GLIPIZIDE AND METFORMIN HYDROCHLORIDE TABLETS
2.5 mg/250 mg, 2.5 mg/500 mg and 5 mg/500 mg

Glipizide and metformin HCl tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes, glipizide and metformin hydrochloride.

Glipizide is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl] urea. Glipizide is white to almost white crystalline powder with a molecular formula of C₂₁H₂₇N₅O₄S, a molecular weight of 445.54 and a pK_a of 5.9. It is practically insoluble in water and in ethanol, sparingly soluble in acetone; soluble in chloroform. It dissolves in dilute solutions of alkali hydroxides. The structural formula is represented below.

Metformin hydrochloride is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white crystalline powder with a molecular formula of C₄H₁₁N₅• HCl and a molecular weight of 165.62. Metformin hydrochloride is very soluble in water, slightly soluble in ethanol practically insoluble in ether and in chloroform. The pK_a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

Glipizide and metformin HCl tablets are available for oral administration in tablets containing 2.5 mg glipizide, USP with 250 mg metformin hydrochloride, USP; 2.5 mg glipizide, USP with 500 mg metformin hydrochloride, USP; and 5 mg glipizide, USP with 500 mg metformin hydrochloride, USP. In addition, each film-coated tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium lauryl sulfate, titanium dioxide and triacetin. The 5 mg/500 mg also contains iron oxide red and iron oxide yellow.

Glipizide and metformin hydrochloride tablets combines glipizide and metformin hydrochloride, two 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.

Glipizide and metformin HCl tablets are indicated as initial therapy, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone.

Glipizide and metformin HCl tablets are indicated as second-line therapy when diet, exercise, and initial treatment with a sulfonylurea or metformin do not result in adequate glycemic control in patients with type 2 diabetes.

Glipizide and metformin HCl tablets are contraindicated in patients with:

• Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL [males], ≥ 1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS).
• Congestive heart failure requiring pharmacologic treatment.
• Known hypersensitivity to glipizide or metformin hydrochloride.
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.

Glipizide and metformin HCl tablets should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function. (See also PRECAUTIONS.)

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.

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, glipizide and metformin hydrochloride should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.

Periodic fasting blood glucose and glycosylated hemoglobin (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.

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

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, taking into account the importance of the drug to the mother. If glipizide and metformin hydrochloride is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

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

Of the 345 patients who received glipizide and metformin hydrochloride 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 in the second-line therapy trial, 17 (19.5%) were aged 65 and older while one (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.

Metformin hydrochloride is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, glipizide and metformin hydrochloride should only be used in patients with normal renal function (see CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Pharmacokinetics). Because aging is associated with reduced renal function, glipizide and metformin hydrochloride should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of glipizide and metformin hydrochloride (see also WARNINGS and DOSAGE AND ADMINISTRATION).

In a double-blind 24 week clinical trial involving glipizide and metformin hydrochloride as initial therapy, a total of 172 patients received glipizide and metformin hydrochloride 2.5 mg/250 mg, 173 received glipizide and metformin hydrochloride 2.5 mg/500 mg, 170 received glipizide, and 177 received metformin. The most common clinical adverse events in these treatment groups are uled in Table 4.

In a double-blind 18 week clinical trial involving glipizide and metformin hydrochloride as second-line therapy, a total of 87 patients received glipizide and metformin hydrochloride, 84 received glipizide, and 75 received metformin. The most common clinical adverse events in this clinical trial are uled in Table 5.

In a controlled initial therapy trial of glipizide and metformin hydrochloride 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 2.5 mg/250 mg, and 16 (9.3%) for glipizide and metformin hydrochloride 2.5 mg/500 mg. Among patients taking either glipizide and metformin hydrochloride 2.5 mg/250 mg or glipizide and metformin hydrochloride 2.5 mg/500 mg, nine (2.6%) patients discontinued glipizide and metformin hydrochloride due to hypoglycemic symptoms and one required medical intervention due to hypoglycemia. In a controlled second-line therapy trial of glipizide and metformin hydrochloride 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. One (1.1%) patient discontinued glipizide and metformin hydrochloride therapy due to hypoglycemic symptoms and none required medical intervention due to hypoglycemia. (See PRECAUTIONS section.)

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 dosage strengths than with metformin therapy. There were 4 (1.2%) patients in the initial therapy trial who discontinued glipizide and metformin hydrochloride therapy due to GI adverse events. Gastrointestinal symptoms of diarrhea, nausea/vomiting, and abdominal pain were comparable among glipizide and metformin hydrochloride, 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 therapy due to GI adverse events.

Overdosage of sulfonylureas, including glipizide, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. Clearance of glipizide from plasma would be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.

Among cases of overdosage of metformin hydrochloride, including ingestion of amounts greater than 100 grams, hypoglycemia was reported in approximately 10%, but no causal association with metformin hydrochloride has been established, although lactic acidosis has occurred in such circumstances (see WARNINGS). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

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), to reduce GI side effects (largely due to metformin), and to 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 (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 HCl tablet 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.

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 is 2.5 mg/250 mg once a day with a meal. For patients whose FPG is 280 to 320 mg/dL a starting dose of glipizide and metformin HCl tablets is 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 one tablet per day every two 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 greater than 10 mg/2000 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 HCl 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 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.

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.)

Glipizide and metformin hydrochloride tablets are available containing 2.5 mg glipizide, USP with 250 mg metformin hydrochloride, USP; 2.5 mg glipizide, USP with 500 mg metformin hydrochloride, USP; and 5 mg glipizide, USP with 500 mg metformin hydrochloride, USP.

The 2.5 mg/250 mg tablets are white film-coated, round, unscored tablets debossed with M on one side of the tablet and G31 on the other side. They are available as follows:

NDC 0378-3131-01
bottles of 100 tablets

NDC 0378-3131-05
bottles of 500 tablets

The 2.5 mg/500 mg tablets are white film-coated, oval, unscored tablets debossed with M on one side of the tablet and G32 on the other side. They are available as follows:

NDC 0378-3132-01
bottles of 100 tablets

NDC 0378-3132-05
bottles of 500 tablets

The 5 mg/500 mg tablets are peach film-coated, modified capsule-shaped, unscored tablets debossed with M on one side of the tablet and G33 on the other side. They are available as follows:

NDC 0378-3133-01
bottles of 100 tablets

NDC 0378-3133-05
bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Detach Patient Information Leaflet at each perforation and give leaflet to patient.