Glipizide and Metformin Hcl

INDICATIONS AND USAGE Glipizide and Metformin HCl Tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

DOSAGE AND ADMINISTRATION General Considerations Dosage of Glipizide and Metformin HCl Tablets must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glipizide/2000 mg metformin . Glipizide and Metformin HCl Tablets should be given with meals and should be initiated at a low dose, with gradual dose escalation as described below, in order to avoid hypoglycemia (largely due to glipizide), reduce GI side effects (largely due to metformin), and permit determination of the minimum effective dose for adequate control of blood glucose for the individual patient. With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to determine the therapeutic response to Glipizide and Metformin HCl Tablets and to identify the minimum effective dose for the patient. Thereafter, HbA 1c should be measured at intervals of approximately 3 months to assess 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 , 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 HCl 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 HCl Tablets should be administered at least 4 hours prior to colesevelam. Glipizide and Metformin HCl 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 HCl Tablets are 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 HCl Tablets 2.5 mg/500 mg twice daily should be considered. The efficacy of Glipizide and Metformin HCl 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 1 tablet per day every 2 weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg Glipizide and Metformin HCl Tablets per day given in divided doses. In clinical trials of Glipizide and Metformin HCl Tablets as initial therapy, there was no experience with total daily doses >10 mg/2000 mg per day. Glipizide and Metformin HCl 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 HCl Tablets are 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 HCl 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 HCl 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 HCl 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 HCl Tablets and periodically thereafter. Glipizide and Metformin HCl Tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m 2 . Initiation of Glipizide and Metformin HCl Tablets in patients with an eGFR between 30 - 45 mL/minute/1.73 m 2 is not recommended. In patients taking Glipizide and Metformin HCl Tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit risk of continuing therapy. Discontinue Glipizide and Metformin HCl Tablets 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 HCl Tablets 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 HCl Tablets if renal function is stable. Specific Patient Populations Glipizide and Metformin HCl Tablets are not recommended for use during pregnancy or for use in pediatric patients. The initial and maintenance dosing of Glipizide and Metformin HCl 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 HCl 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 .)

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 1 of 4 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 1 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.

CONTRAINDICATIONS Glipizide and Metformin HCl Tablets are contraindicated in patients with: 1. Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) (see WARNINGS and PRECAUTIONS ). 2. Known hypersensitivity to glipizide or metformin hydrochloride. 3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin. WARNINGS

Drug Interactions Glipizide and Metformin HCl Tablets Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These drugs include 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 and Metformin HCl Tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving Glipizide and Metformin HCl Tablets, the patient should be observed closely for hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins. Glipizide The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal anti-inflammatory agents, some azoles, and other drugs that are highly protein-bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving Glipizide and Metformin HCl Tablets, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving Glipizide and Metformin HCl Tablets, the patient should be observed closely for loss of blood glucose 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 and Metformin HCl Tablets with these drugs. 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 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 fluconazole as a single oral daily dose for 7 days, the mean percent increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35% - 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 coadministered 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 and Metformin HCl Tablets should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of glipizide. Metformin Hydrochloride Furosemide A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide increased the metformin plasma and blood C max by 22% and blood AUC by 15%, without any significant change in metformin renal clearance. When administered with metformin, the C max and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. No information is available about the interaction of metformin and furosemide when coadministered chronically. Nifedipine A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine. Drugs that reduce metformin clearance Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. In healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins. Other Carbonic Anhydrase Inhibitors Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Glipizide and Metformin HCl Tablets may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients. Alcohol Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving Glipizide and Metformin HCl Tablets. Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted with the combined products in Glipizide and Metformin HCl Tablets. The following data are based on findings in studies performed with the individual products. Glipizide A 20-month study in rats and an 18-month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility. Metformin Hydrochloride Long-term carcinogenicity studies were performed with metformin alone in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily (MRHD) dose of 2000 mg of the metformin component of Glipizide and Metformin HCl Tablets based on body surface area comparisons. No evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of metformin alone. There was no evidence of a mutagenic potential of metformin alone in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. Fertility of male or female rats was unaffected by metformin alone when administered at doses as

ADVERSE REACTIONS Glipizide and Metformin HCl Tablets In a double-blind 24-week clinical trial involving Glipizide and Metformin HCl Tablets as initial therapy, a total of 172 patients received Glipizide and Metformin HCl Tablets 2.5 mg/250 mg, 173 received Glipizide and Metformin HCl Tablets 2.5 mg/500 mg, 170 received glipizide, and 177 received metformin. The most common clinical adverse events in these treatment groups are listed in Table 4 . Table 4: Clinical Adverse Events >5% in any Treatment Group, by Primary Term, in Initial Therapy Study Adverse Event Number (%) of Patients Glipizide 5 mg tablets N = 170 Metformin 500 mg tablets N = 177 Glipizide and Metformin HCl 2.5 mg/250 mg tablets N = 172 Glipizide and Metformin HCl 2.5 mg/500 mg tablets N = 173 Upper respiratory infection 12 (7.1) 15 (8.5) 17 (9.9) 14 (8.1) Diarrhea 8 (4.7) 15 (8.5) 4 (2.3) 9 (5.2) Dizziness 9 (5.3) 2 (1.1) 3 (1.7) 9 (5.2) Hypertension 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 HCl Tablets as second-line therapy, a total of 87 patients received Glipizide and Metformin HCl 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 5 mg tablets a N = 84 Metformin 500 mg tablets a N = 75 Glipizide and Metformin HCl 5 mg/500 mg tablets a 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) a The dose of glipizide was fixed at 30 mg daily; doses of metformin and glipizide and metformin hydrochloride tablets were titrated. Hypoglycemia In a controlled initial therapy trial of Glipizide and Metformin HCl 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 HCl Tablets 2.5 mg/250 mg, and 16 (9.3%) for Glipizide and Metformin HCl Tablets 2.5 mg/500 mg. Among patients taking either Glipizide and Metformin HCl Tablets 2.5 mg/250 mg or Glipizide and Metformin HCl Tablets 2.5 mg/500 mg, 9 (2.6%) patients discontinued Glipizide and Metformin HCl Tablets due to hypoglycemic symptoms and 1 required medical intervention due to hypoglycemia. In a controlled second-line therapy trial of Glipizide and Metformin HCl 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 HCl Tablets. One (1.1%) patient discontinued Glipizide and Metformin HCl 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 HCl Tablets dosage strengths than with metformin therapy. There were 4 (1.2%) patients in the initial therapy trial who discontinued Glipizide and Metformin HCl Tablets therapy due to gastrointestinal (GI) adverse events. Gastrointestinal symptoms of diarrhea, nausea/vomiting, and abdominal pain were comparable among Glipizide and Metformin HCl 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 HCl 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 HCl Tablets should be discontinued if this occurs. To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

CLINICAL PHARMACOLOGY Mechanism of Action Glipizide and Metformin HCl Tablets combines glipizide and metformin hydrochloride, 2 antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes. Glipizide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment. Metformin hydrochloride is 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 HCl Tablets In a single-dose study in healthy subjects, the glipizide and metformin components of Glipizide and Metformin HCl Tablets 5 mg/500 mg were bioequivalent to coadministered GLUCOTROL ® and GLUCOPHAGE ® . Following administration of a single Glipizide and Metformin HCl Tablets 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% 1 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 2 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 Cmax is increased, when 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 (±SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Subject Groups: Metformin Dose a (Number of Subjects) C max b (μg/mL) T max c (hrs) Renal Clearance (mL/min) Healthy, Nondiabetic Adults: 500 mg SD d (24) 850 mg SD (74) e 850 mg t.i.d. for 19 doses f (9) 1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42) 2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94) 600 (±132) 552 (±139) 642 (±173) Adults with Type 2 Diabetes: 850 mg SD (23) 850 mg t.i.d. for 19 doses f (9) 1.48 (±0.5) 1.90 (±0.62) 3.32 (±1.08) 2.