Glipizide Er Information
Glipizide er ()
Glipizide er () Description
Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.
The Chemical Abstracts name of glipizide is 1-Cyclohexyl-3-[[-[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea. The molecular formula is CHNOS; the molecular weight is 445.55; the structural formula is shown below:
Glipizide is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 NaOH; it is freely soluble in dimethylformamide.
Glipizide extended-release tablets are formulated as a polymer matrix based once-a-day controlled release tablet for oral use and is designed to deliver 2.5 mg, 5 mg or 10 mg of glipizide. Each tablet contains the following inactive ingredients: acetyltributyl citrate, edible black ink, hydroxyethyl cellulose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer type A and polyethylene glycol.
The 2.5 mg and 5 mg tablets also contain FD&C Yellow #6.
Glipizide er () Clinical Pharmacology
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 also may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Two extrapancreatic effects shown to be important in the action of glipizide are an increase in insulin sensitivity and a decrease in hepatic glucose production. However, the mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. Stimulation of insulin secretion by glipizide in response to a meal is of major importance. The insulinotropic response to a meal is enhanced with glipizide administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. In 2 randomized, double-blind, dose-response studies comprising a total of 347 patients, there was no significant increase in fasting insulin in all glipizide-treated patients combined compared to placebo, although minor elevations were observed at some doses. There was no increase in fasting insulin over the long term.
Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs, including glipizide. Alternatively, glipizide may be effective in some patients who have not responded or have ceased to respond to other sulfonylureas.
The effectiveness of glipizide extended-release tablets in type 2 diabetes at doses from 5-60 mg once daily has been evaluated in 4 therapeutic clinical trials each with long-term open extensions involving a total of 598 patients. Once daily administration of 5, 10 and 20 mg produced statistically significant reductions from placebo in hemoglobin A, fasting plasma glucose and postprandial glucose in patients with mild to severe type 2 diabetes. In a pooled analysis of the patients treated with 5 mg and 20 mg, the relationship between dose and glipizide extended-release tablet's effect of reducing hemoglobin A was not established. However, in the case of fasting plasma glucose patients treated with 20 mg had a statistically significant reduction of fasting plasma glucose compared to the 5 mg-treated group.
The reductions in hemoglobin A and fasting plasma glucose were similar in younger and older patients. Efficacy of glipizide extended-release tablets was not affected by gender, race or weight (as assessed by body mass index). In long term extension trials, efficacy of glipizide extended-release tablets was maintained in 81% of patients for up to 12 months.
In an open, two-way crossover study 132 patients were randomly assigned to either glipizide extended-release tablets or glipizide tablets for 8 weeks and then crossed over to the other drug for an additional 8 weeks. Glipizide extended-release tablets administration resulted in significantly lower fasting plasma glucose levels and equivalent hemoglobin A levels, as compared to glipizide tablets.
It has been shown that glipizide extended-release tablet therapy is effective in controlling blood glucose without deleterious changes in the plasma lipoprotein profiles of patients treated for type 2 diabetes.
In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity, and, in fact, led to a slight increase in free water clearance.
Glipizide is rapidly and completely absorbed following oral administration in an immediate release dosage form. The absolute bioavailability of glipizide was 100% after single oral doses in patients with type 2 diabetes. Beginning 2 to 3 hours after administration of glipizide extended-release tablets, plasma drug concentrations gradually rise reaching maximum concentrations within 6 to 12 hours after dosing. With subsequent once daily dosing of glipizide extended-release tablets, effective plasma glipizide concentrations are maintained throughout the 24 hour dosing interval with less peak to trough fluctuation than that observed with twice daily dosing of immediate release glipizide. The mean relative bioavailability of glipizide in 21 males with type 2 diabetes after administration of 20 mg glipizide extended-release tablets, compared to immediate release glipizide (10 mg given twice daily), was 90% at steady-state. Steady-state plasma concentrations were achieved by at least the fifth day of dosing with glipizide extended-release tablets in 21 males with type 2 diabetes and patients younger than 65 years. Approximately 1 to 2 days longer were required to reach steady-state in 24 elderly (≥65 years) males and females with type 2 diabetes. No accumulation of drug was observed in patients with type 2 diabetes during chronic dosing with glipizide extended-release tablets. Administration of glipizide extended-release tablets with food has no effect on the 2 to 3 hour lag time in drug absorption. In a single dose, food effect study in 21 healthy male subjects, the administration of glipizide extended-release tablets immediately before a high fat breakfast resulted in a 40% increase in the glipizide mean C value, which was significant, but the effect on the AUC was not significant. There was no change in glucose response between the fed and fasting state. Markedly reduced GI retention times of the glipizide extended-release tablets over prolonged periods (e.g., short bowel syndrome) may influence the pharmacokinetic profile of the drug and potentially result in lower plasma concentrations. In a multiple dose study in 26 males with type 2 diabetes, the pharmacokinetics of glipizide were linear over the dose range of 5 to 60 mg of glipizide extended-release tablets in that the plasma drug concentrations increased proportionately with dose. In a single dose study in 24 healthy subjects, four 5 mg, two 10 mg, and one 20 mg glipizide extended-release tablets were bioequivalent. In a separate single dose study in 36 healthy subjects, four 2.5 mg glipizide extended-release tablets were bioequivalent to one 10 mg glipizide extended-release tablet.
Glipizide is eliminated primarily by hepatic biotransformation: less than 10% of a dose is excreted as unchanged drug in urine and feces; approximately 90% of a dose is excreted as biotransformation products in urine (80%) and feces (10%). The major metabolites of glipizide are products of aromatic hydroxylation and have no hypoglycemic activity. A minor metabolite which accounts for less than 2% of a dose, an acetylamino-ethyl benzene derivative, is reported to have 1/10 to 1/3 as much hypoglycemic activity as the parent compound. The mean total body clearance of glipizide was approximately 3 liters per hour after single intravenous doses in patients with type 2 diabetes. The mean apparent volume of distribution was approximately 10 liters. Glipizide is 98-99% bound to serum proteins, primarily to albumin. The mean terminal elimination half-life of glipizide ranged from 2 to 5 hours after single or multiple doses in patients with type 2 diabetes. There were no significant differences in the pharmacokinetics of glipizide after single dose administration to older diabetic subjects compared to younger healthy subjects. There is only limited information regarding the effects of renal impairment on the disposition of glipizide, and no information regarding the effects of hepatic disease. However, since glipizide is highly protein bound and hepatic biotransformation is the predominant route of elimination, the pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with renal or hepatic impairment.
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.
Glipizide er () Indications And Usage
Glipizide extended-release tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Glipizide er () Contraindications
Glipizide extended-release tablets are contraindicated in patients with:
Glipizide er () Warnings
As with any other non-deformable material, caution should be used when administering glipizide extended-release tablets in patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of another drug in this non-deformable sustained release formulation.
Glipizide er () Precautions
Macrovascular Outcomes:
Renal and Hepatic Disease:
GI Disease:
Hypoglycemia:
Loss of Control of Blood Glucose:
The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.
Patients should be informed that glipizide extended-release tablets should be swallowed whole. Patients should not chew, divide or crush tablets.
Patients should be informed of the potential risks and advantages of glipizide extended-release tablets and of alternative modes of therapy. They should also be informed about the importance of adhering to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.
The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure also should be explained.
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents 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, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for loss of control. 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 with these drugs.
Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the 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, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for hypoglycemia.
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 daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after fluconazole administration was 56.9% (range: 35 to 81%).
Glipizide er () Adverse Reactions
In U.S. controlled studies the frequency of serious adverse experiences reported was very low and causal relationship has not been established.
The 580 patients from 31 to 87 years of age who received glipizide extended-release tablets in doses from 5 mg to 60 mg in both controlled and open trials were included in the evaluation of adverse experiences. All adverse experiences reported were tabulated independently of their possible causal relation to medication.
Only 3.4% of patients receiving glipizide extended-release tablets had hypoglycemia documented by a blood-glucose measurement
In double-blind, placebo-controlled studies the adverse experiences reported with an incidence of 3% or more in glipizide extended-release tablet-treated patients include:
The following adverse experiences occurred with an incidence of less than 3% in glipizide extended-release tablet-treated patients:
Body as a whole–pain
Nervous system–insomnia, paresthesia, anxiety, depression and hypesthesia
Gastrointestinal–nausea, dyspepsia, constipation and vomiting
Metabolic–hypoglycemia
Musculoskeletal–arthralgia, leg cramps and myalgia
Cardiovascular–syncope
Skin–sweating and pruritus
Respiratory–rhinitis
Special senses–blurred vision
Urogenital–polyuria
Other adverse experiences occurred with an incidence of less than 1% in glipizide extended-release tablet-treated patients:
Body as a whole–chills
Nervous system–hypertonia, confusion, vertigo, somnolence, gait abnormality and decreased libido
Gastrointestinal–anorexia and trace blood in stool
Metabolic–thirst and edema
Cardiovascular–arrhythmia, migraine, flushing and hypertension
Skin–rash and urticaria
Respiratory–pharyngitis and dyspnea
Special senses–pain in the eye, conjunctivitis and retinal hemorrhage
Urogenital–dysuria
Although these adverse experiences occurred in patients treated with glipizide extended-release tablets, a causal relationship to the medication has not been established in all cases.
There have been rare reports of gastrointestinal irritation and gastrointestinal bleeding with use of another drug in this non-deformable sustained release formulation, although causal relationship to the drug is uncertain.
In post-marketing experience of glipizide extended-release tablets, the additional adverse reaction of abdominal pain has been reported.
The following are adverse experiences reported with immediate release glipizide and other sulfonylureas, but have not been observed with glipizide extended-release tablets:
Glipizide er () Overdosage
There is no well-documented experience with glipizide extended-release tablets overdosage in humans. There have been no known suicide attempts associated with purposeful overdosing with glipizide extended-release tablets. In nonclinical studies the acute oral toxicity of glipizide was extremely low in all species tested (LD greater than 4 g/kg). Overdosage of sulfonylureas including glipizide can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic 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 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 may be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.
Glipizide er () Dosage And Administration
There is no fixed dosage regimen for the management of diabetes mellitus with glipizide extended-release tablets or any other hypoglycemic agent. Glycemic control should be monitored with hemoglobin A and/or blood-glucose levels to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response after an initial period of effectiveness. Home blood-glucose monitoring may also provide useful information to the patient and physician. Short-term administration of glipizide extended-release tablets may be sufficient during periods of transient loss of control in patients usually controlled on diet.
In general, glipizide extended-release tablets should be given with breakfast.
Dosage adjustment should be based on laboratory measures of glycemic control. While fasting blood-glucose levels generally reach steady-state following initiation or change in glipizide extended-release tablet dosage, a single fasting glucose determination may not accurately reflect the response to therapy. In most cases, hemoglobin A level measured at three month intervals is the preferred means of monitoring response to therapy.
Hemoglobin A should be measured as glipizide extended-release tablet therapy is initiated and repeated approximately three months later. If the result of this test suggests that glycemic control over the preceding three months was inadequate, the glipizide extended-release tablet dose may be increased. Subsequent dosage adjustments should be made on the basis of hemoglobin A levels measured at three month intervals. If no improvement is seen after three months of therapy with a higher dose, the previous dose should be resumed. Decisions which utilize fasting blood glucose to adjust glipizide extended-release tablet therapy should be based on at least two or more similar, consecutive values obtained seven days or more after the previous dose adjustment.
Most patients will be controlled with 5 mg to 10 mg taken once daily. However, some patients may require up to the maximum recommended daily dose of 20 mg. While the glycemic control of selected patients may improve with doses which exceed 10 mg, clinical studies conducted to date have not demonstrated an additional group average reduction of hemoglobin A beyond what was achieved with the 10 mg dose.
Based on the results of a randomized crossover study, patients receiving immediate release glipizide may be switched safely to glipizide extended-release tablets once-a-day at the nearest equivalent total daily dose. Patients receiving immediate release glipizide also may be titrated to the appropriate dose of glipizide extended-release tablets starting with 5 mg once daily. The decision to switch to the nearest equivalent dose or to titrate should be based on clinical judgment.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see section).
When adding glipizide extended-release tablets to other blood-glucose-lowering agents, glipizide extended-release tablets can be initiated at 5 mg. Those patients who may be more sensitive to hypoglycemic drugs may be started at a lower dose. Titration should be based on clinical judgment.
For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and glipizide extended-release tablet therapy may begin at usual dosages. Several days should elapse between titration steps.
For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced by 50% and glipizide extended-release tablet therapy may begin at usual dosages. Subsequent reductions in insulin dosage should depend on individual patient response. Several days should elapse between titration steps.
During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies at least three times daily. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when the patient has been receiving greater than 40 units of insulin daily, it may be advisable to consider hospitalization during the transition period.
Glipizide er () Patient Information
Read this information carefully before you start taking this medicine. Read the information you get with your medicine each time you refill your prescription. There may be new information. This information does not take the place of your healthcare provider’s advice. Ask your healthcare provider or pharmacist if you do not understand some of this information or if you want to know more about this medicine.
Glipizide er () is a medicine you take by mouth. It is used to treat type 2 diabetes (also called non-insulin-dependent diabetes mellitus). Your healthcare provider has prescribed Glipizide er () because your current treatment, including diet and exercise, has not been able to bring your blood sugar level under good control.
Your body makes insulin to keep the amount of sugar (glucose) in your blood at the right level. With type 2 diabetes:
If your blood sugar level is not under control, it can lead to serious medical problems, such as kidney damage, nerve damage, blindness, problems with circulation (blood movement in your body), loss of feet, legs, or other limbs, high blood pressure, heart attack, or stroke.
Glipizide er () works mainly by:
Even after you start taking Glipizide er () , you must continue to follow your program of diet and exercise.
Do not use Glipizide er () if you:
Only your healthcare provider can decide if Glipizide er () is right for you. Before you start Glipizide er () , tell the healthcare provider if you:
Glipizide er () tablets come in three different strengths (2.5 mg, 5 mg and 10 mg). Your healthcare provider will prescribe the dose that is right for you.
It is important to take Glipizide er () every day to help keep your blood sugar level under good control. Your healthcare provider may adjust your dose depending on your blood glucose test results. If your blood sugar level is not under control, call your healthcare provider. Do not change your dose without your healthcare provider's approval.
In case of overdose, call the poison control center or your healthcare provider right away, or have someone drive you to the nearest emergency room.
You must continue your diet and exercise program while taking Glipizide er () . You must also have your blood and urine tested regularly to be sure Glipizide er () is working.
Glipizide er () may not work for everyone. If it does work, you may find that Glipizide er () is not working as well for you after you have used it for a while. Tell your healthcare provider if Glipizide er () is not working well.
Be sure you know how to recognize your body’s signs that your blood sugar is too low. These signs include:
If you notice any of these signs, eat or drink something with sugar in it right away, such as a regular (not diet) soft drink, orange juice, honey, sugar candy. You can also keep glucose tablets on hand that are available at your pharmacy. If you do not feel better shortly or your blood sugar level does not go up, call your healthcare provider. If you cannot reach your healthcare provider in an emergency, call 911 or have someone drive you to the nearest emergency room.
Glipizide er () may cause other less common side effects besides those listed here. For a list of all side effects that have been reported, ask your healthcare provider or pharmacist.
While it has never been reported with Glipizide er () , another similar type of diabetes medicine has been linked to a higher risk of heart attacks. If you have risk factors for heart disease and take Glipizide er () , be sure to see your healthcare provider for regular checkups.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Keep Glipizide er () and all medicines out of the reach of children. Store Glipizide er () in a dry place, in its original container, and at room temperature (between 68°-77°F or 20°-25°C).
Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. If you have any concerns about Glipizide er () , ask your healthcare provider. Your healthcare provider or pharmacist can give you information about Glipizide er () that was written for healthcare professionals. Do not use Glipizide er () for a condition for which it was not prescribed. Do not share Glipizide er () with other people.
Corona, CA 92880 USA
Cincinnati, OH 45237 USA
January 2009
Glipizide er () Glipizide Er Mg Tablet
