Approval Date: 09/04/2007
Revision Date: 11/05/2009; 01/10/2010; 03/18/2015; 01/12/2015
Glipizide Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician
[Medication Name].
Generic Name: Glipizide Tablets
English Name: Glipizide Tablets
Hanyu Pinyin: Geliebiqin Pian
[Ingredients] The main ingredient of this product is: Glipizide.
Chemical name: 5-methyl-N-[2-[4-[[[(cyclohexylamino)carbonyl]amino]sulfonyl]phenyl]ethyl]-pyrazinecarboxamide.
The chemical structure formula is.
Molecular Formula: C21H27N5O4S
Molecular weight: 445.54
[Properties] This product is a white tablet.
[Indications]
Glipizide is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
[Specifications] 5mg
[Dosage]
Orally, the dose varies from person to person. The general recommended dose is 2.5 to 20 mg/day, taken 30 minutes before breakfast. For daily doses over 15mg, it is advisable to take it in the morning, midday and evening before three meals.
People who have failed diet alone: Start at 2.5-5 mg/day, then increase or decrease the dose by 2.5-5.0 mg each time depending on blood glucose and urine glucose; for doses over 15 mg/day, divide into 2-3 doses before meals.
People who are already using other oral sulfonylureas for hypoglycemia: Stop other sulfonylureas for 3 days and start taking this product after reviewing blood glucose. Gradually increase the dose from 5mg until desired efficacy is achieved. The maximum daily dose should not exceed 30 mg.
[Adverse Reactions] According to the literature
In controlled studies, the reported incidence of serious adverse reactions was low. 11.8% of 702 patients experienced adverse reactions and only 1.5% discontinued glipizide.
Low blood sugar.
See the Precautions and Drug Overdose sections.
Gastrointestinal System.
Gastrointestinal disturbances are the most common reactions. The incidence of gastrointestinal disorders has been reported at roughly the following rates: nausea and diarrhea were reported in 1 in 70 patients and constipation and stomach pain in 1 in 100 patients. These adverse reactions appear to be dose related and usually disappear with dose fractionation or reduction. Rarely, cholestatic jaundice reactions may occur with sulfonylureas. If this occurs, glipizide should be discontinued.
Dermal system.
Allergic skin reactions, including erythema, pityriasis or maculopapular rash, urticaria, pruritus, and eczema, have been reported in about 1 in 70 patients. Such adverse reactions may be temporary and may resolve even with continued use, but if anaphylactic skin reactions persist, the drug should be discontinued. Delayed porphyria and photosensitivity reactions have been reported with sulfonylurea use.
Hematologic.
Sulfonylureas have been reported to cause leukopenia, granulocyte deficiency, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and allogeneic cytopenia.
Metabolic and nutritional systems.
Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas. The administration of ethanol to mice premedicated with glipizide did not cause accumulation of acetaldehyde. Clinical experience to date suggests that the incidence of disulfiram-like reactions induced by glipizide is very low.
Endocrine System.
Glipizide and other sulfonylureas have been reported to cause hyponatremia and syndrome of abnormal secretion of antidiuretic hormone (SIADH).
Other adverse effects.
Dizziness, drowsiness, and headache have been reported in about 1 in 50 patients treated with glipizide; these symptoms are usually transient and rarely require discontinuation of therapy.
Laboratory Tests.
The abnormalities observed in laboratory tests for glipizide are similar to those observed with other classes of sulfonylureas, with occasional mild to moderate elevations of glutamic oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH), alkaline phosphatase, urea nitrogen (BUN), and creatinine. One case of jaundice was reported. The relationship of these abnormalities to glipizide has not been clearly established and has rarely been associated with clinical symptoms.
Adverse reactions reported in postmarketing surveillance.
The following adverse reactions were reported for postmarketing surveillance.
Hepatobiliary system: Rarely, cholestasis and liver injury with jaundice have been reported with glipizide. If this occurs, the drug should be discontinued.
[Contraindications].
1. Hypersensitivity to this product and to sulfonamides.
2. Patients with clearly diagnosed type 1 diabetes mellitus.
3. Patients with type 2 diabetes with stressful conditions such as ketoacidosis, coma, severe burns, infection, trauma and major surgery.
4. Patients with hepatic or renal insufficiency.
5. Patients with leukopenia.
[Caution].
Warnings:
Increased risk of cardiovascular death.
The use of oral hypoglycemic agents has been reported to be associated with increased cardiovascular mortality compared with diet alone or diet plus insulin therapy. This warning is based on a long-term prospective clinical trial by the University Group Diabetes Program (UGDP) in the United States to assess the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups. The UGDP reported that cardiovascular mortality was approximately 2.5 times greater in patients treated with diet plus a fixed dose of tosylurea (1.5 grams per day) for 5 to 8 years than in patients treated with diet alone. No significant increase in overall mortality was observed, limiting the chances of an increase in overall mortality in the study due to increased cardiovascular mortality discontinuing the use of tosylbutazone. Although the interpretation of the results of this study is controversial, the results of the UGDP study provide an adequate basis for this caution. Patients should be informed of the potential risks and benefits of glipizide and other alternative treatment modalities.
Although there was only one sulfonylurea (toluenosulfonylurea) in this study, from a safety perspective and based on the similar mode of action and chemical structure, it is prudent that this warning could apply equally to other oral hypoglycemic agents in this class.
General:
Liver and kidney disease.
Metabolism and excretion of glipizide may be slowed in patients with impaired renal or hepatic function. When hypoglycemia occurs in such patients, the duration of hypoglycemia is likely to be prolonged and appropriate therapeutic measures should be taken.
Hypoglycemia.
All sulfonylureas, which can cause severe hypoglycemia, are important to avoid hypoglycemia by choosing the right patient, dosing, and following dosing instructions. Hepatic and renal insufficiency may lead to elevated blood levels of glipizide and subsequently may also reduce the ability to produce gluconeogenesis, both of which increase the risk of severe hypoglycemic reactions. Elderly, frail and malnourished patients and patients with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic effects of hypoglycemic drugs. Hypoglycemia may be difficult to recognize in the elderly and in those using beta-blocker medications. Hypoglycemia is more likely to occur when caloric intake is inadequate, after strenuous and prolonged exercise, when alcohol is consumed, or when multiple hypoglycemic drugs are used.
Uncontrolled blood glucose.
Uncontrolled blood glucose may occur in patients with stable blood glucose control on a particular diabetes regimen when they experience stressful situations such as fever, trauma, infection, or surgery. This situation may necessitate discontinuation of glipizide and treatment with insulin.
A decrease in the effectiveness of any oral hypoglycemic agent, including glipizide, in lowering blood glucose to desired levels in many patients after a period of use may be due to progression in the severity of diabetes or a diminished response to the drug, a phenomenon called secondary failure to distinguish it from primary failure when the drug is not effective in individual patients when first administered.
Hemolytic anemia.
Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylureas can lead to hemolytic anemia. Because glipizide is a sulfonylurea, it should be used with caution in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. Post-marketing, there are reports of hemolytic anemia in patients with as yet unclear whether G6PD deficiency occurs.
Laboratory Tests.
Glucose and urine glucose should be monitored regularly, and measurement of glycosylated hemoglobin may be useful.
Information for patients.
Patients should be informed of the potential risks and benefits of glipizide and alternative treatment modalities. The importance of adherence to dietary guidelines, regular exercise, and routine monitoring of urine and/or blood glucose should also be understood. Patients and their families should be informed of the risk of hypoglycemia, symptoms and treatment, and possible occurrences. Primary and secondary lapses should also be described.
This drug contains lactose and is contraindicated in patients with rare hereditary galactose intolerance, Lapp lactase deficiency, and glucose-galactose malabsorption.
[For pregnant and lactating women].
Sulfonylurea hypoglycemic drugs have been shown in animal studies and clinical observations to cause stillbirth and fetal malformation, and are therefore contraindicated in pregnant women.
This class of drugs can be excreted by breast milk and should not be used by lactating mothers to avoid hypoglycemia in the infant.
[Medication for Children].
The safety and efficacy of medications for children have not been established.
[Medication in the Elderly]
It has not been determined whether a sufficient number of elderly subjects aged 65 years and older were included in controlled clinical studies of glipizide to determine differences in response from younger subjects. Other reported clinical experiences have not yet determined differences in response between older and younger patients. In general, given the more common and concomitant disease or other drug therapy of decreased hepatic, renal, or cardiac function, dose selection in elderly patients should be cautious, usually starting with the lowest dose.
[Drug interactions].
1. The hypoglycemic effect of this drug may be increased in combination with bicoumarins, monoamine oxidase inhibitors, pautazone, sulfonamides, chloramphenicol, cyclophosphamide, probenecid, and salicylates.
2. When combined with epinephrine, adrenocorticotropic hormone, oral contraceptives, and thiazide diuretics, their hypoglycemic effect can be reduced.
3. Caution should be exercised when used with beta-blockers.
4. Although no studies have been conducted, voriconazole has the potential to increase blood levels of sulfonylureas (eg, tosylurea, glipizide, glibenclamide), which can lead to hypoglycemia. It is recommended that blood glucose should be carefully monitored when co-administering medications.
5. In studies evaluating the pharmacokinetic effects of colevelam on glipizide controlled-release tablets in healthy volunteers, a 12% and 13% reduction in glipizide AUC 0-∞ and Cmax, respectively, was observed when colevelam and glipizide controlled-release tablets were coadministered. There was no significant change in glipizide AUC 0-∞ or Cmax (between -4% and 0%, respectively) when glipizide controlled-release tablets were administered 4 hours earlier than colesevelam. Therefore, this product should be administered at least 4 hours earlier than colesevelam to ensure that colesevelam does not reduce the absorption of glipizide.
[Drug overdose].
Detailed records of glipizide overdose are not available. Acute oral toxicity was extremely low (LD50 >4 g/kg) in all animals tested. Overdose of sulfonylureas, including glipizide, can result in hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic manifestations should be treated by prompt oral glucose administration, medication dose adjustment, and/or dietary modifications, with close monitoring until the physician confirms that the patient is out of danger. Severe hypoglycemic reactions with coma, convulsions or other signs of neurological damage are rare, but if detected, immediate hospitalization is required for emergency treatment. If a hypoglycemic coma is diagnosed or suspected, a high concentration (50%) intravenous glucose solution should be administered immediately, followed by a continuous drip of dilute glucose (10%) solution to maintain blood glucose levels above 100 mg/dL. Patients should be closely monitored for at least 24-48 hours due to the possibility of relapse after significant recovery from clinical manifestations has been achieved. Plasma clearance of glipizide is prolonged in patients with liver disease, and because glipizide is mostly protein bound, dialysis may not be effective.
[Pharmacology and Toxicology]
Pharmacological effects
Glipizide achieves its hypoglycemic effect primarily by stimulating insulin secretion from the pancreas, and its action is dependent on isletbcell function. Sulfonylureas cause sulfonylurea receptors on the isletcell membranes by binding to the closure of ATP-sensitive potassium channels, which stimulates insulin release.
Toxicological studies
Genotoxicity: Bacterial and in vivo mutagenicity tests were negative.
Carcinogenicity: In rats20months and in mice18months, doses up to the maximum human dose75 times, no drug-related carcinogenic effects were seen.
[Pharmacokinetics].
Glipizide is uniformly, rapidly and largely completely absorbed in the human gastrointestinal tract, with peak blood concentrations reaching 1 to 3 hours after a single oral dose. The drug has an elimination half-life of 2-4 hours in normal subjects, whether administered intravenously or orally. The metabolism and excretion patterns were similar for both routes of administration, indicating a nonsignificant first-pass effect. There was no accumulation of glipizide in plasma when repeatedly administered. In healthy volunteers, overall absorption and elimination of the oral dose is unaffected by food, but is delayed by approximately 40 minutes. Therefore, the drug is more effective when taken 30 minutes before a meal than with a meal in patients with diabetes.
Serum protein binding was studied in volunteers who received glipizide orally or intravenously, and plasma protein binding was found to be 98% to 99% after 1 hour of administration by either route of administration. The apparent volume of distribution after intravenous administration of glipizide, was 11 L localized in the extracellular fluid. Glipizide or its metabolites were not detected in the brain or spinal cord of female and male mice, nor in the fetuses of female mice. However, in another study, very small amounts of radioactivity were detected in fetuses of rats that had taken the labeled drug.
Glipizide is metabolized in a broad and predominantly hepatic pathway, with the major metabolites being inactive hydroxylated products and polar conjugates, which are excreted primarily in the urine. Less than 10% of the prototype drug is found in the urine.
[Storage] Store below 30°C.
[Packaging] Packaged in high-density polyethylene bottles for oral administration, 100 tablets/bottle.
[Validity] 24 months.
[Executive Standard].
[Approval Number] State Drug Certificate H19983201
[Manufacturer]
Company name: Yuanda Pharmaceutical (China) Co.
Production Address: No. 11, Huanhuzhong Road, Jinyin Lake Ecological Park, East-West Lake District, Wuhan, China
Postcode: 430040
Business Inquiry Tel: 027-83382850 400-990-9697
Complaints, adverse reactions phone, fax: 027-83382826
Complaints, adverse reactions email: [email protected]
Website: http://www.grandpharma.cn