Professional Information — Glipizide And Metformin Hydrochloride

Indications and Usage

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 and Administration

General Considerations

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/2000 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 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.

When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total exposure to glipizide is reduced. Therefore, glipizide and metformin hydrochloride tablets should be administered at least 4 hours prior to colesevelam.

Glipizide and Metformin Hydrochloride Tablets in Patients with Inadequate Glycemic Control on Diet and Exercise Alone

For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and exercise alone, the recommended starting dose of glipizide and metformin hydrochloride tablets is 2.5 mg/250 mg once a day with a meal. For patients whose FPG is 280 mg/dL to 320 mg/dL a starting dose of glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg twice daily should be considered. The efficacy of glipizide and metformin hydrochloride tablets in patients whose FPG exceeds 320 mg/dL has not been established. Dosage increases to achieve adequate glycemic control should be made in increments of 1 tablet per day every 2 weeks up to maximum of 10 mg/1000 mg or 10 mg/2000 mg glipizide and metformin hydrochloride tablets per day given in divided doses. In clinical trials of glipizide and metformin hydrochloride tablets as initial therapy, there was no experience with total daily doses > 10 mg/2000 mg per day.

Glipizide and Metformin Hydrochloride Tablets in Patients with Inadequate Glycemic Control on a Sulfonylurea and/or Metformin

For patients not adequately controlled on either glipizide (or another sulfonylurea) or metformin alone, the recommended starting dose of glipizide and metformin hydrochloride tablets is 2.5 mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the starting dose of glipizide and metformin hydrochloride tablets should not exceed the daily doses of glipizide or metformin already being taken. The daily dose should be titrated in increments of no more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose or to a maximum dose of 20 mg/2000 mg per day.

Patients previously treated with combination therapy of glipizide (or another sulfonylurea) plus metformin may be switched to glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg or 5 mg/500 mg; the starting dose should not exceed the daily dose of glipizide (or equivalent dose of another sulfonylurea) and metformin already being taken. The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment. Patients should be monitored closely for signs and symptoms of hypoglycemia following such a switch and the dose of glipizide and metformin hydrochloride tablets should be titrated as described above to achieve adequate control of blood glucose.

Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of glipizide and metformin hydrochloride tablets and periodically thereafter.

Glipizide and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m².

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

In patients taking glipizide and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m², assess the benefit risk of continuing therapy.

Discontinue glipizide and metformin hydrochloride tablets if the patient’s eGFR later falls below 30 mL/minute/1.73 m². (See WARNINGS.)

Discontinuation for Iodinated Contrast Imaging Procedure

Discontinue glipizide and metformin hydrochloride 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 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 tablets if renal function is stable.

Specific Patient Populations

Glipizide and metformin hydrochloride tablets are not recommended for use during pregnancy or for use in pediatric patients. The initial and maintenance dosing of glipizide and metformin hydrochloride tablets should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of glipizide and metformin hydrochloride tablets to avoid the risk of hypoglycemia. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly. (See WARNINGS and PRECAUTIONS.)

Contraindications

Glipizide and metformin hydrochloride tablets are contraindicated in patients with:

1. Severe renal impairment (eGFR below 30 mL/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.

Adverse Reactions

Glipizide and Metformin Hydrochloride Tablets

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.

Hypoglycemia

In a controlled initial therapy trial of glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg the numbers of patients with hypoglycemia documented by symptoms (such as dizziness, shakiness, sweating, and hunger) and a fingerstick blood glucose measurement ≤ 50 mg/dL were 5 (2.9%) for glipizide, 0 (0%) for metformin, 13 (7.6%) for glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, and 16 (9.3%) for glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg. Among patients taking either glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg or glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, 9 (2.6%) patients discontinued glipizide and metformin hydrochloride tablets due to hypoglycemic symptoms and 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 tablet therapy due to hypoglycemic symptoms and none required medical intervention due to hypoglycemia (see PRECAUTIONS).

Gastrointestinal Reactions

Among the most common clinical adverse events in the initial therapy trial were diarrhea and nausea/vomiting; the incidences of these events were lower with both glipizide and metformin hydrochloride tablets dosage strengths than with metformin therapy. There were 4 (1.2%) patients in the initial therapy trial who discontinued glipizide and metformin hydrochloride tablet 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 tablet 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.

To report SUSPECTED ADVERSE EVENTS, contact Teva Pharmaceuticals USA, Inc., at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

Drug Interactions

Glipizide and Metformin Hydrochloride 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 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.

Glipizide

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including non-steroidal 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.

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 hydrochloride 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 hydrochloride tablets.

Use in Specific Populations

Glipizide and metformin hydrochloride tablets are not recommended for use during pregnancy or for use in pediatric patients. The initial and maintenance dosing of glipizide and metformin hydrochloride tablets should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of glipizide and metformin hydrochloride tablets to avoid the risk of hypoglycemia. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly. (See WARNINGS and PRECAUTIONS.)

Overdosage

Glipizide

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.

Metformin Hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts > 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (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.

Description

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

Glipizide, USP is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glipizide, USP is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea. Glipizide, USP is a whitish, odorless powder with a pK_a of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. The structural formula is represented below.

C₂₁H₂₇N₅O₄S M.W. 445.55

Metformin hydrochloride, USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride, USP (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound. Metformin hydrochloride, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK_a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride, USP is 6.68. The structural formula is as shown:

C₄H₁₂ClN₅ M.W. 165.63

Glipizide and metformin hydrochloride tablets, USP for oral administration contain 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 tablet contains the following inactive ingredients: corn starch, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, povidone, talc, and titanium dioxide. Additionally, 2.5 mg/250 mg and 5 mg/500 mg tablets contain iron oxide black, iron oxide red, and iron oxide yellow. The tablets are film-coated, which provides color differentiation.

Clinical Pharmacology

Mechanism of Action

Glipizide and metformin hydrochloride tablets combine 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 hydrochloride tablets

In a single-dose study in healthy subjects, the glipizide and metformin components of glipizide and metformin hydrochloride tablets, 5 mg/500 mg were bioequivalent to coadministered glipizide tablets and metformin hydrochloride tablets. Following administration of a single glipizide and metformin hydrochloride 5 mg/500 mg tablet in healthy subjects with either a 20% glucose solution or a 20% glucose solution with food, there was a small effect of food on peak plasma concentration (C_max) and no effect of food on area under the curve (AUC) of the glipizide component. Time to peak plasma concentration (T_max) for the glipizide component was delayed 1 hour with food relative to the same tablet strength administered fasting with a 20% glucose solution. C_max for the metformin component was reduced approximately 14% by food whereas AUC was not affected. T_max for the metformin component was delayed 1 hour after food.

Glipizide

Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes.

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin hydrochloride tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg and 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower AUC in plasma and a 35 minute prolongation of time to peak plasma concentration following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Glipizide

Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98% to 99% 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 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/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 C_max 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).

Pediatrics

No data from pharmacokinetic studies in pediatric subjects are available for glipizide.

After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin C_max and AUC differed < 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.

Gender

There is no information on the effect of gender on the pharmacokinetics of glipizide.

Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Race

No information is available on race differences in the pharmacokinetics of glipizide.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics (n = 24).

Clinical Studies

Patients with Inadequate Glycemic Control on Diet and Exercise Alone

In a 24 week, double-blind, active-controlled, multicenter international clinical trial, patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (hemoglobin A_1c [HbA_1c] > 7.5% and ≤ 12%, and fasting plasma glucose [FPG] < 300 mg/dL) were randomized to receive initial therapy with glipizide 5 mg, metformin 500 mg, glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, or glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg. After 2 weeks, the dose was progressively increased (up to the 12 week visit) to a maximum of 4 tablets daily in divided doses as needed to reach a target mean daily glucose (MDG) of ≤ 130 mg/dL. Trial data at 24 weeks are summarized in Table 2.

After 24 weeks, treatment with glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg resulted in significantly greater reduction in HbA_1c compared to glipizide and metformin therapy. Also, glipizide and metformin hydrochloride tablet, 2.5 mg/250 mg therapy resulted in significant reductions in FPG versus metformin therapy.

Increases above fasting glucose and insulin levels were determined at baseline and final study visits by measurement of plasma glucose and insulin for 3 hours following a standard mixed liquid meal. Treatment with glipizide and metformin hydrochloride tablets lowered the 3 hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Compared to baseline, glipizide and metformin hydrochloride tablets enhanced the postprandial insulin response, but did not significantly affect fasting insulin levels.

There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablet therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, -0.4 kg; glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, -0.5 kg; glipizide, -0.2 kg; and metformin, -1.9 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.

Patients with Inadequate Glycemic Control on Sulfonylurea Monotherapy

In an 18-week, double-blind, active-controlled U.S. clinical trial, a total of 247 patients with type 2 diabetes not adequately controlled (HbA_1c ≥ 7.5% and ≤ 12%, and FPG < 300 mg/dL) while being treated with at least one-half the maximum labeled dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glipizide (fixed dose, 30 mg), metformin (500 mg), or glipizide and metformin hydrochloride tablets, 5 mg/500 mg. The doses of metformin and glipizide and metformin hydrochloride tablets were titrated (up to the 8 week visit) to a maximum of 4 tablets daily as needed to achieve MDG ≤ 130 mg/dL. Trial data at 18 weeks are summarized in Table 3.

After 18 weeks, treatment with glipizide and metformin hydrochloride tablets at doses up to 20 mg/2000 mg per day resulted in significantly lower mean final HbA_1c and significantly greater mean reductions in FPG compared to glipizide and metformin therapy. Treatment with glipizide and metformin hydrochloride tablets lowered the 3 hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Glipizide and metformin hydrochloride tablets did not significantly affect fasting insulin levels.

There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablet therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets, 5 mg/500 mg, -0.3 kg; glipizide, -0.4 kg; and metformin, -2.7 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.

Clinical Studies

Patients with Inadequate Glycemic Control on Diet and Exercise Alone

In a 24 week, double-blind, active-controlled, multicenter international clinical trial, patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (hemoglobin A_1c [HbA_1c] > 7.5% and ≤ 12%, and fasting plasma glucose [FPG] < 300 mg/dL) were randomized to receive initial therapy with glipizide 5 mg, metformin 500 mg, glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, or glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg. After 2 weeks, the dose was progressively increased (up to the 12 week visit) to a maximum of 4 tablets daily in divided doses as needed to reach a target mean daily glucose (MDG) of ≤ 130 mg/dL. Trial data at 24 weeks are summarized in Table 2.

After 24 weeks, treatment with glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg resulted in significantly greater reduction in HbA_1c compared to glipizide and metformin therapy. Also, glipizide and metformin hydrochloride tablet, 2.5 mg/250 mg therapy resulted in significant reductions in FPG versus metformin therapy.

Increases above fasting glucose and insulin levels were determined at baseline and final study visits by measurement of plasma glucose and insulin for 3 hours following a standard mixed liquid meal. Treatment with glipizide and metformin hydrochloride tablets lowered the 3 hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Compared to baseline, glipizide and metformin hydrochloride tablets enhanced the postprandial insulin response, but did not significantly affect fasting insulin levels.

There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablet therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, -0.4 kg; glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, -0.5 kg; glipizide, -0.2 kg; and metformin, -1.9 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.

Patients with Inadequate Glycemic Control on Sulfonylurea Monotherapy

In an 18-week, double-blind, active-controlled U.S. clinical trial, a total of 247 patients with type 2 diabetes not adequately controlled (HbA_1c ≥ 7.5% and ≤ 12%, and FPG < 300 mg/dL) while being treated with at least one-half the maximum labeled dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glipizide (fixed dose, 30 mg), metformin (500 mg), or glipizide and metformin hydrochloride tablets, 5 mg/500 mg. The doses of metformin and glipizide and metformin hydrochloride tablets were titrated (up to the 8 week visit) to a maximum of 4 tablets daily as needed to achieve MDG ≤ 130 mg/dL. Trial data at 18 weeks are summarized in Table 3.

After 18 weeks, treatment with glipizide and metformin hydrochloride tablets at doses up to 20 mg/2000 mg per day resulted in significantly lower mean final HbA_1c and significantly greater mean reductions in FPG compared to glipizide and metformin therapy. Treatment with glipizide and metformin hydrochloride tablets lowered the 3 hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Glipizide and metformin hydrochloride tablets did not significantly affect fasting insulin levels.

There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablet therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets, 5 mg/500 mg, -0.3 kg; glipizide, -0.4 kg; and metformin, -2.7 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.

How Supplied / Storage and Handling

Glipizide and metformin hydrochloride tablets, USP are available as follows:

2.5 mg/250 mg are pink, film-coated, modified capsule-shaped tablets, debossed with “93” on one side and “7455” on the other in bottles of 100 (NDC 0093-7455-01).

2.5 mg/500 mg are white, film-coated, modified capsule-shaped tablets, debossed with “93” on one side and “7456” on the other in bottles of 100 (NDC 0093-7456-01).

5 mg/500 mg are pink, film-coated, modified capsule-shaped tablets, debossed with “93” on one side and “7457” on the other in bottles of 100 (NDC 0093-7457-01).

STORAGE

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

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Kfar Saba, 4410202, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

Parsippany, NJ 07054

Rev. M 12/2020

Patient Counseling Information

Glipizide and Metformin Hydrochloride Tablets

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 printed below).