ive alcohol intake, and hepatic impairment. steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see precautions ]. if metformin-associated lactic acidosis is suspected, immediately discontinue glipizide and metformin hydrochloride and institute general supportive measures in a hospital setting. prompt hemodialysis is recommended [see precautions ]. 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 (suppl. 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 benefits 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 hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

sess the effectiveness of therapy. the therapeutic goal in all patients with type 2 diabetes is to decrease fpg, ppg, and hba 1c to normal or as near normal as possible. ideally, the response to therapy should be evaluated using hba 1c (glycosylated hemoglobin), which is a better indicator of long-term glycemic control than fpg alone. no studies have been performed specifically examining the safety and efficacy of switching to glipizide and metformin hydrochloride tablets therapy in patients taking concomitant glipizide (or other sulfonylurea) plus metformin. changes in glycemic control may occur in such patients, with either hyperglycemia or hypoglycemia possible. any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring. when colesevelam is coadministered with glipizide er, maximum plasma concentration and total exposure to glipizide is reduced. therefore, glipizide and metformin hydrochloride tablets should be administered at least 4 hours prior to colesevelam. glipizide and metformin hydrochloride tablets in patients with inadequate glycemic control on diet and exercise alone for patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of glipizide and metformin hydrochloride tablets is 2.5 mg/250 mg once a day with a meal. for patients whose fpg is 280 mg/dl to 320 mg/dl a starting dose of glipizide and metformin hydrochloride tablets 2.5 mg/500 mg twice daily should be considered. the efficacy of glipizide and metformin hydrochloride tablets in patients whose fpg exceeds 320 mg/dl has not been established. dosage increases to achieve adequate glycemic control should be made in increments of one tablet per day every two weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg glipizide and metformin hydrochloride tablets per day given in divided doses. in clinical trials of glipizide and metformin hydrochloride tablets as initial therapy, there was no experience with total daily doses greater than 10 mg/2000 mg per day. glipizide and metformin hydrochloride tablets in patients with inadequate glycemic control on a sulfonylurea and/or metformin for patients not adequately controlled on either glipizide (or another sulfonylurea) or metformin alone, the recommended starting dose of glipizide and metformin hydrochloride tablets is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. in order to avoid hypoglycemia, the starting dose of glipizide and metformin hydrochloride tablets should not exceed the daily doses of glipizide or metformin already being taken. the daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day. patients previously treated with combination therapy of glipizide (or another sulfonylurea) plus metformin may be switched to glipizide and metformin hydrochloride tablets 2.5 mg/500 mg or 5 mg/500 mg; the starting dose should not exceed the daily dose of glipizide (or equivalent dose of another sulfonylurea) and metformin already being taken. the decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment. patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of glipizide and metformin hydrochloride tablets should be titrated as described above to achieve adequate control of blood glucose. recommendations for use in renal impairment assess renal function prior to initiation of glipizide and metformin hydrochloride and periodically thereafter. glipizide and metformin hydrochloride is contraindicated in patients with an estimated glomerular filtration rate (egfr) below 30 ml/minute/1.73 m 2 . initiation of glipizide and metformin hydrochloride in patients with an egfr between 30 – 45 ml/minute/1.73 m 2 is not recommended. in patients taking glipizide and metformin hydrochloride whose egfr later falls below 45 ml/min/1.73 m 2 , assess the benefit risk of continuing therapy. discontinue glipizide and metformin hydrochloride if the patient's egfr later falls below 30 ml/minute/1.73 m 2 . (see warnings.) discontinuation for iodinated contrast imaging procedures discontinue glipizide and metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an egfr between 30 and 60 ml/min/1.73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. re-evaluate egfr 48 hours after the imaging procedure; restart glipizide and metformin hydrochloride if renal function is stable. specific patient populations: glipizide and metformin hydrochloride tablets are not recommended for use during pregnancy or for use in pediatric patients. the initial and maintenance dosing of glipizide and metformin hydrochloride tablets should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. any dosage adjustment requires a careful assessment of renal function. generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of glipizide and metformin hydrochloride tablets to avoid the risk of hypoglycemia. monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see warnings and precautions ).

n 17 (10.0) 10 (5.6) 5 (2.9) 6 (3.5) nausea/vomiting 6 (3.5) 9 (5.1) 1 (0.6) 3 (1.7) in a double-blind 18-week clinical trial involving glipizide and metformin hydrochloride tablets as second-line therapy, a total of 87 patients received glipizide and metformin hydrochloride tablets, 84 received glipizide, and 75 received metformin. the most common clinical adverse events in this clinical trial are listed in table 5 . table 5 clinical adverse events >5% in any treatment group, by primary term, in second-line therapy study adverse event number (%) of patients glipizide tablets the dose of glipizide was fixed at 30 mg daily; doses of metformin andglipizide and metformin hydrochloride tablets were titrated. 5 mg n = 84 metformin tablets 500 mg n = 75 glipizide and metformin hydrochloride tablets 5 mg / 500 mg n = 87 diarrhea 11 (13.1) 13 (17.3) 16 (18.4) headache 5 (6.0) 4 (5.3) 11 (12.6) upper respiratory infection 11 (13.1) 8 (10.7) 9 (10.3) musculoskeletal pain 6 (7.1) 5 (6.7) 7 (8.0) nausea/vomiting 5 (6.0) 6 (8.0) 7 (8.0) abdominal pain 7 (8.3) 5 (6.7) 5 (5.7) uti 4 (4.8) 6 (8.0) 1 (1.1) hypoglycemia: in a controlled initial therapy trial of glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg the numbers of patients with hypoglycemia documented by symptoms (such as dizziness, shakiness, sweating, and hunger) and a fingerstick blood glucose measurement ≤50 mg/dl were 5 (2.9%) for glipizide, 0 (0%) for metformin, 13 (7.6%) for glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, and 16 (9.3%) for glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg. among patients taking either glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg or glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, 9 (2.6%) patients discontinued glipizide and metformin hydrochloride tablets due to hypoglycemic symptoms and one required medical intervention due to hypoglycemia. in a controlled second-line therapy trial of glipizide and metformin hydrochloride tablets, 5 mg/500 mg, the numbers of patients with hypoglycemia documented by symptoms and a fingerstick blood glucose measurement ≤50 mg/dl were 0 (0%) for glipizide, 1 (1.3%) for metformin, and 11 (12.6%) for glipizide and metformin hydrochloride tablets. one (1.1%) patient discontinued glipizide and metformin hydrochloride tablets therapy due to hypoglycemic symptoms and none required medical intervention due to hypoglycemia (see precautions ). gastrointestinal reactions: among the most common clinical adverse events in the initial therapy trial were diarrhea and nausea/vomiting; the incidences of these events were lower with both glipizide and metformin hydrochloride tablets dosage strengths than with metformin therapy. there were 4 (1.2%) patients in the initial therapy trial who discontinued glipizide and metformin hydrochloride tablets therapy due to gi adverse events. gastrointestinal symptoms of diarrhea, nausea/vomiting, and abdominal pain were comparable among glipizide and metformin hydrochloride tablets, glipizide and metformin in the second-line therapy trial. there were 4 (4.6%) patients in the second-line therapy trial who discontinued glipizide and metformin hydrochloride tablets therapy due to gi adverse events. glipizide gastrointestinal reactions cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely in association with glipizide; glipizide and metformin hydrochloride tablets should be discontinued if this occurs.

an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. pharmacokinetics: absorption and bioavailability: glipizide and metformin hydrochloride tablets: in a single dose study in healthy subjects, the glipizide and metformin components of glipizide and metformin hydrochloride tablets 5 mg/500 mg were bioequivalent to co-administered glipizide and metformin hydrochloride. following administration of a single glipizide and metformin hydrochloride 5 mg/500 mg tablet in healthy subjects with either a 20% glucose solution or a 20% glucose solution with food, there was a small effect of food on peak plasma concentration (c max ) and no effect of food on area under the curve (auc) of the glipizide component. time to peak plasma concentration (t max ) for the glipizide component was delayed 1 hour with food relative to the same tablet strength administered fasting with a 20% glucose solution. c max for the metformin component was reduced approximately 14% by food whereas auc was not affected. t max for the metformin component was delayed 1 hour after food. glipizide: gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. peak plasma concentrations occur 1 to 3 hours after a single oral dose. 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. metformin hydrochloride: the absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50% to 60%. studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower auc in plasma and a 35-minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. the clinical relevance of these decreases is unknown. distribution: glipizide: 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 labeled drug. metformin hydrochloride: the apparent volume of distribution (v/f) of metformin following single oral doses of 850 mg averaged 654±358 l. metformin is negligibly bound to plasma proteins. metformin partitions into erythrocytes, most likely as a function of time. at usual clinical doses and dosing schedules of metformin, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 µg/ml. during controlled clinical trials, maximum metformin plasma levels did not exceed 5 µg/ml, even at maximum doses. metabolism and elimination: glipizide: 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. 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. metformin hydrochloride: intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. renal clearance (see table 1 ) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. in blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. specific populations: patients with type 2 diabetes: in the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see table 1 ), nor is there any accumulation of metformin in either group at usual clinical doses. renal impairment the metabolism and excretion of glipizide may be slowed in patients with impaired renal function (see contraindications , warnings , precautions , and dosage and administration ). in patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see table 1; also, see warnings ). hepatic impairment the metabolism and excretion of glipizide may be slowed in patients with impaired hepatic function (see precautions ). no pharmacokinetic studies have been conducted in patients with hepatic insufficiency for metformin. geriatrics: there is no information on the pharmacokinetics of glipizide in elderly patients. limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and c max is increased, compared to healthy young subjects. from these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see table 1 ). table 1 select mean (±s.d.) metformin pharmacokinetic parameters following single or multiple oral doses of metformin subject groups : metformin dose all doses given fasting except the first 18 doses of the multiple-dose studies ( number of subjects ) cmax peak plasma concentration ( µg / ml ) tmax time to peak plasma concentration ( hrs ) renal clearnance ( ml / min ) healthy , nondiabetic adults : 500 mg sd sd = single dose (24) 1.03 (±0.33) 2.75 (±0.81) 600 (±132) 850 mg sd (74) combined results (average means) of five studies: mean age 32 years (range 23 to 59 years) 1.60 (±0.38) 2.64 (±0.42) 552 (±139) 850 mg t.i.d. for 19 doses kinetic study done following dose 19, given fasting (9) 2.01(±0.42) 1.79 (±0.94) 642 (±173) adults with type 2 diabetes : 850 mg sd (23) 1.48 (±0.5) 3.32 (±1.08) 491 (±138) 850 mg t.i.d. for 19 doses (9) 1.90 (±0.62) 2.01 (±1.22) 550 (±160) elderly elderly subjects, mean age 71 years (range 65 to 81 years) , healthy nondiabetic adults : 850 mg sd (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) renal - impaired adults : 850 mg sd mild (clcr clcr= creatinine clearance normalized to body surface area of 1.73 m 2 61 to 90 ml/min) (5) 1.86 (±0.52) 3.20 (±0.45) 384 (±122) moderate (clcr 31 to 60 ml/min) (4) 4.12 (±1.83) 3.75 (±0.50) 108 (±57) severe (clcr 10 to 30 ml/min) (6) 3.93 (±0.92) 4.01 (±1.10) 130 (±90) pediatrics: no data from pharmacokinetic studies in pediatric subjects are available for glipizide. after administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin c max and auc differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. gender: there is no information on the effect of gender on the pharmacokinetics of glipizide. metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males=19, females=16). similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females. race: no information is available on race differences in the pharmacokinetics of glipizide. no studies of metformin pharmacokinetic parameters according to race have been performed. in controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and hispanics (n=24). clinical studies: patients with inadequate glycemic control on diet and exercise alone: in a 24-week, double-blind, active-controlled, multicenter international clinical trial, patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (hemoglobin a 1c [hba 1c ]>7.5% and ≤12% and fasting plasma glucose [fpg]<300 mg/dl) were randomized to receive initial therapy with glipizide 5 mg, metformin 500 mg, glipizide and metformin hydrochloride tablets 2.5 mg/250 mg, or glipizide and metformin hydrochloride tablets 2.5 mg/500 mg. after two weeks, the dose was progressively increased (up to the 12-week visit) to a maximum of four tablets daily in divided doses as needed to reach a target mean daily glucose (mdg) of ≤130 mg/dl. trial data at 24 weeks are summarized in table 2 . table 2 active-controlled trial of glipizide and metformin hydrochloride tablets as initial therapy: summary of trial data at 24 weeks glipizide tablets 5 mg metformin tablets 500 mg glipizide and metformin hydrochloride tablets 2 . 5 mg / 250 mg glipizide and metformin hydrochloride tablets 2 . 5 mg / 500 mg mean final dose 16.7 mg 1749 mg 7.9 mg/791 mg 7.4 mg/1477 mg hemoglobin a 1 c (%) n = 168 n = 171 n = 166 n = 163 baseline mean 9.17 9.15 9.06 9.10 final mean 7.36 7.47 6.93 6.95 adjusted mean change from baseline -1.77 -1.46 -2.15 -2.14 different from glipizide -0.38 p <0.001 -0.37 different from metformin -0.70 -0.69 % patients with final hba 1 c <7% 43.5% 35.1% 59.6% 57.1% fasting plasma glucose ( mg / dl ) n = 169 n = 176 n = 170 n = 169 baseline mean 210.7 207.4 206.8 203.1 final mean 162.1 163.8 152.1 148.7 adjusted mean change from baseline -46.2 -42.9 -54.2 -56.5 different from glipizide -8.0 -10.4 different from metformin -11.3 -13.6 after 24 weeks, treatment with glipizide and metformin hydrochloride tablets 2.5 mg/250 mg and 2.5 mg/500 mg resulted in significantly greater reduction in hba 1c compared to glipizide and to metformin therapy. also, glipizide and metformin hydrochloride tablets 2.5 mg/250 mg therapy resulted in significant reductions in fpg versus metformin therapy. increases above fasting glucose and insulin levels were determined at baseline and final study visits by measurement of plasma glucose and insulin for three hours following a standard mixed liquid meal. treatment with glipizide and metformin hydrochloride tablets lowered the three-hour postprandial glucose auc, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. compared to baseline, glipizide and metformin hydrochloride tablets enhanced the postprandial insulin response, but did not significantly affect fasting insulin levels. there were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablets therapy and either metformin therapy or glipizide therapy. the adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets 2.5 mg/250 mg, -0.4 kg; glipizide and metformin hydrochloride tablets 2.5 mg/500 mg, -0.5 kg; glipizide, -0.2 kg; and metformin, -1.9 kg. weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets. patients with inadequate glycemic control on sulfonylurea monotherapy: in an 18-week, double-blind, active-controlled u.s. clinical trial, a total of 247 patients with type 2 diabetes not adequately controlled (hba 1c ≥ 7.5% and ≤ 12% and fpg < 300 mg/dl) while being treated with at least one-half the maximum labeled dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glipizide (fixed dose, 30 mg), metformin (500 mg), or glipizide and metformin hydrochloride tablets 5 mg/500 mg. the doses of metformin and glipizide and metformin hydrochloride tablets were titrated (up to the eight-week visit) to a maximum of four tablets daily as needed to achieve mdg ≤ 130 mg/dl. trial data at 18 weeks are summarized in table 3 . table 3 glipizide and metformin hydrochloride tablets as second-line therapy: summary of trial data at 18 weeks glipizide tablets 5 mg metformin tablets 500 mg glipizide and metformin hydrochloride tablets 5 mg / 500 mg mean final dose 30.0 mg 1927 mg 17.5 mg/1747 mg hemoglobin a 1 c (%) n = 79 n = 71 n = 80 baseline mean 8.87 8.61 8.66 final adjusted mean 8.45 8.36 7.39 different from glipizide -1.06 p <0.001 different from metformin -0.98 % patients with final hba 1 c <7% 8.9% 9.9% 36.3% fasting plasma glucose ( mg / dl ) n = 82 n = 75 n = 81 baseline mean 203.6 191.3 194.3 adjusted mean change from baseline 7.0 6.7 -30.4 difference from glipizide -37.4 different from metformin -37.2 after 18 weeks, treatment with glipizide and metformin hydrochloride tablets at doses up to 20 mg/2000 mg per day resulted in significantly lower mean final hba 1c and significantly greater mean reductions in fpg compared to glipizide and to metformin therapy. treatment with glipizide and metformin hydrochloride tablets lowered the three-hour postprandial glucose auc, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. glipizide and metformin hydrochloride tablets did not significantly affect fasting insulin levels. there were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablets therapy and either metformin therapy or glipizide therapy. the adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets 5 mg/500 mg, -0.3 kg; glipizide, -0.4 kg; and metformin, -2.7 kg. weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.

debossed with "ze66" on one side and plain on other side and are supplied as follows: ndc 68382-186-16 in bottle of 90 tablets ndc 68382-186-01 in bottle of 100 tablets ndc 68382-186-10 in bottle of 1000 tablets ndc 68382-186-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets