Date of approval.
Date of revision.
Glipizide Controlled Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Glipizide Controlled Release Tablets
English name: Glipizide Extended Release Tablets
Hanyu Pinyin：Geliebiqin Kongshi Pian
Ingredients
The main ingredient of this product is glipizide.
Chemical name: 5-methyl-N-[2-[4-[[[(cyclohexylamino)carbonyl]amino]sulfonyl]phenyl]ethyl]-pyrazinecarboxamide.
Chemical structure formula.
Molecular formula: C21H27N5O4S
Molecular weight: 445.54
【Properties】.
This product is white film-coated tablet, after removing the coating, it shows red and light red double layer tablet core.
Indications
This product is indicated as an adjunct to diet and exercise therapy to improve glycemic control in adult patients with type 2 diabetes.
Specification
5mg
Dosage]
This product should be taken with breakfast or the first meal of the day.
This product is indicated for hyperglycemia that is not controlled by dietary therapy alone. Dietary control is still important even if the patient is already taking this product. When starting treatment for type 2 diabetes, diet control should be emphasized as the basic treatment. For obese patients, calorie restriction and weight loss are necessary. In controlling blood glucose and relieving symptoms of hyperglycemia, treatment with appropriate dietary management alone may be effective. The importance of regular and routine physical exercise, identification of cardiovascular risk factors, and appropriate therapeutic measures should be emphasized.
If the above treatments fail to relieve symptoms and/or lower blood glucose, oral sulfonylureas should be considered. For further relief of symptoms and/or lowering of blood glucose, the addition of insulin therapy may be considered. Both physicians and patients should recognize that this product is an additional treatment to diet therapy and that it is neither a substitute for diet therapy nor a convenient way to avoid dietary control. In some cases, the failure of dietary therapy alone to control blood glucose may be temporary and require only short-term treatment with glipizide.
In cases of primary or secondary failure of sulfonylureas, including glipizide controlled-release tablets, this product may be considered in combination with other oral hypoglycemic agents. Options also include the use of other oral hypoglycemic agents or insulin instead of this product. If the product is no longer effective in lowering blood glucose, it should be discontinued. Efficacy must be judged on the basis of routine clinical and laboratory tests.
When considering the use of this product in asymptomatic patients, it should be understood that glycemic control in patients with type 2 diabetes has not been proven to be effective in preventing long-term cardiovascular and neurological complications in patients with diabetes. However, controlling blood glucose in patients with insulin-dependent diabetes is effective in slowing the progression of diabetic retinopathy, nephropathy, and neuropathy.
Recommended Dose
The recommended starting dose of this product is 5 mg once daily.
Patients who are more sensitive to this product should be evaluated for hypoglycemic reactions after the 5mg dose initiation to decide whether to continue or discontinue the product.
The dose can be adjusted according to the patient’s glycemic control. The maximum recommended dose is 20 mg once daily.
HbA1c should be measured at the start of treatment and after three months of treatment, and the dose may be increased if the test results indicate inadequate glycemic control in the first three months. Subsequent dose adjustments should be based on the HbA1c level measured every three months. If three months of higher dose treatment does not improve, the previous dose should be resumed. If the dose is adjusted based on fasting glucose, the dose adjustment should be followed by at least two consecutive dose adjustments with glucose measurements 7 days or more apart.
Patients receiving immediate-release glipizide may be switched to treatment with the closest equivalent total daily dose of this product once daily.
In elderly patients, frail or malnourished patients, and patients with renal or hepatic impairment, conservative principles should be used for both starting and maintenance doses to avoid hypoglycemic reactions (see [Precautions] section).
Combination with other hypoglycemic agents
When other oral hypoglycemic agents are added to this product for combination therapy, the combined drug should be started at the lowest recommended dose and the patient should be closely monitored to prevent hypoglycemia. For more information, refer to the product information of the combination drug.
When adding this product to other oral hypoglycemic therapy for combination therapy, this product may be started at 5 mg. Patients on initial therapy with increased risk of hypoglycemia should be started at a lower dose.
When colesevelam is used in combination with glipizide controlled-release tablets, the maximum blood concentration and total exposure of glipizide are reduced. Therefore, this product should be administered at least 4 hours earlier than colesevelam.
Patients on insulin therapy: As with other sulfonylurea hypoglycemic agents, many patients with stable type 2 diabetes on insulin therapy can be safely switched to this product. The following principles should be considered for conversion from insulin to this treatment.
Patients with insulin dosage of 20 units or less per day may discontinue insulin and start treatment with a regular dose of this product, and dose adjustments should be made several days apart.
In patients with insulin dosage of more than 20 units per day, the insulin dose should be reduced by 50% and treated with the regular dose of this product, and the subsequent reduction of insulin should be determined according to the patient’s response to treatment. Dose adjustments should be made several days apart.
Urine glucose and ketone bodies should be checked at least three times a day while insulin is discontinued. Patients should be advised to contact their physician immediately if the test results are abnormal. For some patients, especially those with insulin dosages exceeding 40 units per day, hospitalization for medication conversion is recommended.
Patients using other oral hypoglycemic agents: As with other sulfonylureas, no transition period is required when patients switch to this product. Considering the potential superimposed effects of the drug, when switching from a sulfonylurea with a long half-life (e.g., chlorosulfopropurea) to this product, the patient should be closely observed (1-2 weeks) for hypoglycemic reactions.
Or follow medical advice.
Adverse reactions】According to the literature
The following serious adverse reactions are described in detail below and in other parts of the instruction manual.
Hypoglycemia (see [Precautions])
Hemolytic anemia (see [Precautions])
Clinical trial experience
Because clinical trials are done under different conditions, the rate of adverse reactions observed in clinical trials for one drug cannot be directly compared to the rate of adverse reactions for other drugs in clinical trials and may not reflect the rate of adverse reactions in actual use.
In controlled and open clinical trials, 580 patients aged 31-87 years have been treated with 5 mg to 60 mg of this drug. Doses above 20 mg are not recommended. In these trials, approximately 180 patients were treated with this product for at least 6 months.
Table 1 summarizes the incidence of ≥3% of adverse reactions other than hypoglycemia reported in double-blind, placebo-controlled trials (which occurred in patients treated with this product and were more common than in patients treated with placebo).
Table 1: Incidence (%) of adverse reactions in placebo-controlled clinical trials in ≥3% of treated patients and more common in patients treated with this product (excluding hypoglycemia)
Glipizide controlled-release tablets (%)
N=278 Placebo (%)
N=69 Adverse reactions Dizziness 6.85.8 Diarrhea 5.40.0 Nervousness 3.62.9 Tremor 3.60.0 Gastrointestinal distention 3.21.4 Hypoglycemia
Of the 580 patients treated with this product in clinical trials, 3.4% developed hypoglycemia (defined as blood glucose measurements < 60 mg/dL and/or symptoms related to hypoglycemia) and 2.6% discontinued treatment as a result. No hypoglycemia was reported in any of the patients in the placebo group.
Gastrointestinal reactions
In clinical trials, gastrointestinal (GI) side effects (nausea, vomiting, constipation, dyspepsia) occurred in less than 3% of patients treated with this product and were more common in patients treated with this product than in those treated with placebo.
Skin reactions
Allergic skin reactions (i.e., urticaria) occurred less than 1.5% of the time in clinical trials and were more common in patients treated with this product than in those treated with placebo. These reactions may be temporary and may resolve despite continued use of the product; if skin reactions persist, the drug should be discontinued.
Laboratory Tests
There are mild to moderate elevations in glutamate transaminase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase, blood urea nitrogen (BUN), and creatinine. The relationship of these abnormalities to glipizide has not been determined. The incidence of elevated blood lactate dehydrogenase levels and elevated blood urea levels is unknown (cannot be assessed from the data available).
Adverse events with an incidence of less than 3% in patients taking this product include
Systemic – pain
Neurologic – insomnia, abnormal sensation, anxiety, depression, hypoesthesia
Gastrointestinal – nausea, indigestion, constipation, abdominal pain, diarrhea and vomiting
Metabolic —- hypoglycemia
Muscle and bone – joint pain, leg cramps and myalgia
Cardiovascular system —- fainting
Skin – sweating and itching
Respiratory system – rhinitis
Special sensations —- blurred vision
Genitourinary – polyuria
Other adverse events with an incidence of less than 1% in patients taking this product include
Systemic —- chills
Neurologic – increased muscle tone, confusion, headache, tremor, vertigo, drowsiness, abnormal gait and decreased libido
Gastrointestinal – anorexia and trace amounts of blood in the stool
Metabolic —- thirst and edema
Cardiovascular – arrhythmias, migraines, flushing, and hypertension
Skin – rash and urticaria
Respiratory – pharyngitis and dyspnea
Special sensations – eye pain, conjunctivitis and retinal hemorrhage
Genitourinary – difficulty in urination
Other adverse events of unknown incidence (which cannot be confirmed by available information) in patients taking this product include
Ocular abnormalities – blurred vision and decreased visual acuity
Gastrointestinal abnormalities – upper abdominal discomfort
Hepatobiliary abnormalities – cholestatic jaundice, toxic hepatitis
Skin and subcutaneous tissue abnormalities – allergic dermatitis, mucosal skin rash, maculopapular rash
Congenital, familial and genetic anomalies – non-acute porphyrias
Systemic disease and administration site conditions – discomfort
Postmarketing Experience
The following adverse reactions have been reported post-marketing from this product. Because these reactions were spontaneously reported from a variable number of people, it is not always possible to reliably estimate their frequency or to determine a causal relationship with drug exposure.
Abdominal Pain
cholestatic and hepatocellular liver injury with jaundice
leukopenia, granulocyte deficiency, thrombocytopenia, hemolytic anemia (see [Precautions]), aplastic anemia, and allohemocytopenia
Hepatic porphyria and disulfiram-like alcohol reaction
Hyponatremia and abnormal secretion of antidiuretic hormone (SIADH) syndrome
Skin rashes
Gastrointestinal irritation and gastrointestinal bleeding have been reported with the administration of another drug belonging to this non-dissolvable controlled release dosage form.
Contraindications
Glipizide is contraindicated in the following patients.
1. known hypersensitivity reactions to glipizide or any component of this product.
2. hypersensitivity reactions to sulfonamide derivatives. 3.
3. Patients with type 1 diabetes mellitus, diabetic ketoacidosis with or without coma.
Precautions]
Hypoglycemia
All sulfonylureas, including this product, can cause severe hypoglycemia (see [Adverse Reactions]). The risk of hypoglycemia may be increased by combining this product with other antidiabetic drugs. When used in combination with other antidiabetic drugs, it may be necessary to reduce the dose of this product to minimize the risk of hypoglycemia.
Advise patients how to recognize and manage hypoglycemia. Patients who are more sensitive to this product need to be evaluated comprehensively for hypoglycemic reactions after the initiation of the 5 mg dose to decide whether to continue or discontinue the product. Patients who are very weak or malnourished, and patients with adrenal, pituitary or hepatic impairment are particularly susceptible to the hypoglycemic effects of antidiabetic drugs. Hypoglycemia may also occur when caloric intake is inadequate, during strenuous exercise or prolonged exercise, or when alcohol is ingested.
Patients’ concentration and responsiveness may be affected by hypoglycemia. Early warning signs of hypoglycemia may be different or less obvious in patients with autonomic neuropathy, in the elderly, and in those receiving beta-blockers or other sympathetic blocking drugs. These conditions may lead to severe hypoglycemia before the patient is aware of the hypoglycemia.
These impairments may be dangerous in situations where special skills are particularly important, such as driving or operating other machinery. Severe hypoglycemia may lead to loss of consciousness or fainting, and can also lead to temporary or permanent damage to brain function or death.
Loss of blood sugar control
Patients with stable blood glucose control on a certain diabetes treatment regimen may experience blood glucose loss in stressful situations such as fever, trauma, infection, or surgery. In such cases, the product must be discontinued and replaced with insulin therapy.
Any oral hypoglycemic drug, including glipizide, can cause a reduction in the effect of lowering blood glucose to desired levels in many patients over a period of time, possibly because diabetes has progressed to a severe level or the response to the drug has decreased. This phenomenon is referred to as secondary failure to distinguish it from primary failure, where the drug is ineffective in a patient at the time of initial administration, and adequate dose modifications and continued adherence to diet therapy should be taken until the patient is determined to be a secondary failure.
Hemolytic anemia
The use of sulfonylureas, including this product, in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may result in hemolytic anemia and should be avoided in patients with G6PD deficiency. Post-marketing reports of hemolytic anemia in non-G6PD deficient patients have also been reported.
Macrovascular Events
There are no clinical trials demonstrating that glipizide reduces the risk of macrovascular events.
Gastrointestinal Disorders
A significant reduction in the gastrointestinal retention time of glipizide controlled-release tablets may affect its pharmacokinetic properties and, consequently, the clinical effect of the drug. As with any other drug using similar extended-release dosage form technology, glipizide controlled-release tablets should be avoided in patients with pre-existing severe gastrointestinal strictures (pathologic or medically induced). There have been isolated reports of gastrointestinal obstruction in patients with gastrointestinal strictures while taking another drug using this non-dissolvable controlled-release dosage form.
Impaired renal and hepatic function
There is no information on the effect of hepatic impairment on the distribution of glipizide. However, the pharmacokinetic and pharmacodynamic properties of glipizide may be altered in patients with renal or hepatic impairment due to the high protein binding of glipizide and the fact that hepatic biotransformation is the primary elimination pathway of the product. If hypoglycemia occurs in patients, the duration of hypoglycemia may be prolonged and appropriate therapeutic measures should be taken. (See [Dosage] and [Pharmacology and Toxicology]).
Information for patients
Inform patients of the potential adverse effects of this product, including hypoglycemia. Patients and family members should be explained the risk of hypoglycemia, symptoms and treatment, and conditions that may trigger hypoglycemia. Patients should also be informed of the importance of adherence to dietary therapy, regular exercise, and regular blood glucose control.
Advise patients that this product should be swallowed whole and not chewed, separated or crushed. Patients may occasionally see in their stool a pill-like substance that is encased in an insoluble shell, which is designed to allow for slow release of the drug for absorption by the body.
Warning]
A specific warning about the increased risk of cardiovascular mortality with sulfonylureas: An association has been reported between oral hypoglycemic drug therapy and increased cardiovascular mortality compared to diet alone or diet plus insulin therapy. This warning is based on a long-term prospective clinical trial by the UGDP (University Group Diabetes program), which was designed to evaluate the effectiveness of glucose-lowering drugs in preventing and delaying vascular complications in patients with type 2 diabetes. A total of 823 patients were enrolled in the study and randomized to one of four treatment groups.
The UGDP reported that patients treated with dietary control plus a fixed dose of tosylbutamide (1.5 g/day) for 5-8 years had a cardiovascular mortality rate 2.5 times higher than that of patients treated with diet alone. The observation of overall mortality was affected by the early termination of tosylbutazone in this trial due to the increased cardiovascular mortality, and no significant increase in overall mortality was observed as a result. Although there is controversy over how to interpret these results, the findings of the UGDP study are still sufficient to raise this caveat. Patients should be aware of the potential risks and benefits of glipizide and the other treatment options available.
Although only one sulfonylurea (tosylurea) was included in the above study, given the similarity in mechanism of action and chemical structure of this class of drugs, this caution should be considered to apply to other sulfonylureas from a safety perspective.
Pregnant women and nursing mothers
Pregnancy
Risk Summary
Based on the available data from a small number of published studies and decades of post-marketing experience with this product in pregnant women, no drug-related risks of major birth defects, miscarriage, or adverse maternal prognosis have been identified. However, sulfonylureas (including glipizide) cross the placenta and may cause neonatal adverse effects, such as hypoglycemia. Therefore, it must be discontinued at least two weeks before the expected date of delivery (see Clinical Precautions). Poorly controlled gestational diabetes can also pose a risk to the mother and fetus (see Clinical Precautions).
The background risk of major birth defects in pregnant women with diabetes before pregnancy has been reported to be 6-10% if HbA1c >7% and up to 20-25% if HbA1c >10%. The estimated background risk of miscarriage in this population is unknown. In clinically confirmed pregnancy cases in the general US population, the background risks for major birth defects and miscarriage are estimated to be 2-4% and 15-20%, respectively.
Clinical considerations
Disease-related maternal and/or embryonic/fetal risk
Poorly controlled diabetes in pregnancy increases maternal risk, including diabetic ketoacidosis, toxemia of pregnancy, miscarriage, preterm delivery, stillbirth, and delivery complications. Poorly controlled diabetes mellitus increases fetal risk, including major birth defects, stillbirth, and death associated with a large fetus.
Fetal/neonatal adverse effects
Newborns born to pregnant women with gestational diabetes treated with sulfonylureas have a high risk of requiring admission to the neonatal intensive care unit and may develop respiratory distress, hypoglycemia, birth trauma, and may be older than gestational age. Prolonged and severe hypoglycemia lasting 4-10 days has been reported in newborns born to some pregnant women who used sulfonylureas at delivery, and has been reported with some agents with long half-lives. Observe the neonate for signs of hypoglycemia and respiratory distress and treat accordingly.
Dose adjustment during pregnancy and postpartum period
Because prolonged severe hypoglycemia has been reported in neonates born to pregnant women using sulfonylureas during labor, it is important to discontinue this product at least two weeks prior to the expected date of delivery (see Fetal/Neonatal Adverse Reactions).
Breastfeeding
Summary of risks
If a mother is breastfeeding her infant while using this product, the infant should be monitored for signs of hypoglycemia (see Clinical Precautions). Although glipizide was not detected in human breast milk in a small clinical breastfeeding study, this result is not conclusive due to limitations of the assay used in that study. No data are available on whether glipizide affects lactation. When considering the need for breastfeeding, the benefits of breastfeeding on the development and health of the infant, the clinical need of the mother for the product, and any potential adverse effects of the product or the mother’s underlying medical condition on the infant should be weighed together.
Clinical Precautions
Adverse Reaction Monitoring
If the infant is breastfed, the infant should be monitored for signs of hypoglycemia (e.g., shaking, cyanosis, asphyxia, hypothermia, excessive lethargy, feeding difficulties, seizures).
[Pediatric Use].
The safety and efficacy of pediatric use have not been established.
Geriatric use】According to the literature
In clinical studies of this product, patients aged 65 years and older accounted for 33% of all patients. The time for the drug to reach steady state was approximately 1-2 days longer in elderly patients than in younger patients (see [Pharmacology and Toxicology] and [Dosage and Administration] sections for details).
No overall differences in efficacy or safety were observed between younger and older patients, but a higher sensitivity to the drug in some patients cannot be excluded. Therefore, it should be noted that elderly, frail or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to hypoglycemia caused by hypoglycemic agents. Hypoglycemia may be difficult to recognize in the elderly. In addition, in elderly, frail or malnourished patients and patients with renal or hepatic insufficiency, the starting and maintenance doses should be decided carefully to avoid hypoglycemic reactions.
Drug Interactions】According to the literature
Drugs that affect glucose metabolism
A variety of drugs can affect glucose metabolism, so it may be necessary to adjust the dose of this product and closely monitor hypoglycemia and control the deterioration of blood glucose.
The following drugs may increase the hypoglycemic effect of this product and increase the likelihood and/or severity of hypoglycemia: antidiabetic drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, propyzamide, fibrates, fluoxetine, monoamine oxidase inhibitors, hexoketococine, pramlintide, propoxyphene, salicylic acid, growth inhibitor analogues (such as octreotide), sulfonamide antibiotics NSAIDs, chloramphenicol, probenecid, coumarin, voriconazole, H2 receptor antagonists, and quinolones. Patients taking this product should be closely monitored for hypoglycemia while receiving these drugs. When these drugs are discontinued in patients taking this product, the deterioration of blood glucose should be closely monitored and controlled.
The following drugs can reduce the hypoglycemic effect of this product and lead to uncontrolled blood glucose: atypical antipsychotics (such as olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazine, progestins (such as oral contraceptives), protease inhibitors, growth hormones, sympathomimetics (such as salbutamol, epinephrine, terbutaline ), thyroid hormones, phenytoin, niacin, and calcium channel blockers. Close monitoring and control of blood glucose deterioration should be performed when these drugs are administered to patients taking this product. Close monitoring of hypoglycemia should be performed when these medications are discontinued in patients taking this product.
Alcohol, beta-blockers, colistin and reserpine may enhance or diminish the hypoglycemic effect of this product. Increased monitoring frequency may be required when this product is used in combination with these drugs.
Symptoms of hypoglycemia may be diminished or disappeared in patients taking sympathetic neuroleptic drugs such as beta-blockers, colistin, guanethidine, and reserpine. The frequency of monitoring may need to be increased when this product is used in combination with these drugs.
Miconazole
When this product is used in combination with miconazole, patients must be monitored closely for hypoglycemia. There have been reports of possible interactions between oral miconazole and glucose-lowering medications resulting in severe hypoglycemia. It is not known whether such interactions occur when miconazole is administered intravenously, topically, or vaginally.
Fluconazole
When this product is used in combination with fluconazole, patients must be monitored closely for hypoglycemia. Combined treatment with fluconazole increases the blood levels of glipizide and thus may lead to hypoglycemia (see [Pharmacologic Toxicology]). A placebo-controlled, crossover trial was conducted in healthy volunteers to study the effects of combining Daflucanâ (fluconazole) and glipizide. All subjects first took glipizide alone and then were given Daifukangâ 100 mg once daily for 7 days. The area under the drug-time curve (AUC) of glipizide increased by a mean of 56.9% (range 35-81%) after the use of fluconazole.
Voriconazole
Although no studies have been conducted, voriconazole has the potential to increase blood levels of sulfonylureas (e.g., tosylurea, glipizide, glibenclamide) and cause hypoglycemia. It is recommended that blood glucose should be carefully monitored when co-administering medications.
Kolayvilan
This product should be taken at least 4 hours prior to the administration of colevelam. When the two drugs are given together, colevelam may reduce blood levels and total exposure to glipizide (see [Pharmacology and Toxicology]). In a study evaluating the pharmacokinetic effects of colevelam on glipizide controlled-release tablets in healthy volunteers, a 12% and 13% reduction in glipizide AUC0-∞ and Cmax, respectively, was observed when colevelam and glipizide controlled-release tablets were administered in combination. There was no significant change in glipizide AUC0-∞ 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 kolevulan to ensure that kolevulan does not reduce the absorption of glipizide.
[Drug overdose].
Overdose of sulfonylureas, including this product, can lead to severe hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurological manifestations should be treated with oral glucose. Severe hypoglycemic reactions with coma, convulsions, or other signs of neurological damage are medical emergencies requiring immediate treatment, and patients should receive glucagon or intravenous glucose therapy. Patients should be closely monitored for at least 24-48 hours, as hypoglycemia can occur again after significant clinical improvement. Clearance of plasma glipizide is prolonged in patients with liver disease. Since glipizide is mostly protein bound, dialysis may not achieve results.
Pharmacology and toxicology]
Pharmacological effects
Glipizide achieves its hypoglycemic effect mainly by stimulating insulin secretion from the pancreas, and its effect depends on the function of pancreatic b-cells. Sulfonylureas stimulate insulin release by binding to sulfonylurea receptors on the pancreatic β-cell membrane and causing ATP-sensitive potassium channel closure.
Toxicological studies
Genotoxicity: Bacterial and in vivo mutagenicity tests were negative.
Reproductive toxicity: No effect on fertility was seen in studies in male and female rats at doses up to 75 times the human dose. Mild embryotoxicity was found at all dose levels (5-50 mg/kg) in a perinatal reproductive toxicity study in rats, similar to that observed in other sulfonylureas such as toluenosulfonylurea and tolarsulfonylurea, and is thought to be directly related to the glucose-lowering pharmacological effects of glipizide.
Carcinogenicity: In a 20-month study in rats and 18-month study in mice at doses up to 75 times the maximum human dose, no drug-related carcinogenic effects were observed.
Pharmacokinetics】According to the literature
Absorption
The absolute bioavailability of a single oral dose of glipizide in patients with type 2 diabetes was 100%. Blood concentrations begin to rise 2-3 hours after oral administration of this product and peak within 6-12 hours. When given once daily continuously, glipizide maintained effective blood concentrations over a 24-hour dose interval, with significantly lower peak-to-valley fluctuations than twice-daily glipizide immediate-release tablets.
In 21 male type 2 diabetic patients taking 20 mg of this product, the relative bioavailability of glipizide controlled-release tablets at steady state averaged 90% compared with glipizide immediate-release tablets (10 mg twice daily). 21 male type 2 diabetic patients aged less than 65 years reached steady-state blood concentrations after day 5 of this product. No drug accumulation was observed with long-term use in type 2 diabetic patients.
The concomitant administration of this product with food had no effect on the delay in drug absorption (2-3 hours). 21 single-dose food effect studies in healthy male subjects showed a significant 40% increase in mean peak concentration Cmax of glipizide when taken before a high-fat breakfast, but the effect on the area under the drug-time curve (AUC) was not significant. There was no difference in the glycemic response to this product when taken in the fed and fasted states. A significant reduction in the duration of gastrointestinal residence (e.g., short bowel syndrome) would affect the pharmacokinetic properties of the product and may result in a decrease in plasma concentrations.
A multiple-dose study in 26 men with type 2 diabetes showed linear pharmacokinetics of glipizide, i.e., blood concentrations increased proportionally with increasing dose. 24 single-dose studies in healthy subjects suggested bioequivalence of 4 tablets of 5 mg, 2 tablets of 10 mg, and 1 tablet of 20 mg. Another single-dose study in 36 healthy subjects confirmed bioequivalence between 4 tablets of 2.5 mg and 1 tablet of 10 mg.
Distribution
The mean apparent volume of distribution of a single dose of glipizide given intravenously to patients with type 2 diabetes is approximately 10 liters. 98 – 99% of glipizide is bound to serum proteins (primarily albumin).
Metabolism
The major metabolite of glipizide is an aromatic hydroxylation product with no hypoglycemic activity. The secondary metabolite, the acetyl ethyl benzene derivative, accounts for less than 2% of the administered dose and has been reported to have 1/10 – 1/3 the hypoglycemic activity of the parent compound.
Elimination
Glipizide is primarily cleared by hepatic biotransformation, with less than 10% of the dose excreted in its original form in urine and feces and approximately 90% of the dose biotransformed and excreted in urine (80%) and feces (10%).
The mean total clearance of glipizide is approximately 3 liters per hour when given intravenously as a single dose in patients with type 2 diabetes.The mean clearance half-life of glipizide is 2-5 hours after single and multiple dose administration in patients with type 2 diabetes.
Specific Populations
Children.
The pharmacokinetics of glipizide in pediatric patients have not been evaluated.
Elderly.
No significant differences in pharmacokinetic parameters were observed in elderly diabetic subjects following a single dose of glipizide compared to young healthy subjects.
Impaired renal function.
No pharmacokinetic studies of glipizide have been performed in patients with various renal impairments. Limited data suggest that glipizide biotransformation products may be retained longer in the circulatory system of subjects with renal impairment than in subjects with normal renal function.
Hepatic impairment.
Pharmacokinetic studies of glipizide have not been conducted in patients with impaired hepatic function.
Storage】Hermetically sealed and stored below 30℃ to prevent moisture.
Package】Polyamide/aluminum/polyvinyl chloride cold pressed solid pharmaceutical compound hard tablets and pharmaceutical aluminum foil, 7 tablets/plate x 2 plates/box.
Expiration date】24 months
【Execution standard
【Approval number】
【Drug marketing license holder
Name: Nanjing Yi Heng Pharmaceutical Co.
Registered Address: No. 22, Tianpu Road, Jiangbei New District, Nanjing
Contact: 025-58286666
Fax: 025-58288000
Website: http://www.easeheal.com
Manufacturer
Company name: Nanjing Yiheng Pharmaceutical Co.
Address: No. 22, Tianpu Road, Jiangbei New District, Nanjing
Postcode：211800
Contact：025-58286666
Fax: 025-58288000
Website: http://www.easeheal.com