other oral hypoglycemic agents: as with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring patients to glipizide. patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide due to potential overlapping of drug effect. when colesevelam is coadministered with glipizide er, maximum plasma concentration and total exposure to glipizide is reduced. therefore, glipizide should be administered at least 4 hours prior to colesevelam.

t, 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 antidiuretic 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. postmarketing experience the following adverse events have been reported in postmarketing 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 events, contact teva pharmaceuticals usa, inc., at 1-888-838-2872 or fda at 1-800-fda-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

tients, but elevated insulin levels do not persist beyond the time of the meal challenge. extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. blood sugar control persists in some patients for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that time (see pharmacokinetics below). some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. alternatively, glipizide may be effective in some patients who have not responded or have ceased to respond to other sulfonylureas. other effects: it has been shown that glipizide therapy was effective in controlling blood sugar without deleterious changes in the plasma lipoprotein profiles of patients treated for niddm. in a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity and, in fact, led to a slight increase in free water clearance. pharmacokinetics: gastrointestinal absorption of glipizide in man is uniform, rapid, and essentially complete. peak plasma concentrations occur 1 to 3 hours after a single oral dose. the half-life of elimination ranges from 2 to 4 hours in normal subjects, whether given intravenously or orally. the metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. glipizide does not accumulate in plasma on repeated oral administration. total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes. thus, glipizide was more effective when administered about 30 minutes before, rather than with, a test meal in diabetic patients. protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98 to 99% one hour after either route of administration. the apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. in mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. in another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labelled drug. the metabolism of glipizide is extensive and occurs mainly in the liver. the primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. less than 10% unchanged glipizide is found in the urine.