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Uses

Diabetes Mellitus

Glipizide is used as an adjunct to diet for the management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone. Sulfonylureas, including glipizide, may be used in combination with one or more other oral antidiabetic agents (e.g., metformin, thiazolidinedione derivatives, α-glucosidase inhibitors) or insulin as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. Glipizide is commercially available in fixed combination with metformin for use as initial therapy in patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone and as second-line therapy in patients with type 2 diabetes who are inadequately controlled with either sulfonylurea or metformin monotherapy.

The American Diabetes Association (ADA) currently classifies diabetes mellitus as type 1 immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug- or chemical-induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes). Type 1 diabetes mellitus was previously described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth. Type 2 diabetes mellitus was previously described as adult-onset (AODM) diabetes mellitus. However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on age of onset. Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2 diabetes mellitus, although other types, including idiopathic or nonimmune-mediated type 1 diabetes mellitus, also have been reported.

Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency. Most patients with type 2 diabetes mellitus (about 80-90%) are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk. While children with immune-mediated type 1 diabetes generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population. Distinguishing between type 1 and type 2 diabetes in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).

Oral antidiabetic agents are not effective as sole therapy in patients with type 1 diabetes mellitus; insulin is necessary in these patients. Sulfonylurea antidiabetic agents are not routinely recommended in hospitalized patients with diabetes mellitus. Because of their long duration of action (24 hours with glipizide), sulfonylureas do not allow rapid dosage adjustments to meet changing needs of hospitalized patients. In addition, the risk of hypoglycemia during sulfonylurea therapy is increased in such patients with irregular eating patterns.

Patients with type 2 diabetes mellitus are not dependent initially on insulin (although many patients eventually require insulin for glycemic control) nor are they prone to ketosis; however, insulin may occasionally be required for correction of symptomatic or persistent hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents (e.g., sulfonylureas), and ketosis occasionally may develop during periods of severe stress (e.g., acute infections, trauma, surgery). Type 2 diabetes mellitus is a heterogeneous subclass of the disease, and subclassification criteria (e.g., basal and stimulated plasma insulin concentrations, insulin resistance) remain to be clearly established. Endogenous insulin is present in type 2 diabetic patients, although plasma insulin concentrations may be decreased, increased, or normal. In type 2 diabetic patients, glucose-stimulated secretion of endogenous insulin is frequently, but not always, reduced and decreased peripheral sensitivity to insulin is almost always associated with glucose intolerance.

Glycemic Control and Microvascular Complications

Current evidence from epidemiologic and clinical studies supports an association between chronic hyperglycemia and the pathogenesis of microvascular complications in patients with diabetes mellitus, and results of randomized, controlled studies in patients with type 1 or type 2 diabetes mellitus indicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) concentrations provides substantial benefits in terms of reducing chronic microvascular (e.g., retinopathy, nephropathy, neuropathy) complications associated with the disease. HbA_1c concentration reflects the glycosylation of other proteins throughout the body as a result of recent hyperglycemia and is used as a predictor of risk for development of diabetic microvascular complications. Microvascular complications of diabetes are the principal causes of blindness and renal failure in developed countries and are more closely associated with hyperglycemia than are macrovascular complications.

In the Diabetes Control and Complications Trial (DCCT), the reduction in risk of microvascular complications in patients with type 1 diabetes mellitus correlated continuously with the reduction in HbA_1c concentration produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in HbA_1c). These data imply that any decrease in HbA_1c levels is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic complications. Data from the largest United Kingdom Prospective Diabetes Study (UKPDS) and other smaller studies in patients with type 2 diabetes mellitus generally are consistent with the same benefits on microvascular complications as those observed with type 1 diabetes mellitus in the DCCT study.

Data from long-term follow-up (over 10 years) of UKPDS patients with type 2 diabetes mellitus who received initial therapy with conventional (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia) antidiabetic treatment or intensive (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide], then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) antidiabetic regimens indicate that intensive treatment with monotherapy generally is not capable of maintaining strict glycemic control (i.e., maintenance of blood glucose concentrations of 108 mg/dL or normal values) over time and that combination therapy eventually becomes necessary in most patients to attain target glycemic levels in the long term; in UKPDS, intensive treatment that eventually required combination therapy in most patients resulted in median HbA_1c concentrations of 7%. Because of the benefits of strict glycemic control, the goal of therapy for type 2 diabetes mellitus is to lower blood glucose to as close to normal as possible, which generally requires aggressive management efforts (e.g., mixing therapy with various antidiabetic agents including sulfonylureas, metformin, insulin, and/or possibly others) over time. For additional information on clinical studies demonstrating the benefits of strict glycemic control on microvascular complications in patients with type 1 or 2 diabetes mellitus, .

Glycemic Control and Macrovascular Complications

Current evidence indicates that appropriate management of dyslipidemia, blood pressure, and vascular thrombosis provides substantial benefits in terms of reducing macrovascular complications associated with diabetes mellitus; intensive glycemic control generally has not been associated with appreciable reductions in macrovascular outcomes in controlled trials. Reduction in blood pressure to a mean of 144/82 mm Hg (''tight blood pressure control'') in patients with diabetes mellitus and uncomplicated mild to moderate hypertension in UKPDS substantially reduced the incidence of virtually all macrovascular (e.g., stroke, heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure) outcomes and diabetes-related mortality; blood pressure and glycemic control were additive in their beneficial effects on these end points. While intensive antidiabetic therapy titrated with the goal of reducing HbA_1c to near-normal concentrations (6-6.5% or less) has not been associated with appreciable reductions in cardiovascular events during the randomized portion of controlled trials examining such outcomes, results of long-term follow-up (10-11 years) from DCCT and UKPDS indicate a delayed cardiovascular benefit in patients treated with intensive antidiabetic therapy early in the course of type 1 or type 2 diabetes mellitus.

Treatment Goals

The ADA currently states that it is reasonable to attempt to achieve in patients with type 2 diabetes mellitus the same blood glucose and HbA_1c goals recommended for patients with type 1 diabetes mellitus. Based on target values for blood glucose and HbA_1c used in clinical trials (e.g., DCCT) for type 1 diabetic patients, modified somewhat to reduce the risk of severe hypoglycemia, ADA currently recommends target preprandial (fasting) and peak postprandial (1-2 hours after the beginning of a meal) plasma glucose concentrations of 70-130 and less than 180 mg/dL, respectively, and HbA_1c concentrations of less than 7% (based on a nondiabetic range of 4-6%) in general in patients with type 1 or type 2 diabetes mellitus who are not pregnant. HbA_1c concentrations of 7% or greater should prompt clinicians to initiate or adjust antidiabetic therapy in nonpregnant patients with the goal of achieving HbA_1c concentrations of less than 7%. Patients with diabetes mellitus who have elevated HbA_1c concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1-2 hours after the start of a meal. Treatment with agents (e.g., α-glucosidase inhibitors, exenatide, pramlintide) that principally lower postprandial glucose concentrations to within target ranges also should reduce HbA_1c.

More stringent treatment goals (i.e., an HbA_1c less than 6%) may be considered in selected patients. An individualized HbA_1c concentration goal that is closer to normal without risking substantial hypoglycemia is reasonable in patients with a short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy. Less stringent treatment goals may be appropriate in patients with long-standing diabetes mellitus in whom the general HbA_1c concentration goal of less than 7% is difficult to obtain despite adequate education on self-management of the disease, appropriate glucose monitoring, and effective dosages of multiple antidiabetic agents, including insulin. Achievement of HbA_1c values of less than 7% is not appropriate or practical for some patients, and clinical judgment should be used in designing a treatment regimen based on the potential benefits and risks (e.g., hypoglycemia) of more intensified therapy.

Considerations in Initiating and Maintaining Antidiabetic Therapy

When initiating therapy for patients with type 2 diabetes mellitus who do not have severe symptoms, most clinicians recommend that diet be emphasized as the primary form of treatment; caloric restriction and weight reduction are essential in obese patients. Although appropriate dietary management and weight reduction alone may be effective in controlling blood glucose concentration and symptoms of hyperglycemia, many patients receiving dietary advice fail to achieve and maintain adequate glycemic control with dietary modification alone.

Recognizing that lifestyle interventions often fail to achieve or maintain the target glycemic goal within the first year of initiation of such interventions, ADA currently suggests initiation of metformin concurrently with lifestyle interventions at the time of diagnosis of type 2 diabetes mellitus. Other experts suggest concurrent initiation of lifestyle interventions and antidiabetic agents only when HbA_1c levels of 9% or greater are present at the time of diagnosis of type 2 diabetes mellitus. ADA and other clinicians state that lifestyle interventions should remain a principal consideration in the management of diabetes even after pharmacologic therapy is initiated. The manufacturer states that patients and clinicians should recognize that dietary management is the principal consideration in the management of diabetes mellitus and that antidiabetic therapy is used only as an adjunct to, and not as a substitute for or a convenient means to avoid, proper dietary management. In addition, loss of blood glucose control on diet alone may be temporary in some patients, requiring only short-term management with drug therapy. The importance of regular physical activity should be emphasized, and cardiovascular risk factors should be identified and corrective measures employed when feasible.

If lifestyle interventions alone are initiated and these interventions fail to reduce symptoms and/or blood glucose concentration, initiation of monotherapy with an oral antidiabetic agent (e.g., sulfonylurea, metformin, acarbose) or insulin should be considered.

Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents. The ADA currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients to outweigh the risks overall.

Glipizide Monotherapy

Clinical studies indicate that glipizide is as effective as chlorpropamide, glyburide, tolazamide, or tolbutamide for the management of type 2 diabetes mellitus. A relative advantage of glipizide compared with other sulfonylurea antidiabetic agents has not been clearly established. Although the glipizide-induced increase in glucose- or meal-stimulated secretion of endogenous insulin appears to be sustained during long-term therapy, the clinical importance of this effect in the long-term efficacy of the drug and any resultant therapeutic difference compared with other sulfonylureas remain to be determined. Reversal of basement-membrane thickening of muscle capillaries in asymptomatic individuals with impaired glucose tolerance (chemical diabetes) treated with glipizide has been reported, suggesting that early drug therapy to improve control of blood glucose concentration might reverse or delay microangiopathy, but this finding requires further evaluation.

Clinical trial data indicate that sulfonylureas are as effective as metformin in managing hyperglycemia (approximately 1.5% average reduction in HbA_1c values), but sulfonylurea use is associated with hypoglycemia and weight gain. ADA generally recommends metformin as initial oral antidiabetic therapy because of the absence of weight gain or hypoglycemia, relatively low expense, and generally low adverse effect profile compared with other oral antidiabetic agents.

Glipizide may be useful in some patients with type 2 diabetes mellitus who have primary or secondary failure to other sulfonylurea antidiabetic agents; however, primary or secondary failure to glipizide also may occur. Adequate adjustment of dosage and adherence to diet should be assessed before determining if secondary failure to glipizide has occurred. If primary or secondary failure to glipizide extended-release tablets has occurred, another oral antidiabetic agent may be added to glipizide therapy. Patients with secondary failure to one oral antidiabetic agent occasionally may respond to another agent.

Secondary failure to sulfonylurea antidiabetic agents is characterized by progressively decreasing diabetic control following 1 month to several years of good control. Interim data from a substudy (UKPD 26) of the UKPD study in newly diagnosed type 2 diabetic patients receiving intensive therapy (maintenance of fasting plasma glucose below 108 mg/dL by increasing doses of either a sulfonylurea [i.e., glyburide or chlorpropamide] to maximum recommended dosage) showed that secondary failure (defined as fasting plasma glucose exceeding 270 mg/dL or symptoms of hyperglycemia despite maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide) occurred overall at about 7% per year. The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide. In the UKPD studies, stepwise addition of insulin or metformin to therapy with maximal dosage of a sulfonylurea was required periodically over time to improve glycemic control. In another substudy (UKPD 49), progressive deterioration in diabetes control was such that monotherapy was effective in only about 50% of patients after 3 years and in only about 25% of patients after 9 years; thus, most patients require multiple-drug antidiabetic therapy over time to maintain such target levels of disease control. At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.

In some type 2 diabetic patients who are being treated with insulin, glipizide alone may be effective alternative therapy. However, glipizide is not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management of these conditions requires the use of insulin.

Combination Therapy with Metformin or Other Oral Antidiabetic Agents

Sulfonylureas may be used in combination with one or more other oral antidiabetic agents (e.g., metformin, thiazolidinedione derivatives, α-glucosidase inhibitors) as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. Combined therapy with metformin or other oral antidiabetic agents generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control with monotherapy.

The sequence in which metformin or a sulfonylurea is used at initiation of therapy does not appear to alter the effectiveness of combined therapy with the drugs. However, ADA and other clinicians currently recommend initiating therapy with metformin and adding another antidiabetic agent, such as a sulfonylurea, insulin, or a thiazolidinedione, if patients fail to achieve or maintain target HbA_1c goals. Optimal benefit generally is obtained by addition of a second antidiabetic agent as soon as monotherapy with metformin at the maximum tolerated dosage no longer provides adequate glycemic control (i.e., when the target glycemic goal is not achieved within 2-3 months of initiation of therapy with metformin or at any other time when the HbA_1c goal is not achieved).

A major factor in choosing additional therapy is the degree of glycemic control obtained during metformin monotherapy. In patients with a HbA_1c exceeding 8.5% or symptoms secondary to hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin. When glycemic control is closer to the target HbA_1c goal with metformin monotherapy (e.g., HbA_1c less than 7.5%), agents with a lesser potential to lower hyperglycemia and/or slower onset of action may be considered (e.g., sulfonylurea, thiazolidinedione) as additional therapy to metformin. ADA states that other antidiabetic agents such as α-glucosidase inhibitors, meglitinides, exenatide, and pramlintide generally are less effective, less well studied, and/or more expensive than recommended therapies (i.e., metformin, sulfonylurea, thiazolidinedione, insulin). However, these agents may be appropriate for treatment of type 2 diabetes mellitus in selected patients.

Glipizide is used in fixed combination with metformin as initial therapy in the management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone. In a comparative study in such patients, therapy with the fixed combination of glipizide and metformin was more effective in improving glycemic control (as determined by HbA_1c values, fasting plasma glucose concentrations) than monotherapy with either component. A greater percentage of patients receiving the fixed combination achieved strict glycemic control (HbA_1c values below 7%) than did those receiving metformin or glipizide monotherapy.

Glipizide also is used in fixed combination with metformin as second-line therapy in patients with type 2 diabetes whose hyperglycemia is inadequately controlled with either sulfonylurea or metformin monotherapy. In a comparative study, greater glycemic control (as determined by HbA_1c values and fasting plasma glucose concentrations) was achieved with the fixed combination of glipizide and metformin than with either drug as monotherapy. Strict glycemic control (e.g., HbA_1c values less than 7%) also was achieved in a greater percentage of patients receiving the fixed combination of glipizide and metformin.

When lifestyle interventions, metformin, and a second oral antidiabetic agent are not effective in maintaining the target glycemic goal in patients with type 2 diabetes mellitus, ADA and other clinicians generally recommend the addition of insulin therapy. In patients whose HbA_1c is close to the target level (less than 8%) on metformin and a second oral antidiabetic agent, addition of a third oral antidiabetic agent instead of insulin may be considered. However, ADA states that triple combination oral antidiabetic therapy is more costly and potentially not as effective as adding insulin therapy to dual combination oral antidiabetic therapy.

Combination Therapy with Insulin

Combined therapy with insulin and oral antidiabetic agents may be useful in some patients with type 2 diabetes mellitus whose blood glucose concentrations are not adequately controlled with maximal dosages of the oral agent and/or as a means of providing increased flexibility with respect to timing of meals and amount of food ingested. Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin at meal times) and one or more oral antidiabetic agents appears to improve glycemic control with lower dosages of insulin than would be required with insulin alone and may decrease the potential for body weight gain associated with insulin therapy. Oral antidiabetic therapy combined with insulin therapy may delay progression to either intensive insulin monotherapy or to a second daytime injection of insulin combined with oral antidiabetic agents. Preliminary data indicate that combination therapy with glipizide and insulin may be useful in some type 2 diabetic patients. However, combined therapy may increase the risk of hypoglycemic reactions.

ADA and other clinicians state that combined therapy with insulin and metformin with or without other oral antidiabetic agents is one of several options for the management of hyperglycemia in patients not responding adequately to oral monotherapy with metformin, the preferred initial oral antidiabetic agent. In patients with a HbA_1c exceeding 8.5% or symptoms secondary to hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin. When patients are not controlled with metformin with or without other oral antidiabetic agents (i.e., sulfonylurea, thiazolidinedione) and basal insulin (e.g., given as intermediate- or long-acting insulin at bedtime or in the morning), therapy with insulin should be intensified by adding additional short-acting or rapid-acting insulin injections at mealtimes. Therapy with insulin secretagogues (i.e., sulfonylureas, meglitinides) should be tapered and discontinued when intensive insulin therapy is initiated, as insulin secretagogues do not appear to be synergistic with such insulin therapy.

For additional information on combination therapy with sulfonylureas and other oral antidiabetic agents, see the sections on combination therapy in Uses in the individual monographs in 68:20.

Dosage and Administration

Administration

Glipizide is administered orally. The extended-release tablets should be swallowed whole and should not be divided, chewed, or crushed. Patients receiving the extended-release tablets become alarmed if they notice a tablet-like substance in their stools; this is normal since the tablet containing the drug is designed to remain intact and slowly release the drug from a nonabsorbable shell during passage through the GI tract.

Extended-release tablets of glipizide are administered once daily, generally with breakfast. Conventional tablets of the drug usually are administered as a single daily dose given each morning before breakfast. It is generally recommended that glipizide be administered approximately 30 minutes before a meal(s) to achieve the maximum reduction in postprandial blood glucose concentration. Once-daily dosing of glipizide at dosages up to 15-20 mg daily provides adequate control of blood glucose concentration throughout the day in most patients with usual meal patterns; however, some patients may have a more satisfactory response when the drug is administered in 2 or 3 divided doses daily as conventional tablets. When glipizide dosage exceeds 15-20 mg daily as conventional tablets, the drug should usually be administered in divided doses before meals of sufficient caloric content. The maximum once-daily dose as conventional tablets recommended by the manufacturer is 15 mg. When a divided-dosing regimen as conventional tablets is employed in patients receiving more than 15 mg of glipizide daily, the doses and schedule of administration should be individualized according to the patient's meal pattern and response. Dosages greater than 30 mg daily have been given safely in twice-daily dosing regimens for prolonged periods.

Dosage

Dosage of glipizide must be based on blood and urine glucose determinations and must be carefully individualized to obtain optimum therapeutic effect. Patients must be closely monitored (i.e., glycosylated hemoglobin [hemoglobin A_1c, HbA_1c], fasting blood glucose concentrations) to determine the minimum effective glipizide dosage and to detect primary or secondary failure to the drug. Self-monitoring of blood glucose concentrations may provide useful information to the patient and their clinician.If appropriate glipizide dosage regimens are not followed, hypoglycemia may be precipitated.

Patients receiving glipizide should be monitored carefully to determine the need for continued therapy and to ensure that the drug continues to be effective; if adequate lowering of blood glucose concentration is no longer achieved during maintenance therapy, the drug should be discontinued. Following initiation of glipizide therapy and dosage titration, determination of HbA_1c concentrations at intervals of approximately 3 months is the preferred method for assessing the patient's continued response to therapy. While fasting blood glucose concentrations generally reach steady-state following initiation or change in glipizide dosage, a single fasting blood glucose determination may not accurately assess glycemic response. If fasting blood glucose concentrations are used to assess the need for dosage adjustments, 2 consecutive determinations of similar value should be obtained 7 or more days after the previous dosage adjustment. Patients who do not adhere to their prescribed dietary and drug regimens are more likely to have an unsatisfactory response to therapy. In patients usually well controlled by dietary management alone, short-term therapy with glipizide may be sufficient during periods of transient loss of diabetic control.

Initial Dosage in Previously Untreated Patients

For the management of type 2 diabetes mellitus in patients not previously receiving insulin or sulfonylurea antidiabetic agents, the recommended initial adult dosage of glipizide is 5 mg daily as conventional or extended-release tablets; in geriatric patients or those with hepatic disease, an initial dosage of 2.5 or 5 mg daily as conventional or extended-release tablets, respectively, may be used. Initial glipizide dosage should be conservative in debilitated, malnourished, or geriatric patients, patients with impaired renal or hepatic function, or those who may otherwise be more sensitive to oral hypoglycemic agents because of an increased risk of hypoglycemia in these patients.(See Cautions: Precautions and Contraindications.) Subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response; dosage adjustments in increments of 2.5-5 mg daily at intervals of at least several days (usually 3-7 days) are recommended when conventional tablets are used. The manufacturer of extended-release glipizide tablets states that if fasting plasma glucose determinations are used to monitor response, dosage adjustment should be based on at least 2 similar consecutive values obtained at least 7 days after the previous dose adjustment.

Initial Dosage in Patients Transferred from Conventional to Extended-release Tablets

Based on results of a randomized crossover study, patients receiving conventional glipizide tablets may be switched safely to extended-release glipizide tablets by giving the nearest equivalent total daily dose once daily. Alternatively, dosage can be titrated beginning with an initial dosage of 5 mg once daily as extended-release tablets. The decision to switch to the nearest equivalent dosage versus re-titration should be individualized using clinical judgment.

Initial Dosage in Patients Transferred from Other Antidiabetic Agents

A transition period generally is not required when transferring from other sulfonylurea antidiabetic agents to glipizide, and administration of the other agent may be abruptly discontinued. Because of the prolonged elimination half-life of chlorpropamide, an exaggerated hypoglycemic response may occur in some patients during the transition from chlorpropamide to glipizide, and patients being transferred from chlorpropamide should be closely monitored for the occurrence of hypoglycemia during the initial 2 weeks of the transition period with conventional glipizide tablets or 1-2 weeks with extended-release glipizide tablets. A drug-free interval of 2-3 days may be advisable before glipizide therapy is initiated as conventional tablets in patients being transferred from chlorpropamide, particularly if blood glucose concentration was adequately controlled with chlorpropamide. An initial or loading dose of glipizide is not necessary when transferring from other sulfonylurea antidiabetic agents to glipizide. The transfer should be performed conservatively.

For the management of type 2 diabetes mellitus in patients previously receiving other sulfonylurea antidiabetic agents, the usual initial dosage of glipizide is 5-10 mg daily, but the initial dosage is variable and must be carefully individualized. Subsequent dosage is adjusted according to the patient's tolerance and therapeutic response. Although an exact dosage relationship between glipizide and other sulfonylurea antidiabetic agents does not exist, approximate dosage equivalencies have been estimated.(See Pharmacology: Antidiabetic Effect.)

In general, patients who were previously maintained on insulin dosages up to 20 units daily may be transferred directly to the usual recommended initial dosage of glipizide, and administration of insulin may be abruptly discontinued. In patients requiring insulin dosages greater than 20 units daily, the usual recommended initial dosage of glipizide should be started and insulin dosage reduced by 50%. Subsequently, insulin is withdrawn gradually and dosage of glipizide is adjusted in increments of 2.5-5 mg daily at intervals of at least several days, according to the patient's tolerance and therapeutic response. During the period of insulin withdrawal, patients should test their urine at least 3 times daily for glucose and ketones, and should be instructed to report the results to their physician so that appropriate adjustments in therapy may be made, if necessary; when feasible, patient or laboratory monitoring of blood glucose concentration is preferable. The presence of persistent ketonuria with glycosuria, ketosis, and/or inadequate lowering or persistent elevation of blood glucose concentration indicates that the patient requires insulin therapy. In some patients, especially those requiring greater than 40 units of insulin daily, the manufacturer suggests that it may be advisable to consider hospitalization during the transition from insulin to glipizide; however, some clinicians believe that hospitalization should rarely be necessary.

Maintenance Dosage

The adult maintenance dosage of glipizide for the management of type 2 diabetes mellitus varies considerably, ranging from 2.5-40 mg daily. Most patients appear to require 5-25 mg daily as conventional tablets or 5-10 mg daily as extended-release tablets, but some clinicians report that higher dosages may be necessary in many patients. Dosage adjustments in patients receiving glipizide extended-release tablets may be made at approximately 3-month intervals, based on HbA_1c measurements. In patients receiving an initial dosage of 5 mg daily of extended-release glipizide tablets, dosage may be increased to 10 mg daily after 3 months if glycemic response is inadequate, based on a HbA_1c measurement. Subsequent dosage should be adjusted according to patient's therapeutic response, using the lowest possible effective dosage. If an enhanced glycemic response is not observed after 3 months at a higher dosage, the dosage should be decreased to the previous equally effective dosage.

Maintenance dosage of glipizide should be conservative in debilitated, malnourished, or geriatric patients or patients with impaired renal or hepatic function because of an increased risk of hypoglycemia in these patients.(See Cautions: Precautions and Contraindications.) The maximum recommended dosage is 40 mg daily as conventional tablets or 20 mg daily as extended-release tablets. While glycemic control may improve with glipizide extended-release tablets in certain patients receiving dosages exceeding 10 mg daily, clinical studies to date have not demonstrated an additional group average reduction in HbA_1c beyond what was achieved with the 10-mg daily dosage. Dosages up to 50 mg daily have been employed in some patients. Although the mechanism(s) has not been elucidated and further documentation is needed, some clinicians have reported that an increase in glipizide maintenance dosage actually resulted in a worsening of diabetic control in a few patients.

Combination Therapy with Other Oral Antidiabetic Agents

Glipizide may be used in combination with other oral antidiabetic agents if glycemic control is inadequate with glipizide, either upon initiation of therapy or after a period of effectiveness. The second oral antidiabetic agent should be added to glipizide at the lowest recommended dosage, and patients should be observed carefully. Titration of the additional oral antidiabetic agent should be based on clinical judgment.

When glipizide is added to therapy with other antidiabetic agents, glipizide extended-release tablets may be initiated at a dosage of 5 mg daily. Initiation of therapy with glipizide extended-release tablets at a lower dosage may be appropriate in patients who may be more sensitive to oral hypoglycemic agents. Titration of glipizide as add-on therapy to another oral antidiabetic agent should be based on clinical judgment.

If the fixed combination of glipizide and metformin is used as initial therapy, the recommended initial dosage is 2.5 mg of glipizide and 250 mg of metformin hydrochloride once daily with a meal. In patients with more severe hyperglycemia (i.e., fasting plasma glucose concentrations of 280-320 mg/dL), an initial dosage of 2.5 mg of glipizide and 500 mg of metformin hydrochloride twice daily may be considered. Dosage may be increased in increments of one tablet (using the tablet strength at which therapy was initiated, either 2.5 mg glipizide/250 mg metformin hydrochloride or 2.5 mg glipizide/500 mg metformin hydrochloride) daily every 2 weeks until the minimum effective dosage required to achieve adequate glycemic control or a maximum daily dosage of 10 mg of glipizide and 2 g of metformin hydrochloride given in divided doses is reached. A total daily dosage exceeding 10 mg of glipizide and 2 g of metformin hydrochloride has not been evaluated in clinical trials in patients receiving the fixed-combination preparation as initial therapy. The efficacy of glipizide in fixed combination with metformin hydrochloride has not been established in patients with fasting plasma glucose concentrations exceeding 320 mg/dL.

When the commercially available fixed-combination preparation is used as second-line therapy in patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled by therapy with a sulfonylurea antidiabetic agent or metformin alone, the recommended initial dosage in previously treated patients is 2.5 or 5 mg of glipizide and 500 mg of metformin hydrochloride twice daily with the morning and evening meals. In order to minimize the risk of hypoglycemia, the initial dosage of glipizide and metformin hydrochloride in fixed combination should not exceed the daily dosage of glipizide or metformin hydrochloride previously received. The dosage of glipizide and metformin hydrochloride in fixed combination should be titrated upward in increments not exceeding 5 mg of glipizide and 500 mg of metformin hydrochloride until adequate glycemic control or a maximum daily dosage of 20 mg of glipizide and 2 g of metformin hydrochloride is reached.

For patients being switched from combination therapy using separate preparations of glipizide (or another sulfonylurea antidiabetic agent) and metformin, the initial dosage of the fixed-combination preparation should not exceed the daily dosages of glipizide (or equivalent dosage of another sulfonylurea) and metformin hydrochloride currently being taken. Such patients should be monitored for signs and symptoms of hypoglycemia following the switch. In the transfer from previous antidiabetic therapy to the fixed combination of glipizide and metformin hydrochloride, the decision to switch to the nearest equivalent dosage or to titrate dosage is based on clinical judgment. Hypoglycemia or hyperglycemia are possible in such patients, and any change in the therapy of type 2 diabetic patients should be undertaken with appropriate monitoring. The safety and efficacy of switching from combined therapy with separate preparations of glipizide (or another sulfonylurea antidiabetic agent) and metformin hydrochloride to the fixed-combination preparation containing these drugs have not been established in clinical studies.

Cautions

When glipizide is used in fixed combination with metformin, the cautions, precautions, and contraindications associated with metformin must be considered in addition to those associated with glipizide.

Hypoglycemia

Hypoglycemia may occur in patients receiving glipizide alone or in fixed combination with metformin. Hypoglycemia (defined as blood glucose of less than 60 mg/dL or symptoms associated with hypoglycemia) occurred in 3.4% of patients receiving glipizide extended-release tablets in clinical trials.Appropriate patient selection and careful attention to dosage are important to avoid glipizide-induced hypoglycemia.(See Cautions: Precautions and Contraindications.) Hypoglycemia may occur as a result of excessive glipizide dosage; however, since the development of hypoglycemia is a function of many factors, including diet, or exercise without adequate caloric supplementation, this effect may occur in some patients receiving usual dosages of the drug. Although glipizide-induced hypoglycemia has been reported infrequently and has usually been mild, severe hypoglycemia has occurred, principally in patients with predisposing conditions (e.g., impaired renal and/or hepatic function).

Management of glipizide-induced hypoglycemia depends on the severity of the reaction; patients with severe reactions require immediate hospitalization and treatment and observation until complete recovery is assured. Because of glipizide's elimination characteristics, the risk of prolonged hypoglycemia is likely to be low. Hypoglycemia is usually, but not always, readily controlled by administration of glucose. If hypoglycemia occurs during therapy with the drug, immediate reevaluation and adjustment of glipizide dosage and/or the patient's meal pattern are necessary.

For further discussion of the pathogenesis, manifestations, and treatment of glipizide-induced hypoglycemia, see Acute Toxicity.

Other Endocrine and Metabolic Effects

Therapy with sulfonylureas, including glipizide, may be associated with weight gain. Although the exact mechanisms associated with such alterations in weight have not been established, suggested mechanisms include an increase in insulin secretion (which may increase appetite), stimulation of lipogenesis in fat tissue, or an increase in blood leptin concentrations. Data from the United Kingdom Prospective Diabetes (UKPD) study in patients receiving long-term therapy (over 10 years) with glyburide and other antidiabetic agents indicate that weight gain was greatest in those receiving intensive therapy (stepwise introduction of a sulfonylurea then insulin or an oral sulfonylurea and insulin, or insulin alone to achieve fasting glucose concentrations of 108 mg/dL) than conventional therapy (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations less than 270 mg/dL without symptoms of hyperglycemia), and weight gain was greatest in those initially receiving insulin or chlorpropamide compared with those receiving glyburide.

GI Effects

Adverse GI effects such as nausea, anorexia, vomiting, pyrosis, gastralgia, diarrhea, and constipation are the most common adverse reactions to glipizide conventional tablets, occurring in about 1-2% of patients. Diarrhea or flatulence occurred in 5 or 3%, respectively, of patients receiving extended-release glipizide tablets in controlled clinical trials. Diarrhea was reported in 2.3-5.2 or 8.5% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as initial therapy for type 2 diabetes mellitus, and in 18.4 or 17.3% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy. Abdominal pain occurred in 5.7 or 6.7% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, in clinical trials as second-line therapy for type 2 diabetes mellitus. Nausea, dyspepsia, constipation, or vomiting occurred in less than 3% of patients receiving extended-release glipizide tablets in clinical trials. Anorexia, thirst, or trace blood in the stool has been reported in less than 1% of patients receiving extended-release glipizide in clinical trials. Nausea or vomiting was reported in 0.6-1.7 or 5.1% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as initial therapy for type 2 diabetes mellitus, and in 8% of patients receiving either the fixed combination of glipizide and metformin or metformin monotherapy as second-line therapy. Glipizide-induced adverse GI effects appear to be dose related and may subside following a reduction in dosage or administration of the drug in divided doses.

Dermatologic Effects

Allergic skin reactions including pruritus, erythema, eczema, urticaria, and morbilliform or maculopapular eruptions occur in about 1.5% of patients receiving glipizide conventional tablets. Rash or urticaria has been reported in less than 1% of patients receiving extended-release glipizide tablets in clinical trials. Glipizide-induced adverse dermatologic effects may be transient and disappear despite continued therapy; however, if adverse dermatologic effects persist with continued glipizide therapy, the drug should be discontinued. Photosensitivity reactions and porphyria cutanea tarda have been reported with other sulfonylurea antidiabetic agents.

Hepatic Effects

One case of glipizide-associated jaundice has been reported. Cholestatic jaundice has occurred with other sulfonylureas and is an indication for discontinuing glipizide. Although a causal relationship has not been established, mild to moderate increases in serum LDH, AST (SGOT), and alkaline phosphatase concentration have occurred occasionally in patients receiving glipizide. Exacerbation of hepatic porphyria has been reported with other sulfonylurea antidiabetic agents, but has not been reported to date with glipizide.

Hematologic Effects

Like other sulfonylurea antidiabetic agents, glipizide may rarely cause leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, and hemolytic anemia.

Nervous System Effects

Dizziness, drowsiness, and headache have been reported in about 2% of patients receiving glipizide conventional tablets, usually as manifestations of mild hypoglycemia. Asthenia, headache, dizziness, nervousness, pain, or tremor has been reported in 10, 9, 7, or 4% of patients receiving glipizide extended-release tablets in controlled clinical trials. Headache has been reported in 12.6 or 5.3% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy for type 2 diabetes mellitus. Dizziness has been reported in 1.7-5.2 or 1.1% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, in clinical trials as initial therapy for type 2 diabetes mellitus. Insomnia, paresthesia, anxiety, depression, and hypesthesia have been reported in less than 3% of patients receiving glipizide extended-release tablets in clinical trials. Chills, hypertonia, confusion, vertigo, somnolence, or gait abnormality has been reported in less than 1% of patients receiving extended-release glipizide in clinical trials.

Other Adverse Effects

Arthralgia, leg cramps, or myalgia has been reported in less than 3% of patients receiving extended-release glipizide in clinical trials. Musculoskeletal pain has been reported in 8 or 6.7% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy for type 2 diabetes mellitus. Syncope has been reported in less than 3%, and arrhythmia, migraine, flushing, hypertension, or edema has been reported less than 1% of patients receiving extended-release glipizide tablets in clinical trials. Hypertension has been reported in 2.9-3.5 or 5.6 % of patients receiving glipizide in fixed combination with metformin or metformin alone, respectively, as initial therapy for type 2 diabetes mellitus. Rhinitis has reported in less than 3%, and pharyngitis or dyspnea has been reported in than 1% of patients receiving extended-release glipizide tablets in clinical trials. Upper respiratory tract infection was reported in 8.1-9.9 or 8.5% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as initial therapy for type 2 diabetes mellitus, and in 10.3 or 10.7% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy. Blurred vision has been reported in less than 3%, and ocular pain, conjunctivitis, or retinal hemorrhage has been reported in less than 1% of patients receiving extended-release glipizide tablets in clinical trials. Although a causal relationship has not been established, mild to moderate increases in BUN and serum creatinine concentration have occurred occasionally in patients receiving glipizide. Urinary tract infection has been reported in 1.1 or 8% of patients receiving the fixed combination of glipizide and metformin or metformin monotherapy, respectively, as second-line therapy for type 2 diabetes mellitus. Decreased libido or polyuria has been reported in less than 3%, and dysuria has been reported in less than 1% of patients receiving extended-release glipizide tablets in clinical trials.

Like other sulfonylureas, hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have occurred in patients receiving glipizide.

Precautions and Contraindications

Glipizide shares the toxic potentials of other sulfonylurea antidiabetic agents, and the usual precautions associated with their use should be observed. The diagnostic and therapeutic measures for managing diabetes mellitus that are necessary to ensure optimum control of the disease with insulin generally are necessary with glipizide. Glipizide should only be prescribed for carefully selected patients by clinicians who are familiar with the indications, limitations, and patient-selection criteria for therapy with oral sulfonylurea antidiabetic agents.

Patients receiving glipizide should be monitored with regular clinical and laboratory evaluations, including blood and urine glucose determinations, to determine the minimum effective dosage and to detect primary failure (inadequate lowering of blood glucose concentration at the maximum recommended dosage) or secondary failure (loss of control of blood glucose concentration following an initial period of effectiveness) to the drug. Glycosylated hemoglobin (hemoglobin A_1c [HbA_1c]) measurements may also be useful for monitoring the patient's response to glipizide therapy. During the withdrawal period in patients in whom glipizide is replacing insulin, patients should be instructed to test their urine for glucose and ketones at least 3 times daily, and to report the results to their physician; when feasible, patient or laboratory monitoring of blood glucose concentration is preferable. Care should be taken to avoid ketosis, acidosis, and coma during the withdrawal period in patients being switched from insulin to glipizide. If adequate lowering of blood glucose concentration is no longer achieved during maintenance therapy with glipizide, the drug should be discontinued. When use of glipizide in asymptomatic type 2 diabetic patients is being considered, it should be recognized that control of blood glucose concentration in these patients has not been definitely established as effective for prevention of long-term cardiovascular or nervous system complications of the disease. There is limited evidence that sulfonylureas may reverse basement-membrane thickening of muscle capillaries in asymptomatic individuals with impaired glucose tolerance (chemical diabetes) and possibly reverse or retard the progression of microangiopathy in type 2 diabetic patients, but these findings require further evaluation.

Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents. In 1970, the University Group Diabetes Program (UGDP) reported that administration of oral antidiabetic agents (i.e., tolbutamide or phenformin) was associated with increased cardiovascular mortality as compared to treatment with dietary regulation alone or with dietary regulation and insulin. The UGDP reported that type 2 diabetic patients who were treated for 5-8 years with dietary regulation and a fixed dose of tolbutamide (1.5 g daily) had a cardiovascular mortality rate approximately 2.5 times that of patients treated with dietary regulation alone; although a substantial increase in total mortality was not observed, the use of tolbutamide was discontinued because of the increase in cardiovascular mortality, thereby limiting the ability of the study to show an increase in total mortality. The results of the UGDP study have been exhaustively analyzed, and there has been general disagreement in the scientific and medical communities regarding the study's validity and clinical importance. However, recent results from the United Kingdom Prospective Diabetes (UKPD) study, a large, long-term (over 10 years) study in newly diagnosed type 2 diabetic patients, did not confirm an increase in cardiovascular events or mortality in the group treated intensively with sulfonylureas, insulin, or combination therapy compared with less intensive conventional antidiabetic therapy.

In the UKPD study, the overall aggregate rates of death from macrovascular diseases such as myocardial infarction, sudden death, stroke, or peripheral vascular disease were not appreciably different among either intensive therapies (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide] then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) or less intensive conventional therapy (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia). However, a trend in reduction in fatal and nonfatal myocardial infarction with intensive therapy was noted with sulfonylurea or insulin, and epidemiologic analysis of the data indicate that each 1% decrease in HbA_1c was associated with an 18% reduction of fatal and nonfatal myocardial infarction. Among the single end points, the incidence of angina increased among patients receiving chlorpropamide, and blood pressure also was higher with chlorpropamide compared with glyburide or insulin intensive therapies. As a result of these and other findings (e.g., beneficial effects on microvascular [retinopathy, nephropathy, and possibly neuropathy] complications, confirmation of the beneficial effects of concomitant antihypertensive therapy and blood pressure lowering) of the UKDP study, the American Diabetes Association (ADA) currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients to outweigh the risks overall.

Patients should be fully and completely advised about the nature of diabetes mellitus, what they must do to prevent and detect complications, and how to control their condition.Patients should be informed of the potential risks and advantages of glipizide therapy and alternative forms of treatment. Patients should be instructed that dietary regulation is the principal consideration in the management of diabetes, and that glipizide therapy is only used as an adjunct to, and not a substitute for or a convenient means to avoid, proper dietary regulation. Patients should also be advised that they should not neglect dietary restrictions, develop a careless attitude about their condition, or disregard instructions about body-weight control, exercise, hygiene, and avoidance of infection. Primary and secondary failure to oral sulfonylurea antidiabetic agents should also be explained to patients.

Patients and responsible family members should be informed of the risks of hypoglycemia, the symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of hypoglycemic reactions, since these reactions may occasionally occur during therapy with glipizide.Appropriate patient selection and careful attention to dosage are important to avoid glipizide-induced hypoglycemia. Debilitated, malnourished, or geriatric patients and patients with impaired hepatic or renal function should be carefully monitored and dosage of glipizide should be carefully adjusted in these patients, since they may be predisposed to developing hypoglycemia (sometimes severe). Renal or hepatic insufficiency may cause increased serum concentrations of glipizide and hepatic insufficiency may also diminish gluconeogenic capacity, both of which increase the risk of severe hypoglycemic reactions. Alcohol ingestion, severe or prolonged exercise, deficient caloric intake, use of more than one antidiabetic agent, and adrenal or pituitary insufficiency may also predispose patients to the development of hypoglycemia. Hypoglycemia may be difficult to recognize in geriatric patients or in patients receiving β-adrenergic blocking agents. Intensive treatment (e.g., IV dextrose) and close medical supervision may be required in some patients who develop severe hypoglycemia during glipizide therapy.(See Acute Toxicity: Treatment.)

To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary discontinuance of glipizide and administration of insulin may be required.

As with other nondeformable material, extended-release glipizide tablets should be used with caution in patients with severe preexisting GI narrowing, since obstruction may occur. The inert portion of glipizide extended-release tablets is not absorbed and is excreted in feces where it may be noticeable. If cholestatic jaundice occurs or if adverse dermatologic effects occur and persist during glipizide therapy, the drug should be discontinued. Glipizide is contraindicated as sole therapy in patients with type 1 diabetes mellitus or in those with diabetes complicated by ketosis, acidosis, or diabetic coma. Like other sulfonylureas, glipizide is generally contraindicated in patients with severe renal or hepatic impairment. Glipizide is also contraindicated in patients with known hypersensitivity or allergy to the drug.

Pediatric Precautions

The manufacturer states that safety and efficacy of glipizide alone or in fixed combination with metformin in children have not been established. However, the American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance and convenience for the patient's family and a lack of evidence demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.

Geriatric Precautions

Safety and efficacy of glipizide extended-release tablets in geriatric patients have not been specifically studied to date; however, in clinical studies of the drug, approximately 33% of patients were 65 years of age or older. It has not been determined whether clinical trials of glipizide conventional tablets did not include sufficient numbers of patients 65 years and older to determine whether they respond differently than younger adults. Although no overall differences in safety or efficacy were observed between geriatric and younger patients in clinical studies of glipizide extended-release tablets, the possibility that some older patients may exhibit increased sensitivity cannot be ruled out. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturer suggests that patients in this age group receive initial dosages of the drug in the lower end of the usual range. Geriatric patients should be carefully monitored and dosage of glipizide should be carefully adjusted in these patients, since they may be predisposed to developing hypoglycemia (sometimes severe).

Mutagenicity and Carcinogenicity

It is not known if glipizide is mutagenic or carcinogenic in humans. The drug did not exhibit mutagenic activity in the Ames microbial mutagen test or in vivo in animal tests. Evidence of carcinogenicity was not observed in rats or mice receiving up to 75 times the maximum human dosage of glipizide daily for 20 or 18 months, respectively.

Pregnancy, Fertility, and Lactation

Although there are no adequate and controlled studies to date in humans, glipizide has been shown to be mildly fetotoxic in rats when given at doses of 5-50 mg/kg; the fetotoxic effect is perinatal and similar to that of some other sulfonylureas, and is believed to be directly related to the hypoglycemic effect of the drug. No teratogenic effects were observed in reproduction studies in rats or rabbits. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration. Use of glipizide in pregnant women is generally not recommended, and the drug should be used during pregnancy only when clearly necessary (e.g., when insulin therapy is infeasible). Prolonged, severe hypoglycemia lasting 4-10 days has been reported in some neonates born to women who were receiving other sulfonylurea antidiabetic agents up to the time of delivery; this effect has been reported more frequently with the use of those agents having prolonged elimination half-lives. To minimize the risk of neonatal hypoglycemia if glipizide is used during pregnancy, the manufacturer recommends that the drug be discontinued at least 1 month before the expected delivery date.

Reproduction studies in rats using glipizide doses up to 75 times the usual human dose have not revealed evidence of impaired fertility.

Although it is not known whether glipizide is distributed into milk in humans, some sulfonylurea antidiabetic agents are distributed into milk. Because of the potential for hypoglycemia in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. If glipizide is discontinued, and if dietary management alone is inadequate for controlling blood glucose concentration, administration of insulin should be considered.

Drug Interactions

Protein-bound Drugs

Because glipizide is highly protein bound, it theoretically could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylate and other nonsteroidal anti-inflammatory agents, and sulfonamides. However, unlike the protein binding of some other sulfonylurea antidiabetic agents (e.g., acetohexamide, chlorpropamide, tolazamide, tolbutamide) and like that of glyburide, the protein binding of glipizide is principally nonionic; in addition, glipizide appears to bind to different but closely related sites on serum albumin than does tolbutamide. Consequently, glipizide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature. In vitro studies indicate that glipizide does not displace dicumarol or salicylate from plasma proteins. Whether any differences in protein binding demonstrated in vitro will result in fewer clinically important drug interactions in vivo has not been established. There appears to be no clinically important interaction between indoprofen and glipizide. Patients receiving highly protein-bound drugs should be observed for adverse effects when glipizide therapy is initiated or discontinued and vice versa.

Cimetidine

Preliminary data indicate that cimetidine may potentiate the hypoglycemic effects of glipizide. The exact mechanism(s) of this interaction is not known, but cimetidine may inhibit hepatic metabolism of the sulfonylurea. Oral cimetidine has been shown to substantially increase the area under the plasma glipizide concentration-time curve and was associated with a substantial reduction in the postprandial increase in blood glucose concentration in diabetic patients receiving the drugs concomitantly. If cimetidine is administered concomitantly with glipizide, the patient should be closely monitored for signs and symptoms of hypoglycemia; dosage adjustment of glipizide may be necessary when cimetidine therapy is initiated or discontinued.

Thiazide Diuretics

Thiazide diuretics may exacerbate diabetes mellitus, resulting in increased requirements of sulfonylurea antidiabetic agents, temporary loss of diabetic control, or secondary failure to the antidiabetic agent. When thiazide diuretics are administered concomitantly with sulfonylurea antidiabetic agents, caution should be used.

Alcohol

Disulfiram-like reactions have occurred very rarely following the concomitant use of alcohol and glipizide.

β-Adrenergic Blocking Agents

Several potential interactions between β-adrenergic blocking agents and sulfonylurea antidiabetic agents exist. β-Adrenergic blocking agents may impair glucose tolerance; increase the frequency or severity of hypoglycemia; block hypoglycemia-induced tachycardia, but not hypoglycemic sweating which may actually be increased; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia;alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation. There is some evidence that many of these effects may be minimized by use of a β₁-selective adrenergic blocking agent rather than a nonselective β-adrenergic blocking agent. In one study in type 2 diabetic patients, tolbutamide-induced insulin secretion was not affected by short-term propranolol therapy, but the hypoglycemic action of a single dose of glipizide in conjunction with an oral glucose load appeared to be slightly reduced. It generally is recommended that concomitant use of β-adrenergic blocking agents and sulfonylurea antidiabetic agents be avoided when possible; if concomitant therapy is necessary, use of a β₁-selective adrenergic blocking agent may be preferred. When glipizide and a β-adrenergic blocking agent are used concomitantly, the patient should be monitored closely for altered antidiabetic response.

Antifungal Antibiotics

Concomitant use of certain antifungal antibiotics (i.e., miconazole, fluconazole) and oral antidiabetic agents has resulted in increased plasma concentrations of glipizide and/or hypoglycemia. In a study in healthy individuals, the area under the plasma concentration-time curve (AUC) of glipizide increased by 57% following concomitant administration with fluconazole (100 mg daily for 7 days). Clinically important hypoglycemia may be precipitated by concomitant use of oral hypoglycemic agents and fluconazole, and at least one fatality has been reported from hypoglycemia in a patient receiving glyburide and fluconazole concomitantly.

Other Drugs

Drugs that may enhance the hypoglycemic effect of sulfonylurea antidiabetic agents, including glipizide, include chloramphenicol, monoamine oxidase inhibitors, and probenecid. When these drugs are administered or discontinued in patients receiving glipizide, the patient should be observed closely for hypoglycemia or loss of diabetic control, respectively. When glipizide was administered to counter the hyperglycemic effect of diazoxide in several severely hypertensive nondiabetic patients with impaired renal function, hypoglycemic reactions resulted, prompting some clinicians to recommend that the drugs not be used concomitantly in such circumstances.

Drugs that may decrease the hypoglycemic effect of sulfonylurea antidiabetic agents, including glipizide, include nonthiazide diuretics (e.g., furosemide), corticosteroids, phenothiazines, thyroid agents, estrogens, oral contraceptives, phenytoin,nicotinic acid, sympathomimetic agents, calcium-channel blocking agents, rifampin, and isoniazid. When these drugs are administered or discontinued in patients receiving glipizide, the patient should be observed closely for loss of diabetic control or hypoglycemia, respectively.

Preliminary data suggest that glipizide may reduce the rate and/or extent of absorption of concomitantly administered oral xylose in type 2 diabetic patients.

Pharmacokinetics

Absorption

Glipizide is rapidly and essentially completely absorbed from the GI tract. First-pass metabolism of glipizide appears to be minimal, and the absolute oral bioavailability of the drug is reported to be 80-100%. Food delays the absorption of glipizide but does not affect peak serum concentrations achieved or the extent of absorption of the drug.

Following oral administration of a single 5-mg dose of glipizide as conventional tablets in fasting and nonfasting individuals, the drug appears in plasma or serum within 15-30 minutes and average peak plasma or serum concentrations of approximately 310-450 ng/mL usually are attained within 1-3 hours (range: 1-6 hours). Peak serum concentrations generally are delayed 20-40 minutes in the nonfasting state compared with the fasting state. A few reports indicate that biphasic peak serum concentrations may occur in some patients, suggesting that the drug may undergo enterohepatic circulation. The area under the serum concentration-time curve (AUC) for glipizide increases in proportion to increasing doses. Time to reach steady-state plasma glipizide concentrations following administration of glipizide extended-release tablets was delayed by 1-2 days in geriatric patients compared with younger patients.

Following administration of glipizide extended-release tablets in men with type 2 diabetes mellitus and patients younger than 65 years of age, steady-state plasma glipizide concentrations were achieved by at least the fifth day of dosing.

Following single oral doses of glipizide as conventional tablets in nonfasting diabetic or healthy individuals, plasma insulin concentration generally begins to increase within 10-30 minutes and is maximal within 0.5-2 hours; increased plasma insulin concentrations generally do not persist beyond the time of the meal challenge. Following single oral doses in fasting healthy individuals, the hypoglycemic action of glipizide generally begins within 15-30 minutes and is maximal within 1-2 hours. In nonfasting diabetic patients, the hypoglycemic action of a single morning dose of the drug may persist for up to 24 hours. Although a correlation between the plasma concentration of glipizide and its hypoglycemic effect has not been established, plasma insulin concentration was increased only when the plasma glipizide concentration was 200 ng/mL or higher in one study.

Distribution

Distribution of glipizide into human body tissues and fluids has not been fully characterized. Following IV administration of glipizide in mice, highest concentrations of the drug were attained in the liver and blood, with lower concentrations in the lungs, kidneys, adrenals, myocardium, salivary glands, and retroscapular fat; the drug was not detected in the brain or spinal cord. In humans, small amounts of glipizide are apparently distributed into bile and very small amounts are distributed into erythrocytes and saliva. Although glipizide apparently did not cross the placenta in mice in one study, the drug was detected in the fetuses of pregnant rats given the drug. It is not known if glipizide is distributed into milk in humans.

Following IV administration in humans, glipizide undergoes rapid distribution. Following IV administration of the drug, the volumes of distribution in the central compartment and at steady-state average 4.2-4.6 L (range: 3.5-13.2 L) and 10.2-11.7 L (range: 4.6-15.1 L), respectively, suggesting that the drug is distributed principally within extracellular fluid. Although pharmacokinetic data from one single-dose study suggest that glipizide might accumulate in a deep tissue compartment, data from other single-dose studies suggest that the drug does not accumulate in tissue depots.

At a concentration of 9-612 ng/mL, glipizide is approximately 92-99% bound to plasma proteins. Glipizide has a lower affinity for binding to serum albumin than does glyburide. Unlike the protein binding of some other sulfonylurea antidiabetic agents (e.g., acetohexamide, chlorpropamide, tolazamide, tolbutamide) and like that of glyburide, the protein binding of glipizide appears to be principally nonionic; consequently, glipizide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature.(See Drug Interactions: Protein-Bound Drugs.)

Elimination

Following IV administration, serum concentrations of glipizide decline in a biphasic manner. Following IV administration of glipizide in healthy individuals or diabetic patients with normal renal and hepatic function, the half-life of the drug averages 8.4-36 minutes (range: 4-36 minutes) in the initial phase and 2.1-3.6 hours (range: 1.1-3.7 hours) in the terminal phase. Following oral administration in healthy individuals or diabetic patients with normal renal and hepatic function, the terminal elimination half-life of glipizide averages 3-4.7 hours (range: 2-7.3 hours). The terminal elimination half-life of total glipizide metabolites reportedly ranges from 2-6 hours in patients with normal renal and hepatic function. Serum glipizide concentrations may be increased in patients with renal or hepatic insufficiency. Data are limited, but the terminal elimination half-life of unchanged glipizide does not appear to be substantially increased in patients with impaired renal function. The terminal elimination half-life of total glipizide metabolites may be prolonged to greater than 20 hours in patients with impaired renal function; however, since glipizide metabolites are considered essentially inactive, this is probably of little clinical importance, at least in patients with moderate renal impairment.

Glipizide is almost completely metabolized, mainly in the liver. The drug is metabolized principally at the cyclohexyl ring to 4-trans-hydroxyglipizide; the drug is also metabolized to the 3-cis-hydroxy derivative, N-(2-acetylaminoethylphenylsulfonyl)-N'-cyclohexyl urea (DCDA), and at least 2 unidentified metabolites.

Glipizide and its metabolites are excreted principally in urine. The drug and its metabolites are also excreted in feces, apparently almost completely via biliary elimination; only small amounts may be excreted in feces as unabsorbed drug following oral administration. Most urinary excretion occurs within the first 6-24 hours after oral administration of the drug. Following oral administration of a single 5-mg dose of glipizide in individuals with normal renal and hepatic function, approximately 60-90% of the dose is excreted in urine as unchanged drug and metabolites within 24-72 hours and about 5-20% is excreted in feces within 24-96 hours; less than 10% of a dose is excreted in urine as unchanged drug within 24 hours, about 20-60% as the 4-trans-hydroxy metabolite, 10-15% as the 3-cis-hydroxy metabolite, 1-2% as DCDA, and the remainder as unidentified metabolites.

Total plasma or serum clearance of glipizide reportedly averages 21-38 mL/hour per kg in individuals with normal renal and hepatic function. Renal clearance of unchanged glipizide increases substantially with increasing urinary pH, but is only about 5% of total plasma clearance at urinary pH of 5-6; the low renal clearance indicates that the drug undergoes renal tubular reabsorption. The effects have not been fully evaluated, but elimination of glipizide may be reduced in patients with impaired renal and/or hepatic function. Limited data indicate that renal excretion and terminal elimination half-life of glipizide metabolites are substantially decreased and increased, respectively, in patients with severe renal impairment.