Approval date: February 10, 2010
Modification date: 06/05/2010
Modification date: 09 December 2015
Date of modification.
Terasin®
Gliclazide Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic Name: Gliclazide Modified Release Tablets
English Name: Gliclazide Modified Release Tablets
Hanyu Pinyin: Gelieqite Huanshi Pian
Ingredients
The main ingredient of this product is Gliclazide.
Chemical name: 1-(3-azabicyclo[3.3.0]octyl)-3-tosylurea.
Chemical structure formula:
Molecular formula: C15H21N3O3S
Molecular weight: 323.41
【Properties】.
This product is a white or off-white tablet.
Indications】
It is used for adult type 2 diabetic patients whose blood glucose level is not sufficiently controlled by diet control, exercise therapy and weight reduction alone.
Specification
30mg
Dosage]
30 to 120mg (1 to 4 tablets) once daily, recommended to be taken with breakfast.
It is recommended to swallow.
If you forget to take the medication on one day, the dose should not be increased on the second day. As with all hypoglycemic drugs, the dose should be adjusted according to the patient’s blood glucose level.
*First dose.
The first recommended dose is 30 mg per day, which may be used as maintenance therapy if blood glucose is effectively controlled.
If blood glucose is not adequately controlled, the dose may be increased to 60mg, 90mg or 120mg daily at intervals of at least 1 month, and for patients whose blood glucose has not decreased after 2 weeks of treatment at one of the above doses, it is recommended that the dose be increased at this time.
The maximum recommended dose should not exceed 120mg per day.
*Replacement of Gliclazide 80mg tablets with.
One tablet of Gliclazide 80mg is equivalent to one tablet of this product. When substituting, blood glucose monitoring must be performed.
*Replacement of other oral hypoglycemic agents with this product.
This product may be substituted for other oral diabetes treatment medications.
In this case, the dose and half-life of the previously used hypoglycemic agent must be considered.
Generally, no transition period is required when switching to this product, and a starting dose of 30 mg should be used. The dose should then be adjusted according to the patient’s blood glucose profile as described above.
If a patient is switching from a sulfonylurea with a long half-life to this drug, a therapeutic window of several days is required for dose adjustment to avoid the risk of hypoglycemia from the superimposed effects of the two drugs.
When switching to this drug, it is recommended to follow the same steps as described above for the first dose of this drug. That is, an initial therapeutic dose of 30 mg per day, followed by a gradual titration according to metabolic conditions.
*In combination with other oral therapeutic agents for diabetes.
This product may be used in combination with a biguanide, alpha glucosidase inhibitor, or insulin.
For patients whose blood glucose is not adequately controlled by this product, it may be combined with insulin therapy under close medical monitoring.
Special Populations
Patients with renal impairment
In patients with mild or moderate renal insufficiency, the treatment regimen is the same as for patients with normal renal function, but careful monitoring is required. This information has been confirmed by clinical trials.
Patients at high risk of hypoglycemia
-Under-nutrition or malnutrition.
-severe or poorly compensated endocrine disease (anterior pituitary insufficiency, hypothyroidism, adrenal insufficiency)
-Prolonged and/or withdrawal of high-dose corticosteroid therapy
-severe vascular disease (severe coronary artery disease, severe carotid artery damage, diffuse vasculopathy), it is recommended to start treatment with a minimum dose of 30 mg/day.
or as directed by the physician.
Adverse reactions】According to the literature
Based on the experience of using gliclazide, the following adverse reactions have been reported.
The most common adverse effect of gliclazide is hypoglycemia
As with other sulfonylureas, treatment with this product may result in the occurrence of hypoglycemia, especially if meals are irregularly spaced or if one or more meals are missed.
Hypoglycemia may include the following symptoms: headache, extreme hunger, nausea, vomiting, lethargy, sleep disturbance, agitation, aggressive behavior, decreased concentration and attention, delayed reaction, depression, confusion, visual and speech disturbance, aphasia, tremor, local paralysis, sensory disturbance, dizziness, feeling of weakness, loss of self-control, delirium, convulsions, shallow breathing, bradycardia, drowsiness and loss of consciousness or even coma to death.
In addition, adrenergic counter-regulatory symptoms have been observed: sweating, damp skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and arrhythmias.
These symptoms usually disappeared after carbohydrate (sugar) intake. However, artificial sugar substitutes are not effective. Experience with other sulfonylureas suggests that hypoglycemia may recur even when these measures are initially effective.
In severe or prolonged cases of hypoglycemia, even if temporarily controlled by sugar ingestion, immediate medication or even hospitalization may still be required.
Gastrointestinal dysfunction including abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and constipation have been reported less frequently, but these symptoms can be avoided or the risk minimized if gliclazide is taken at breakfast.
Rare adverse reactions.
-Dermal and subcutaneous tissue reactions: rash, pruritus, urticaria, angioedema, erythema, maculopapular rash, maculopapular skin reactions (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis relaxans), and eosinophilia and drug rash with systemic symptoms (DRESS).
-Hematologic and lymphatic disorders: Hematologic changes are extremely rare and include anemia, leukopenia, thrombocytopenia, and granulocytopenia. These adverse reactions are usually reversible after discontinuation of the drug.
-Hepatobiliary disorders: increased liver enzyme levels (AST, ALT, alkaline phosphatase), hepatitis (rare). Discontinue treatment if cholestatic jaundice is present. Usually these symptoms usually disappear after interruption of treatment.
-Visual disturbance: Temporary visual disturbance, possibly due to changes in blood glucose levels at the start of treatment.
-Generic reactions.
The following adverse events have been reported with other sulfonylureas: erythrocytopenia, granulocyte deficiency, hemolytic anemia, various types of hematocrit, allergic vasculitis, hyponatremia, increased liver enzyme levels, and even cases of hepatic impairment (cholestasis and jaundice) and hepatitis, which improved after discontinuation of therapy, with a few cases of life-threatening hepatic failure.
Contraindications]
The use of this product is contraindicated in patients with the following conditions.
-known hypersensitivity to gliclazide or one of the excipients, other sulfonylureas, sulfonamides.
-Type 1 diabetes mellitus.
-Diabetic prodromal coma and coma, diabetic ketoacidosis.
-severe renal or hepatic insufficiency: in these cases the application of insulin is recommended.
-People treated with miconazole (see [Drug Interactions])
-Lactation (see [Pregnant and lactating women’s medication])
[Precautions].
Hypoglycemia: This product is recommended for patients who can eat regularly (including breakfast) because delayed meals, insufficient food or low carbohydrate can increase the risk of hypoglycemia, so it is important to consume carbohydrate regularly. Hypoglycemia is more likely to occur in patients who consume low-calorie foods, after considerable or prolonged exercise, after drinking alcohol, or in combination with other hypoglycemic drugs.
Hypoglycemia can occur after the application of sulfonylureas (see [Adverse Reactions]). Some cases can be severe and last for a long time. Hospitalization may be required and glucose drips may need to be continued for several days.
To reduce the risk of hypoglycemic episodes, it is important to choose the patient and the dose used carefully and to explain the hypoglycemia clearly to the patient.
The following factors will increase the risk of hypoglycemia.
-patient refusal or inability to cooperate (especially in the elderly)
-Malnutrition, irregular meals, forgotten meals, fasting or dietary changes.
-Imbalance between exercise and carbohydrate intake.
-Renal insufficiency.
-severe hepatic insufficiency.
-Overdose of this product.
-Some endocrine diseases: reduced thyroid function, pituitary and adrenal insufficiency.
-Combined with certain other drugs (see [Drug Interactions]).
Renal and hepatic insufficiency: The pharmacokinetics and/or pharmacodynamics of gliclazide may be altered in patients with hepatic insufficiency or severe renal insufficiency. Hypoglycemia may persist for a long time in these patients and should be managed appropriately.
Information to be explained to patients: The risks of hypoglycemia, including symptoms (see [Adverse Reactions]), treatment, and causes of hypoglycemia should be clearly explained to patients and their families. Patients should also be informed of the importance of compliance with dietary therapy, regular exercise and monitoring of blood glucose levels.
Poor blood glucose control: Patients receiving antidiabetic medications may have their blood glucose control affected by the following conditions: St. John’s Wort (Hypericum perforatum) preparations, fever, trauma, infection, surgery. Certain conditions may require the application of insulin.
The effectiveness of all oral hypoglycemic agents, including gliclazide, diminishes for many patients when applied for long periods of time. This may be due to progression in the severity of diabetes or to a reduced response to treatment, a phenomenon known as secondary failure, which should be distinguished from primary failure, where the drug proves to be ineffective at the time of first dosing. Appropriate dose adjustments as well as supervision of diet therapy and exercise must be considered before a patient is identified as a secondary failure.
Glucose metabolism disorders: Glucose disorders (including hypoglycemia and hyperglycemia) have been reported in diabetic patients (especially elderly patients) receiving fluoroquinolone combination therapy. All patients taking both this product and fluoroquinolones should have their blood glucose closely monitored.
Laboratory tests: Glycosylated hemoglobin level (or fasting intravenous glucose) is a better indicator to assess the efficacy of glucose-lowering therapy. Self-monitoring of blood glucose is very effective.
Treatment with sulfonylureas in patients with glucose-6-phosphate dehydrogenase deficiency can lead to hemolytic anemia. Because gliclazide is a sulfonylurea, patients with glucose-6-phosphate dehydrogenase deficiency should use this product with caution and consider a non-sulfonylurea option.
Effects on driving and operation of machinery.
This product has no or negligible effect on the ability to drive and/or operate machinery. However, patients should be alert for symptoms of hypoglycemia while driving and/or operating machinery, especially at the start of treatment.
[Pregnant and Lactating Women Use].
Pregnancy: There are very limited data on the use of gliclazide in pregnant women (less than 300 cases) and few data on the use of other sulfonylureas. In animals, gliclazide is not teratogenic (see [Pharmacology and Toxicology]). However, it is still recommended to avoid the use of gliclazide during pregnancy. To reduce the risk of congenital malformations associated with uncontrolled diabetes mellitus, it is important to control diabetes mellitus before pregnancy.
Oral hypoglycemic agents are not indicated during pregnancy, therefore insulin is used as the first choice for the treatment of diabetes mellitus. It is recommended to change from oral hypoglycemic drugs to treatment with insulin from the time you plan to become pregnant or when you find out you are pregnant.
Breastfeeding: There is a lack of information on the entry of gliclazide and its metabolites into breast milk. Considering the risk of hypoglycemia in newborns, the use of gliclazide is contraindicated in nursing women. Risk to newborns and infants cannot be excluded.
Fertility: No effect on fertility or reproductive capacity in male and female rats (see [Pharmacology and Toxicology]).
[Pediatric Use].
The safety and efficacy of the drug for use in children and adolescents have not been established. There is no evidence of pediatric use.
[Geriatric Use].
The dosing regimen should be the same as for patients under 65 years of age.
Drug Interactions]
(1) The following drugs may increase the risk of hypoglycemia
Combination application is prohibited.
-Miconazole (systemic administration, oral gel): increases hypoglycemic effect and may cause hypoglycemic symptoms, even coma.
Not recommended in combination with.
-Poetasone (systemic administration): increases the hypoglycemic effect of sulfonylureas (replaces their binding to plasma proteins and/or reduces their excretion).
The use of another anti-inflammatory drug is preferable; otherwise, patients need to be warned and the importance of self-monitoring emphasized. The dose of this product should be adjusted, if necessary, during and some time after anti-inflammatory drug therapy.
-Alcohol: increases the hypoglycemic response (by suppressing the compensatory response) and may also lead to hypoglycemic coma episodes. Avoid alcohol or drugs containing alcohol.
Caution in combination applications.
Because of potential hypoglycemic effects, hypoglycemia may occur when combined with: other hypoglycemic agents (insulin, acarbose, metformin, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) agonists), beta-blockers, fluconazole, angiotensin-converting enzyme inhibitors (captopril, Enalapril), H2-receptor antagonists, MAOIs, sulfonamides, clarithromycin, and non-steroidal anti-inflammatory drugs.
2) The following drugs may cause elevated blood glucose levels
Combination application is not recommended
-Danazol: diabetogenic effect. If the use of this drug cannot be avoided, patients need to be warned and the importance of self-monitoring of urine glucose and blood glucose needs to be emphasized. Adjustment of the dose of diabetes medication is required when using and discontinuing danazol therapy.
Caution is needed when combining
-Chlorpromazine (antipsychotic): Treatment with high doses of chlorpromazine (daily dose of chlorpromazine > 100 mg) increases blood glucose levels (decreases insulin release). Patients need to be informed and the importance of self-monitoring of blood glucose needs to be emphasized. Dose adjustment of diabetes treatment medication is required during and after discontinuation of treatment with antipsychotics.
Glucocorticoids (systemic and topical: intra-articular, dermal and rectal preparations) and ticoglutide (corticosteroids): increase blood glucose levels and may cause ketosis (reduced carbohydrate tolerance caused by glucocorticoids). Patients need to be informed and the importance of self-monitoring of blood glucose needs to be emphasized. Dose adjustment of diabetes treatment medication is required during and after discontinuation of treatment with adrenocorticosteroids.
-Ritodrine, salbutamol, terbutaline: (sedation) Raise blood glucose levels due to beta-2 agonist action. The importance of self-monitoring of blood glucose needs to be emphasized. Switch to insulin if necessary.
-St. John’s wort (through-leaf canary) preparation: reduces exposure to gliclazide. The importance of self-monitoring of blood glucose needs to be emphasized.
The following drugs can lead to disturbances in glucose metabolism and caution is needed when combined.
-Fluoroquinolones: If combined with fluoroquinolones, patients should be informed of the risk of glucose metabolism disorders and the importance of self-monitoring of blood glucose should be emphasized.
3) Other issues that should be considered for combined medications
-When anticoagulants (warfarin) are combined, sulfonylureas may enhance the anticoagulant’s anticoagulant properties. Dose adjustment of anticoagulant may have to be considered.
Drug overdose]
Sulfonylurea overdose may result in hypoglycemia.
Mild hypoglycemic symptoms without loss of consciousness or neurological manifestations should be treated by carbohydrate intake, medication dose adjustment, and/or diet modification. Close monitoring should be performed until the physician confirms that the patient is out of danger.
Severe hypoglycemic reactions, which may be accompanied by coma, convulsions or other neurological dysfunction, must be treated as an emergency and the patient must be admitted to the hospital immediately.
If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of 20 ml of a high concentration (50%) glucose solution followed by a continuous drip of a relatively low concentration glucose solution (10%) at a rate to maintain a blood glucose concentration of 1 g/L or more.
The physician should monitor the patient closely and decide whether intensive monitoring is needed based on the patient’s condition.
Because gliclazide binds strongly to proteins, dialysis is not effective in these patients.
Pharmacology and Toxicology]
Pharmacological effects
Gliclazide is a sulfonylurea oral hypoglycemic agent with different action characteristics from other sulfonylureas because of the nitrogen heterocyclic ring in its structure. Gliclazide can stimulate the secretion of insulin by pancreatic beta cells, thus lowering blood glucose level. Gliclazide restores peak first-phase insulin secretion in response to glucose, increases second-phase insulin secretion, and significantly increases postprandial or glucose-induced insulin secretory responses in patients with type 2 diabetes.
Gliclazide reduces microthrombosis through two mechanisms of action that may be related to diabetic vascular complications: (1) partial inhibition of platelet coagulation and adhesion and reduction of platelet activation markers (β-platelet globulin with thromboxane B2); and (2) modulation of endothelial fibrinolytic activity by increasing t-PA activity.
Toxicological studies
Genotoxicity tests did not show any abnormal reactions that could suggest harmful effects in humans. No teratogenicity was observed in reproductive toxicity tests, and fetal weight loss was observed at 25 times the maximum recommended human therapeutic dose. No carcinogenicity test was conducted.
Pharmacokinetics
Absorption
After oral administration, the plasma concentration of the drug increased progressively during the first 6 hours and reached steady state between 6 and 12 hours.
In a bioequivalence study comparing imported and domestic formulations in 18 healthy volunteers from China, large inter-individual differences in pharmacokinetic parameters were found, which may be related to genetic polymorphisms of its metabolizing enzymes. This suggests that the clinical use of the drug should be individualized. Foreign data showed little intra-individual variation.
Gliclazide is completely absorbed. Ingestion does not affect the rate and extent of absorption.
Distribution
The plasma protein binding rate is approximately 95%. The volume of distribution is approximately 30 liters. Once daily gliclazide extended-release tablets are capable of maintaining effective plasma concentrations of gliclazide for 24 hours.
Biotransformation
Gliclazide is primarily metabolized in the liver and excreted in the urine after metabolism. Less than 1% of the prototype drug is present in the urine. No active metabolites are detected in plasma.
Clearance
The clearance half-life of gliclazide ranges from approximately 12 hours to 20 hours.
Linearity/non-linearity
There is a linear relationship between the dose administered and the area under the concentration curve over a dose range of 120 mg.
Special Populations
Geriatric Patients
There are no clinically meaningful changes in pharmacokinetic parameters in elderly patients.
Storage
Store under shade and seal.
Package
Pharmaceutical aluminum foil, polyvinyl chloride solid pharmaceutical hard tablets, 10 tablets/plate x 2 plates/box.
Expiration date
18 months
Execution Standard
Approval Number】 State Drug Administration H20103045
Manufacturer
Enterprise name: Yichang Renfu Pharmaceutical Co.
Production Address: No. 99, Mingfeng Avenue, Yuanan County, Hubei Province
Postal Code: 444299
Telephone number: 0717-6345005
0717-6345020(Sales)
0717-6343387(Quality)
Fax number：0717-6345002
Website: http://www.ycrenfu.com.cn
If you have any questions, you can contact with the manufacturer directly.