Glucotrol XL

Glucotrol XL

glipizide

Manufacturer:

Pfizer
Full Prescribing Info
Contents
Glipizide GITS.
Description
Each tablet also contains the following inert ingredients: Polyethylene oxide, hydroxypropyl methylcellulose, ferric oxide and magnesium stearate, cellulose acetate, polyethylene glycol, sodium chloride, Opadry (white or light blue) and black ink.
Glipizide is 1-cyclohexyl-3-[4-[2-(5-methylpyrazine-2-carboxamido)ethyl]benzenesulfonyl]urea.
Glipizide is a member of a group of sulfonamide drugs which are widely used as hypoglycemic agents for the treatment of non-insulin dependent diabetes.
Action
Pharmacology: Glipizide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning β-cells in the pancreatic islets. Stimulation of insulin secretion by glipizide in response to a meal is of major importance. The insulinotropic response to a meal is enhanced with Glucotrol XL administration in diabetic patients. The postprandial insulin and C-peptide responses continue to be enhanced after at least 6 months of treatment. Reductions in HbA1C and fasting plasma glucose were similar in younger and older patients.
Other Effects: One study has shown that glipizide GITS therapy is effective in controlling blood glucose without deleterious effects on the plasma lipoprotein profiles of patients treated for type 2 diabetes. Those changes were well correlated with the reduction achieved in fasting glucose levels.
Pharmacokinetics: Beginning 2-3 hrs after administration of Glucotrol XL, plasma drug concentrations gradually rise reaching maximum concentrations within 6-12 hrs after dosing. With subsequent once-daily dosing of Glucotrol XL, effective plasma glipizide concentrations are maintained throughout the 24-hr 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 Glucotrol XL 20 mg, compared to immediate-release glipizide (10 mg given twice daily) was 81 ± 22% at steady state.
Steady-state plasma concentrations were achieved by at least the 5th day of dosing with Glucotrol XL. Approximately 1-2 days longer were required to reach steady state in patients >65 years. No accumulation of drug was observed in patients with type 2 diabetes during chronic dosing with Glucotrol XL. Administration of Glucotrol XL with food has no effect on the 2-3 hrs lag time in drug absorption. In a single dose, food effect study, the administration of Glucotrol XL immediately before a high-fat breakfast resulted in a 40% increase in the glipizide mean Cmax 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 Glucotrol XL over prolonged periods (eg, 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 Glucotrol XL 5-60 mg 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 Glucotrol XL tablets were bioequivalent.
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%). Glipizide is 98-99% bound to serum proteins, primarily to albumin.
Toxicology: Preclinical Safety Data: In nonclinical studies, the acute oral toxicity of glipizide was extremely low in all species tested (LD50 >4 g/kg). Acute toxicity studies showed no specific susceptibility. Chronic toxicity tests in rats and dogs at doses up to 8 mg/kg did not show any evidence of toxic effects.
A 20-month study in rats and an 18-month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.
Indications/Uses
As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (non-insulin dependent diabetes mellitus).
Dosage/Direction for Use
As for any hypoglycemic agent, dosage must be adapted for each individual case. The GITS tablets should be swallowed whole with a sufficient amount of liquid. Patients should not chew, divide or crush the tablets. (See Precautions).
Initial Dose: The recommended starting dose of glipizide GITS is 5 mg/day, given with breakfast. For elderly patients and other patients at risk for hypoglycemia, see Elderly and High-Risk Patients.
Titration: Dosage adjustments may be in increments of 2.5 or 5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. Steady-state plasma glipizide levels were achieved by the 5th day of dosing with glipizide GITS. Elderly patients may require 1-2 days longer.
Maintenance: Patients are effectively controlled on a once-a-day regimen. The maximum recommended dosage is 20 mg since the maximum blood glucose-lowering effect is observed at this level. Patients receiving immediate release glipizide between 5 and 20 mg daily may be switched safely to glipizide GITS once-a-day at the nearest equivalent or lower total daily dose.
Children: Safety and effectiveness in children have not been established.
Elderly and High-Risk Patients: To decrease the risk of hypoglycemia in patients at risk including elderly patients, debilitated, malnourished or patients with irregular caloric intake and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions. Studies in approximately 200 patients ≥65 years indicate that glipizide GITS is as safe and effective in this age group as in those patients <65 years.
Patients Receiving Insulin: As with other sulfonylurea-class hypoglycemics, many stable non-insulin dependent diabetic patients receiving insulin may be transferred safely to treatment with Glucotrol XL extended-release tablets. When transferring patients from insulin to Glucotrol XL, the following general guidelines should be considered:
For patients whose daily insulin requirement is ≤20 units, insulin may be discontinued and Glucotrol XL therapy may begin at usual dosages. Several days should elapse between titration steps.
For patients whose daily insulin requirement is >20 units, the insulin dose should be reduced by 50% and Glucotrol XL therapy may begin at usual dosages. Subsequent reduction in insulin dosage should depend on individual patient response. Several days should elapse between titration steps.
During the insulin withdrawal period, the patient should self monitor glucose levels. Patients should be instructed to contact the prescriber immediately if these tests are abnormal. In some cases, especially when the patient has been receiving >40 units of insulin daily, it may be advisable to consider hospitalization during the transition period.
Patients Receiving Other Oral Hypoglycemic Agents: As with other sulfonylurea, when switching patients to Glucotrol XL GITS from another sulfonylurea they should be observed carefully for hypoglycemia (eg, by symptoms or by blood glucose monitoring) for at least 2 weeks. When switching patients to Glucotrol XL GITS a conservative dose is recommended. When adding other blood-glucose-lowering agents to Glucotrol XL GITS for combination therapy, the agent should be initiated at the lowest recommended dose, and patients should be observed carefully for hypoglycemia. Refer to the product information supplied with the oral agent for additional information.
When adding Glucotrol XL to other blood-glucose-lowering agents, it 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 judgement.
Overdosage
There is no well-documented experience with Glucotrol XL overdosage in humans. 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 IV 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 >100 mg/dL. Patients should be closely monitored for a minimum of 24-48 hrs 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.
Contraindications
Known hypersensitivity to glipizide or to any of the excipients in the GITS tablets. Type 1 diabetes, diabetic ketoacidosis, diabetic coma. Severe renal or hepatic insufficiency.
Special Precautions
G6PD Deficiency: Since glipizide GITS belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency. Treatment of patients with G6PD deficiency with sulfonylurea agents can lead to haemolytic anemia and a nonsulfonylurea alternative should be considered.
Hypoglycemia: All sulfonylurea drugs, including glipizide GITS are capable of producing severe hypoglycemia which may result in coma, and may require hospitalization. Patients experiencing severe hypoglycemia should be managed with appropriate glucose therapy and should be monitored for a minimum of 24-48 hrs.
Proper patient selection, dosage and instructions are important to avoid hypoglycemic episodes. Regular, timely carbohydrate intake, including breakfast, is important to avoid hypoglycemic events occurring when a meal is delayed or insufficient food is eaten or carbohydrate intake is unbalanced.
Renal or hepatic insufficiency may affect the disposition of glipizide and may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic-blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.
Loss of Control of Blood Glucose: When a patient stabilized on a diabetic regimen is exposed to stress eg, fever, trauma, infection or surgery, a loss of control may occur. At such times, it may be necessary to discontinue glipizide GITS and administer insulin.
The effectiveness of any oral hypoglycemic drug, including glipizide GITS, in lowering blood glucose to a desired level decreases in many patients over a period of time. This 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.
Laboratory Tests: Blood glucose should be monitored periodically. Measurement of glycosylated hemoglobin should be performed and goals assessed by the current standard of care.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Glucotrol XL or any other antidiabetic drug.
Renal and Hepatic Disease: The pharmacokinetics and/or pharmacodynamics of glipizide GITS may be affected in patients with impaired renal or hepatic function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate management should be instituted.
Gastrointestinal Disease: Markedly reduced GI retention times of Glucotrol XL may influence the pharmacokinetic profile and hence the clinical efficacy of the drug. As with any other nondeformable material, caution should be used when administering Glucotrol XL in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known structures in association with the ingestion of another drug in this nondeformable sustained-release formulation.
Information for Patients: The risk 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. Patients should be informed that Glucotrol XL should be swallowed whole. Patients should not chew, divide or crush the tablets. Patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. In Glucotrol XL, the medication is contained within a non-absorbable shell that has been specially designed to slowly release the drug so the body can absorb it. When this process is completed, the empty tablet is eliminated from the body.
Patients should be informed of the potential risks and advantages of glipizide 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 blood glucose.
Effects on the Ability to Drive or Operate Machinery: The effect of glipizide GITS on the ability to drive or operate machinery has not been studied, however, there is no evidence to suggest that glipizide may affect these abilities. Patient should be aware of the symptoms of hypoglycemia and be careful about driving and the use of machinery.
Use in pregnancy: Glipizide GITS was found to be mildly fetotoxic in rat reproductive studies. No teratogenic effects were found in rat or rabbit studies.
Glucotrol XL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many exports recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Prolonged severe hypoglycemia (4-10 days) has been reported in neonates born to mother who were receiving a sulfonylurea drug at the time of delivery. If glipizide GITS is used during pregnancy, it should be discontinued at least 1 month before the expected delivery date and other therapies instituted to maintain blood glucose levels as close to normal as possible.
Use in lactation: Although it is not known whether glipizide GITS is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Use In Pregnancy & Lactation
Use in pregnancy: Glipizide GITS was found to be mildly fetotoxic in rat reproductive studies. No teratogenic effects were found in rat or rabbit studies.
Glucotrol XL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many exports recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Prolonged severe hypoglycemia (4-10 days) has been reported in neonates born to mother who were receiving a sulfonylurea drug at the time of delivery. If glipizide GITS is used during pregnancy, it should be discontinued at least 1 month before the expected delivery date and other therapies instituted to maintain blood glucose levels as close to normal as possible.
Use in lactation: Although it is not known whether glipizide GITS is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Side Effects
As with other sulphonylureas, there is possibility of the following events: Nervous System Disorders: Headache, tremor have been reported in patients treated with glipizide GITS.
Gastrointestinal Disorders: Abdominal pain, nausea, constipation, diarrhea, epigastric discomfort and vomiting.
Blood and Lymphatic System Disorders: Leucopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia and pancytopenia.
Hepatobiliary Disorders: Cholestatic jaundice, toxic hepatitis and hepatic porphyria. Discontinue treatment if cholestatic jaundice occurs. Hepatic porphyria has been reported with sulfonylureas.
Investigations: Occasional mild to moderate elevations of SGOT, LDH, alkaline phosphatase, BUN and creatinine. The relationship to glipizide is uncertain.
Metabolism and Nutrition Disorders: Hypoglycemia may be severe, prolonged and may result in coma. Hyponatremia has been reported. Disulfiram-like reactions have been reported with sulfonylureas.
Psychiatric Disorders: Confusion (this is usually transient and does not require discontinuation of therapy; however, it may also be a symptom of hypoglycemia).
Skin and Subcutaneous Tissue Disorders: Allergic skin reactions including mucocutaneous, eruptions, pruritus, urticaria, maculopapular eruptions.
Eye Disorders: Visual disturbances eg, blurred vision and decreased vision have been reported in patients treated with glipizide GITS.
Drug Interactions
The following products are likely to increase the hypoglycemic effect: Miconazole: Increased in hypoglycemic effect, possibly leading to symptoms of hypoglycemia or even coma.
Fluconazole: There have been reports of hypoglycemia following the co-administration of glipizide and fluconazole, possibly the result an increased half-life of glipizide.
Voriconazole: Although not studied, voriconazole may increase the plasma levels of sulfonylureas, (eg, tolbutamide, glipizide and glyburide), and therefore cause hypoglycemia. Careful monitoring of blood glucose is recommended during co-administration.
Nonsteroidal Anti-Inflammatory Agents (NSAIDS) (eg, Phenylbutazone): Increased hypoglycemic effect of sulfonylureas (displacement of sulfonylurea binding to plasma proteins and/or decrease in sulfonylurea elimination).
Salicylates (Acetylsalicylic Acid): Increased in hypoglycemic effect by high doses of acetylsalicylic acid (hypoglycemic action of the acetylsalicylic acid).
Alcohol: Increased hypoglycemic reaction which can lead to hypoglycemic coma.
Beta-Blockers: All β-blockers mask some of the symptoms of hypoglycemic eg, palpitations and tachycardia. Most noncardioselective β-blockers increase the incidence and severity of hypoglycemia.
Angiotensin-Converting Enzyme Inhibitors: The use of angiotensin-converting enzyme inhibitors may lead to an increased hypoglycemic effect in diabetic patients treated with sulfonylureas, including glipizide GITS. Therefore, a reduction in glipizide dosage may be required.
H2-Receptor Antagonists: The use of H2-receptor antagonists (ie, cimetidine) may potentiate the hypoglycemic effects of sulfonylureas, including glipizide.
The hypoglycemic action of sulfonylureas in general may also be potentiated by monoamine oxidase inhibitors and drugs that are highly protein-bound eg, sulfonamides, chloramphenicol, probenecid, coumarins. When such drugs are administered to (or withdrawn from) a patient receiving glipizide GITS, the patient should be observed closely for hypoglycemia (or loss of control). In vitro binding studies with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact with salicylate or dicoumarol. However, caution must be exercised in extrapolating these findings to the clinical situation and in the use of glipizide with these drugs.
The following products could lead to hyperglycemia: Phenothiazines (eg, chlorpromazine) at high doses (chlorpromazine >100 mg/day): Elevation in blood glucose (reduction in insulin release).
Corticosteroids: Elevation in blood glucose.
Sympathomimetics (eg, Ritodrine, Salbutamol, Terbutaline): Elevation in blood glucose due to β2-adrenoceptor stimulation.
Other drugs that may be produce hyperglycemia, and lead to a loss of control include the thiazides and other diuretics, thyroid products, estrogens, progestogens, oral contraceptive, phenytoin, nicotinic acid, calcium-channel blocking drugs and isoniazid.
When such drugs are withdrawn from (or administered to) a patient receiving glipizide GITS, the patients should be observed closely for hypoglycemia (or loss control).
Storage
Store below 30°C. Keep in a dry place.
Shelf-Life: 48 months.
MIMS Class
ATC Classification
A10BB07 - glipizide ; Belongs to the class of sulfonylureas. Used in the treatment of diabetes.
Presentation/Packing
GITS tab 5 mg x 30's. 10 mg x 30's.
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