Glipizide and metformin hydrochloride tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Dosage of glipizide and metformin hydrochloride tablets must be individualized on the basis of both effectiveness and tolerance while not exceeding the maximum recommended daily dose of 20 mg glipizide/2,000 mg metformin. Glipizide and metformin hydrochloride 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 hydrochloride 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 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.

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 1 tablet per day every 2 weeks up to maximum of 10 mg/1,000 mg or 10 mg/2,000 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 ˃10 mg/2,000 mg per day.

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/2,000 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 m².

Initiation of glipizide and metformin hydrochloride in patients with an eGFR between 30 mL/minute/1.73 m² to 45 mL/minute/1.73 m² is not recommended.

In patients taking glipizide and metformin hydrochloride whose eGFR later falls below 45 mL/min/1.73 m², 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 m². (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 mL/min/1.73 m²and 60 mL/min/1.73 m²; 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.

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).

Glipizide and metformin hydrochloride tablets are contraindicated in patients with:

1. Severe renal impairment (eGFR below 30 mlL/min/1.73 m²) (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.

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 years 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.

Lactic Acidosis —There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increases lactate:pyruvate ratio; metformin plasma levels were generally > 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of glipizide and metformin hydrochloride. In glipizide and metformin hydrochloride treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue glipizide and metformin hydrochloride and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis,recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

o   Renal Impairment —The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include (see Dosage and Administration, Clinical Pharmacology):

• Before initiating glipizide and metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR)
• Glipizide and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Initiation of glipizide and metformin hydrochloride is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2 (see Contraindications)
• Obtain an eGFR at least annually in all patients taking glipizide and metformin hydrochloride. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking glipizide and metformin hydrochloride whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

• Drug interactions —The concomitant use of glipizide and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.
• Age 65 or Greater —The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in  elderly patients.
• Radiologic studies with contrast —Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop 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 mlL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism or heart failure, or in patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure, and restart glipizide and metformin hydrochloride if renal function is stable.
• Surgery and other procedures —With holding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Glipizide and metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake.
• Hypoxic states —Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue glipizide and metformin hydrochloride.
• Excessive Alcohol intake —Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving glipizide and metformin hydrochloride.
• Hepatic impairment —Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of glipizide and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.
• Mitochondrial Diseases — Metformin may increase the risk of lactic acidosis in patients with mitochondrial diseases such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD). Glipizide and metformin hydrochloride tablets are not recommended in patients with mitochondrial diseases such as MELAS syndrome and MIDD.

If a patient taking glipizide and metformin hydrochloride tablets develops elevated lactic acid levels (with or without accompanying neurologic signs and symptoms), discontinue glipizide and metformin hydrochloride tablets. Depending on the clinical context, consider evaluating the patient for MELAS, MIDD, or other mitochondrial disease.

Glipizide and metformin hydrochloride tablets are capable of producing hypoglycemia; therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal insufficiency may cause elevated drug levels of both glipizide and metformin hydrochloride. Hepatic insufficiency may increase drug levels of glipizide and may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and people who are taking beta-adrenergic blocking drugs.

The metabolism and excretion of glipizide may be slowed in patients with impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted.

Hemolytic Anemia:

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glipizide and metformin hydrochloride tablets belong 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.

In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests ).

Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. In these patients, routine serum vitamin B₁₂ measurements at 2 years to 3 years intervals may be useful.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glipizide and metformin hydrochloride or any other antidiabetic drug.

Patients should be informed of the potential risks and benefits of glipizide and metformin hydrochloride tablets and alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions; a regular exercise program, and regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue glipizide and metformin hydrochloride tablets immediately and promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of glipizide and metformin hydrochloride tablets, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving glipizide and metformin hydrochloride tablets (see Patient Information Leaflet printed below ).

Periodic fasting blood glucose (FBG) and HbA_1c measurements should be performed to monitor therapeutic response.

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B₁₂ deficiency should be excluded.

Instruct patients to inform their doctor that they are taking glipizide and metformin hydrochloride tablets prior to any surgical or radiological procedure, as temporary discontinuation of glipizide and metformin hydrochloride tablets may be required until renal function has been confirmed to be normal (see Precautions).

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 hydrochloride 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 hydrochloride 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.

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 hydrochloride tablets, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide and metformin hydrochloride 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 hydrochloride 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% 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 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 hydrochloride tablets should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of glipizide.

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. 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 co-administered chronically.

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration 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.

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.

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 hydrochloride 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 hydrochloride.

No animal studies have been conducted with the combined products in glipizide and metformin hydrochloride tablets. The following data are based on findings in studies performed with the individual products.

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.

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 hydrochloride 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 high as 600 mg/kg/day, which is approximately 3 times the MRHD dose of the metformin component of glipizide and metformin hydrochloride tablets based on body surface area comparisons.

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, glipizide and metformin hydrochloride tablets should not be used during pregnancy unless clearly needed (see below).

There are no adequate and well-controlled studies in pregnant women with glipizide and metformin hydrochloride tablets or its individual components. No animal studies have been conducted with the combined products in glipizide and metformin hydrochloride tablets. The following data are based on findings in studies performed with the individual products.

Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg). This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits, no teratogenic effects were found.

Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 times and 6 times the MRHD dose of 2000 mg of the metformin component of glipizide and metformin hydrochloride tablets based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Prolonged severe hypoglycemia (4 days to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that glipizide and metformin hydrochloride tablets be used during pregnancy. However, if it is used, glipizide and metformin hydrochloride tablets should be discontinued at least 1 month before the expected delivery date (see Pregnancy; Teratogenic Effects: Pregnancy Category C ).

Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue glipizide and metformin hydrochloride tablets, taking into account the importance of the drug to the mother. If glipizide and metformin hydrochloride tablets are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Safety and effectiveness of glipizide and metformin hydrochloride tablets in pediatric patients have not been established.

Of the 345 patients who received glipizide and metformin hydrochloride tablets 2.5 mg/250 mg and 2.5 mg/500 mg in the initial therapy trial, 67 (19.4%) were aged 65 and older while 5 (1.4%) were aged 75 and older. Of the 87 patients who received glipizide and metformin hydrochloride tablets in the second-line therapy trial, 17 (19.5%) were aged 65 and older while 1 (1.1%) was at least aged 75. No overall differences in effectiveness or safety were observed between these patients and younger patients in either the initial therapy trial or the second-line therapy trial, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients (see also WARNINGS, PRECAUTION and DOSAGE AND ADMINISTRATION ).

In a double-blind 24 week clinical trial involving glipizide and metformin hydrochloride tablets as initial therapy, a total of 172 patients received glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, 173 received glipizide and metformin hydrochloride 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.

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.

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 1 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 ).

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 gastrointestinal (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.

Lactic Acidosis —There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increases lactate:pyruvate ratio; metformin plasma levels were generally > 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of glipizide and metformin hydrochloride. In glipizide and metformin hydrochloride treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue glipizide and metformin hydrochloride and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis,recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

o   Renal Impairment —The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patients renal function include (see Dosage and Administration, Clinical Pharmacology):

• Before initiating glipizide and metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR)
• Glipizide and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Initiation of glipizide and metformin hydrochloride is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2 (see Contraindications)
• Obtain an eGFR at least annually in all patients taking glipizide and metformin hydrochloride. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
• In patients taking glipizide and metformin hydrochloride whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

• Drug interactions —The concomitant use of glipizide and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients.
• Age 65 or Greater —The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in  elderly patients.
• Radiologic studies with contrast —Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop 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 mlL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism or heart failure, or in patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure, and restart glipizide and metformin hydrochloride if renal function is stable.
• Surgery and other procedures —With holding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Glipizide and metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake.
• Hypoxic states —Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue glipizide and metformin hydrochloride.
• Excessive Alcohol intake —Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving glipizide and metformin hydrochloride.
• Hepatic impairment —Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of glipizide and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.
• Mitochondrial Diseases — Metformin may increase the risk of lactic acidosis in patients with mitochondrial diseases such as mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS) syndrome and maternally inherited diabetes and deafness (MIDD). Glipizide and metformin hydrochloride tablets are not recommended in patients with mitochondrial diseases such as MELAS syndrome and MIDD.

If a patient taking glipizide and metformin hydrochloride tablets develops elevated lactic acid levels (with or without accompanying neurologic signs and symptoms), discontinue glipizide and metformin hydrochloride tablets. Depending on the clinical context, consider evaluating the patient for MELAS, MIDD, or other mitochondrial disease.

Glipizide and metformin hydrochloride tablets are capable of producing hypoglycemia; therefore, proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents or ethanol. Renal insufficiency may cause elevated drug levels of both glipizide and metformin hydrochloride. Hepatic insufficiency may increase drug levels of glipizide and may also diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and people who are taking beta-adrenergic blocking drugs.

The metabolism and excretion of glipizide may be slowed in patients with impaired renal and/or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted.

Hemolytic Anemia:

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because glipizide and metformin hydrochloride tablets belong 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.

In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B₁₂, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on metformin and any apparent abnormalities should be appropriately investigated and managed (see PRECAUTIONS: Laboratory Tests ).

Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. In these patients, routine serum vitamin B₁₂ measurements at 2 years to 3 years intervals may be useful.

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glipizide and metformin hydrochloride or any other antidiabetic drug.

Patients should be informed of the potential risks and benefits of glipizide and metformin hydrochloride tablets and alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions; a regular exercise program, and regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be explained to patients. Patients should be advised to discontinue glipizide and metformin hydrochloride tablets immediately and promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of glipizide and metformin hydrochloride tablets, gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving glipizide and metformin hydrochloride tablets (see Patient Information Leaflet printed below ).

Periodic fasting blood glucose (FBG) and HbA_1c measurements should be performed to monitor therapeutic response.

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, vitamin B₁₂ deficiency should be excluded.

Instruct patients to inform their doctor that they are taking glipizide and metformin hydrochloride tablets prior to any surgical or radiological procedure, as temporary discontinuation of glipizide and metformin hydrochloride tablets may be required until renal function has been confirmed to be normal (see Precautions).

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 hydrochloride 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 hydrochloride 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.

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 hydrochloride tablets, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide and metformin hydrochloride 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 hydrochloride 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% 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 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 hydrochloride tablets should be administered at least 4 hours prior to colesevelam to ensure that colesevelam does not reduce the absorption of glipizide.

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that pharmacokinetic parameters of both compounds were affected by co-administration. 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 co-administered chronically.

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration 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.

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.

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 hydrochloride 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 hydrochloride.

No animal studies have been conducted with the combined products in glipizide and metformin hydrochloride tablets. The following data are based on findings in studies performed with the individual products.

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.

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 hydrochloride 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 high as 600 mg/kg/day, which is approximately 3 times the MRHD dose of the metformin component of glipizide and metformin hydrochloride tablets based on body surface area comparisons.

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible. Because animal reproduction studies are not always predictive of human response, glipizide and metformin hydrochloride tablets should not be used during pregnancy unless clearly needed (see below).

There are no adequate and well-controlled studies in pregnant women with glipizide and metformin hydrochloride tablets or its individual components. No animal studies have been conducted with the combined products in glipizide and metformin hydrochloride tablets. The following data are based on findings in studies performed with the individual products.

Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg). This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide. The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action of glipizide. In studies in rats and rabbits, no teratogenic effects were found.

Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 times and 6 times the MRHD dose of 2000 mg of the metformin component of glipizide and metformin hydrochloride tablets based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.

Prolonged severe hypoglycemia (4 days to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. It is not recommended that glipizide and metformin hydrochloride tablets be used during pregnancy. However, if it is used, glipizide and metformin hydrochloride tablets should be discontinued at least 1 month before the expected delivery date (see Pregnancy; Teratogenic Effects: Pregnancy Category C ).

Although it is not known whether glipizide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue glipizide and metformin hydrochloride tablets, taking into account the importance of the drug to the mother. If glipizide and metformin hydrochloride tablets are discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Safety and effectiveness of glipizide and metformin hydrochloride tablets in pediatric patients have not been established.

Of the 345 patients who received glipizide and metformin hydrochloride tablets 2.5 mg/250 mg and 2.5 mg/500 mg in the initial therapy trial, 67 (19.4%) were aged 65 and older while 5 (1.4%) were aged 75 and older. Of the 87 patients who received glipizide and metformin hydrochloride tablets in the second-line therapy trial, 17 (19.5%) were aged 65 and older while 1 (1.1%) was at least aged 75. No overall differences in effectiveness or safety were observed between these patients and younger patients in either the initial therapy trial or the second-line therapy trial, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients (see also WARNINGS, PRECAUTION and DOSAGE AND ADMINISTRATION ).