Date of approval.
Date of revision.
Glimepiride Dispersible Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Glimepiride Dispersible Tablets
English name: Glimepiride Dispersible Tablets
Hanyu Pinyin: Geliemeiniao Fensan Pian
Ingredients】The main ingredient of this product is Glimepiride.
Chemical name: 1-[[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carbonylamino)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.
Chemical structure formula.
Molecular formula: C24H34N4O5S
Molecular weight: 490.6
【Properties】This product is a white tablet.
Indications】
It is indicated for type 2 diabetes mellitus whose blood glucose cannot be adequately controlled by diet control, exercise therapy and weight reduction.
Glimepiride dispersible tablets are not indicated for the treatment of type 1 diabetes (e.g., treatment of diabetic patients with a history of ketoacidosis), diabetic ketoacidosis or diabetic prodromal coma or coma.
Specification】(1) 1mg; (2) 2mg (in glimepiride)
Dosage]
Dosage
In principle, the dose of Glimepiride Dispersible Tablets should be adjusted according to the target blood glucose level. The dose of Glimepiride dispersible tablets must be the lowest dose sufficient to achieve the target metabolic control.
During the treatment with Glimepiride Dispersible Tablets, blood glucose and urine glucose levels must be measured regularly. In addition, regular determination of glycosylated hemoglobin is recommended.
If errors such as missed doses occur, they must not be corrected by subsequent administration of larger doses of the drug.
Measures to deal with cases of inability to take the medication at the prescribed time (especially forgetting to take the medication or not eating) or for various reasons must be discussed and agreed upon by both physician and patient.
-Starting dose and dose adjustment
The starting dose is 1 mg of glimepiride dispersible tablets daily.
If necessary, the daily dose may be increased. Regular blood glucose monitoring is recommended for dose adjustment and the recommended dose should be increased gradually, e.g. every 1-2 weeks to 2mg, 3mg, 4mg, 6mg daily.
-Dose range for patients with well-controlled diabetes
The usual daily dose for patients with well-controlled diabetes is 1mg to 4mg of Glimepiride dispersible tablets. Daily doses greater than 6mg are more effective in only a small number of patients.
-Dosing Distribution
The timing and distribution of dosing is determined by the physician based on the patient’s current lifestyle. Generally, one dose a day is sufficient. It is recommended that the dose be taken immediately before breakfast or, if breakfast is not eaten, immediately before the first regular meal.
It is very important not to miss a meal after taking the medication.
Due to improved control of diabetes and increased insulin sensitivity, the need for glimepiride may decrease during treatment. Therefore, to avoid hypoglycemia, timely dose reduction or discontinuation of glimepiride dispersible tablets must be considered. Dose adjustment should also be considered if the patient’s weight, lifestyle changes, or other factors that increase hypoglycemia or hyperglycemia sensitivity are present.
-Duration of treatment
The normal application of Glimepiride Dispersible Tablets is a long-term treatment.
-Change from other oral hypoglycemic agents to glimepiride dispersible tablets
There is no clear dose relationship between Glimepiride Dispersible Tablets and other oral diabetes treatment medications. When replacing other oral hypoglycemic agents with Glimepiride dispersible tablets, the same initial dose is recommended as when starting with 1 mg per day. This also applies to patients who were previously on the maximum dose of another oral diabetes treatment medication.
The efficacy and duration of action of the previously used diabetes treatment medication must be considered. Temporary discontinuation of the medication may be required to avoid the risk of hypoglycemia from the superimposition of drug effects.
-Change from insulin to glimepiride dispersible tablets
Patients with type 2 diabetes treated with insulin may be switched to glimepiride dispersible tablets, with some exceptions.
Replacement of insulin with glimepiride dispersible tablets should be done under close monitoring by a physician.
Dosage
Take this product orally or after dispersion in water.
-Special Populations
Renal insufficiency
There is limited information regarding the use of Glimepiride Dispersible Tablets in patients with renal insufficiency. Patients with impaired renal function may be more sensitive to the hypoglycemic effect of Glimepiride Dispersible Tablets (see [Pharmacokinetics]).
[Adverse Reactions].
According to foreign literature.
-systemic disease
Occasionally, allergic or pseudomorphic reactions such as scratching, urticaria or rash may occur. These mild reactions may progress to severe reactions with respiratory distress and decreased blood pressure, sometimes progressing to shock. If urticaria occurs, it is important to notify your doctor immediately.
In disseminated cases, a decrease in blood sodium concentration and allergic vasculitis or cutaneous photosensitivity may occur.
-Disorders of the blood and lymphatic system.
Hematologic changes during treatment with Glimepiride dispersible tablets: Rarely, thrombocytopenia, in disseminated cases there may be leukopenia, erythrocytopenia, granulocyte deficiency, hemolytic anemia and holocytopenia.
Cases of severe thrombocytopenia and thrombocytopenic purpura with platelet counts less than 10,000/ul have been reported in post-marketing experience (frequency of occurrence unknown).
-Metabolic and nutritional disorders.
Due to the hypoglycemic effect of glimepiride dispersible tablets, hypoglycemia or prolonged hypoglycemia may occur based on information known for other sulfonylureas.
Possible symptoms of hypoglycemia include headache, extreme hunger, nausea, vomiting, lethargy, sleepiness, sleep disturbances, irritability, aggressive behavior, impaired concentration, impaired alertness and responsiveness, depression, confusion, speech disturbances, aphasia, visual disturbances, tremor, local paresthesia, sensory abnormalities, dizziness, weakness, loss of self-control, delirium, convulsions, drowsiness, and loss of consciousness or even coma, the Superficial respiration and bradycardia.
In addition, signs of adrenergic counterregulation such as sweating, moist skin, anxiety, tachycardia, hypertension, palpitations, angina and arrhythmia may be present.
The clinical phenomena of severe hypoglycemic episodes may be similar to a stroke.
When hypoglycemia is corrected, these symptoms almost always resolve.
-Ocular organ disease.
Especially at the beginning of treatment, temporary visual impairment may result due to changes in blood glucose. The cause may be a temporary change in tension leading to a change in lens refractive error, depending on the blood glucose level.
-Gastrointestinal disorders.
Occasionally, gastrointestinal symptoms such as nausea, vomiting, diarrhea, epigastric pressure or fullness, and abdominal pain may occur.
In disseminated cases, hepatitis, elevated liver enzymes and/or bile depression and jaundice) may occur and may progress to life-threatening liver failure, but may recover after withdrawal of glimepiride dispersible tablets.
Taste disorders (frequency of occurrence unknown)
-Dermal and subcutaneous tissue disorders.
Hair loss (frequency of occurrence unknown)
-All types of tests
Like all sulfonylureas, glimepiride may cause weight gain (frequency unknown).
-Other adverse reactions reported post-marketing.
Angioedema and Stevens-Johnson syndrome, delayed cutaneous porphyria, aplastic anemia, thrombocytopenic purpura, hepatic porphyria and disulfiram-like reactions, hyponatremia, and syndrome of abnormal secretion of antidiuretic hormone (SIADH).
Contraindications]
This product should not be used in the following conditions.
-Hypersensitivity to glimepiride, other sulfonylureas, other sulfonamides, or any of the ingredients in this product.
-Women during pregnancy.
-Women during lactation.
-Patients with type 1 diabetes, diabetic coma, ketoacidosis
There is no accumulated experience with the use of Glimepiride Dispersible Tablets in patients with severe hepatic impairment and in dialysis patients. For patients with severe hepatic impairment should be switched to insulin, and more importantly, to achieve optimal metabolic control.
[Caution].
Warnings
In stressful situations (e.g., trauma, surgery, febrile infection) blood glucose regulation may not be optimal, and temporary switch to insulin may be necessary to maintain good metabolic control.
Precautions
During the first few weeks of treatment, the risk of hypoglycemia may increase and careful monitoring is particularly necessary.
Factors that predispose to hypoglycemia include
Reluctance or inability to cooperate (most often seen in older patients)
Poor nutrition, irregular meal times or missed meals
Dietary changes
Imbalance between physical exertion and carbohydrate intake
Use of alcoholic beverages, especially in the absence of meals
Impairment of renal function
Severe liver impairment
Overdose of glimepiride dispersible tablets
Certain disorders of the endocrine system that affect carbohydrate metabolism or reverse regulation of hypoglycemia (e.g., certain thyroid disorders and anterior pituitary or adrenal cortical insufficiency)
Combination with certain other drugs (see [Drug Interactions])
Treatment with Glimepiride dispersible tablets in the absence of an indication
If these risk factors for hypoglycemia are present, it may be necessary to adjust the dose of Glimepiride Dispersible Tablets or the entire treatment regimen. This also applies when disease or changes in the patient’s lifestyle occur during the course of treatment.
In the elderly, when hypoglycemia progresses gradually, in patients with autonomic neuropathy, or in combination with beta-blockers, colistin, reserpine, guanethidine, or other sympathetic blocking drugs, symptoms of hypoglycemia reflecting reverse regulation of adrenaline in the body (see [Adverse Reactions]) may be mild or nonexistent.
Almost all of these hypoglycemic symptoms disappear after immediate oral carbohydrate (glucose or sucrose).
It is known from other sulfonylureas that hypoglycemia can recur despite successful initial control of hypoglycemia. Therefore, patients should still be closely monitored.
Severe hypoglycemia requires immediate treatment and follow-up by the physician, and in some cases, the patient needs to be hospitalized.
Treatment with sulfonylureas in patients with G6PD deficiency may lead to hemolytic anemia. Because glimepiride is a sulfonylurea, patients with G6PD deficiency should be cautioned and non-sulfonylurea alternatives should be considered.
Hypoglycemia or hyperglycemia may lead to impaired alertness and responsiveness, especially after treatment initiation or change, or when glimepiride dispersible tablets are not taken regularly. This may affect, for example, the ability to drive or operate machinery.
Sulfonylureas increase the risk of cardiovascular mortality, and oral hypoglycemic agents (methylsulfonylurea) have been reported to be associated with increased cardiovascular mortality compared to diet alone or diet plus insulin therapy. Patients should be aware of the potential risks and benefits of using this product and alternative treatments.
Pregnant women and nursing mothers
Pregnancy
Glimepiride dispersible tablets are contraindicated during pregnancy. Otherwise there is a risk of fetal harm. Patients must be switched to insulin during pregnancy. Patients who are planning to become pregnant should inform their physicians. It is recommended that these patients be switched to insulin.
Breastfeeding
To prevent possible breast milk ingestion and possible child harm, Glimepiride dispersible tablets are contraindicated in breastfeeding women. If necessary, patients must switch to insulin or stop breastfeeding.
[Pediatric use].
There is a lack of information on the safety and efficacy of this product in children.
A trial evaluating the pharmacokinetics, safety and tolerability of a single dose of glimepiride 1 mg in 30 pediatric patients (aged 10-17 years) with type 2 diabetes showed that the mean AUC (0-last), Cmax and t1/2 were similar to those previously observed in adults.
[Geriatric Dosage].
No special instructions, or as directed by a physician.
Drug Interactions]
Based on experience with glimepiride dispersible tablets and other sulfonylureas, the following drug interactions should be noted.
Glimepiride is metabolized by cytochrome P450 (CYP2C9). The possible effects of glimepiride and CYP2C9 agonists (rifampicin) or inhibitors (fluconazole) need to be considered when used together.
The administration of one of the following drugs that potentially cause a decrease in blood glucose can lead to the development of hypoglycemia in some cases, for example.
Pautazone, azapiazone, hydroxybutazone, insulin and oral hypoglycemic agents, salicylates, para-aminosalicylic acid, proprotein synthesis steroids and androgens, chloramphenicol, coumarin derivatives, fenfluramine, feneladol, fibrates, ACE inhibitors, fluoxetine, guanethidine, cyclophosphamide, propyzamide, isocyclophosphamide, sulfopiridone, clarithromycin, sulfonamide antibiotics, tetracyclines, monoamine oxidase inhibitors, quinolone antibiotics, probenecid, miconazole, hexaconitine (administered parenterally at high doses), tritocin, trimethoprim, fluconazole.
The hypoglycemic effect and elevated blood glucose levels may be diminished by taking one of the following drugs, for example.
Estrogens and progestins, diuretics, thyroid hormones, corticosteroids, chlorpromazine and phenothiazines, epinephrine and other sympathomimetic drugs, niacin (at high doses), laxatives (when used chronically), phenytoin, diazoxide, hyperglycemics, barbiturates, rifampin, acetazolamide.
H2 receptor antagonists, ß-blockers, colistin and rifampin may enhance or diminish the hypoglycemic effect.
The adrenergic counter-regulatory signs of hypoglycemia may be diminished or even absent in the presence of anti-sympathetic drugs such as ß-blockers, colistin, guanethidine and rifampin.
Acute or chronic alcohol intake may enhance or diminish the hypoglycemic effect of glimepiride dispersible tablets in some unpredictable manner.
Glimepiride may potentiate or diminish the effect of coumarin derivatives.
Bile acid polyvalent chelator: The combination of coleviram and glimepiride decreases the absorption of glimepiride in the gastrointestinal tract. No drug interaction was observed between glimepiride and colevelam when taken at least four hours after glimepiride. Therefore, glimepiride should be taken at least four hours earlier than colevelam.
Drug Overdose
Acute overdose and prolonged treatment with excessive doses of glimepiride may result in life-threatening severe hypoglycemia.
Once an overdose of Glimepiride Dispersible Tablets is detected, the physician must be notified immediately without delay. The patient must immediately ingest sucrose and, if possible, glucose, unless the physician is aware of the treatment overdose and is certain of the patient’s progress.
Careful monitoring is necessary until the physician is certain that the patient is out of danger. It is important to remember that hypoglycemia can recur after the initial recovery.
Sometimes hospitalization is necessary and should even be used as a preventive measure. In particular, severe drug overdoses and severe reactions with signs such as loss of consciousness or other severe neurological deficits are medical emergencies and require immediate treatment and hospitalization.
If the patient loses consciousness, concentrated glucose solution should be administered intravenously (e.g., for adults, start with 40 ml of 20% solution). In adults, an intravenous, subcutaneous or intramuscular dose of glucagon at 0.5 mg to 1 mg may be considered as an alternative.
Especially in the treatment of hypoglycemia after inadvertent administration of glimepiride dispersible tablets in infants and children, the dose of glucose must be carefully controlled and the possibility of the occurrence of hyperglycemic risk must be considered and should be controlled by monitoring blood glucose.
Patients who have ingested life-threatening dosages of glimepiride dispersible tablets should be detoxified (e.g., gastric lavage and medicinal charcoal).
After completion of acute glucose replacement, it is often necessary to give glucose infusions intravenously at lower concentrations to ensure that hypoglycemia does not recur. The patient’s blood glucose levels should be carefully monitored for at least 24 hours. The risk of hypoglycemia or recurrent hypoglycemia may persist for several days in severe cases of prolonged drug administration.
Pharmacology and Toxicology]
Pharmacological effects
Glimepiride is an oral sulfonylurea hypoglycemic agent that acts mainly by stimulating insulin release from pancreatic β-cells, which is based on increasing the responsiveness of pancreatic β-cells to physiological concentrations of glucose. In addition, glimepiride also has an extra-pancreatic hypoglycemic effect.
Toxicological studies
Repeated dosing toxicity: Decreased serum glucose levels and pancreatic cell degranulation were observed in repeated dosing and subchronic toxicity tests in rats, mice and dogs. These reactions are usually reversible and are considered to be pharmacodynamically relevant to the product. A repeat dosing toxicity study in dogs found cataracts in two dogs at a dose of 320 mg/kg. In vitro bovine crystal studies, rat studies showed no cataractogenic toxicity and synergistic cataractogenic toxicity of glimepiride.
Genotoxicity: Glimepiride was not found to be mutagenic or genotoxic.
Reproductive toxicity: Glimepiride administration to rats had no adverse effects on fertility, pregnancy or the process of delivery. Fetal growth was slightly retarded in litters born by caesarean section. Deformities of the humerus, femur, shoulder, and hip joints were observed in the natural-born offspring of dams given high doses of glimepiride. Oral administration of glimepiride to females during late gestation and/or lactation resulted in increased stillbirths and limb deformities. No significant effects of glimepiride on offspring growth and development, functional and cognitive behavior, memory, or reproductive performance were seen. Glimepiride can be ingested by young rats through breast milk, and administration of high doses of glimepiride to mothers resulted in hypoglycemia in nursing pups. Fetal malformations (e.g., eye deformities, cleft and bone abnormalities) can occur in rats and rabbits, and abortion and increased intrauterine mortality occur in rabbits. All reproductive toxicities are likely to be pharmacodynamic-related reactions to high doses of the drug and not specific to the drug itself.
Carcinogenicity: A 30-month study in rats given 5000 ppm glimepiride in feed (approximately 340 times the maximum recommended human clinical dose based on body surface area) resulted in no carcinogenic effects. Mice given glimepiride for 24 months resulted in an increased and dose-related incidence of benign pancreatic tumors, considering the possible result of chronic stimulation of the pancreas. The dose that did not form pancreatic tumors in mice was 320 ppm of feed, or 46-54 mg/kg/d, which is approximately 35 times the maximum recommended dose for humans based on body surface area.
【Pharmacokinetics】.
According to foreign literature.
The bioavailability of glimepiride after oral administration is complete. The absorption is not affected by taking it with meals. Maximum serum concentration (Cmax) was reached approximately 2.5 hours after oral administration (309 ng/ml for multiple doses of 4 mg daily), and there was a linear relationship between dose and Cmax and AUC (area under the time/concentration curve).
Glimepiride has a very low volume of distribution (approximately 8.8 liters, roughly equivalent to the distribution space of albumin), a high protein binding rate (>99%), and a low clearance rate (approximately 48 ml/min).
Glimepiride is secreted into the milk of animals.
The mean serum half-life is related to the serum concentration at multiple dose administration and is approximately 5 to 8 hours. A slight prolongation of the half-life is observed with high dose administration.
Following administration of a single dose of radiolabeled glimepiride, 58% of the radioactivity appeared in the urine and 35% in the feces. No prototype drug was detected in the urine. Two metabolites that may be produced by hepatic metabolism (the main enzyme is CYP2C9) were detected in urine and feces: hydroxyl derivatives and carboxyl derivatives. The half-lives of these metabolites after oral administration of glimepiride were 3-6 hours and 5-6 hours, respectively.
Comparison of daily single dose administration with multiple doses did not show significant differences in pharmacokinetics and intra-individual variability was very low. There was no drug accumulation.
The pharmacokinetics of this product were similar in both men and women, and in older (over 65 years) and younger patients.
In a single-dose, open trial in 15 patients with renal insufficiency, glimepiride (3 mg) was administered to three groups of patients with different levels of mean creatinine clearance (CLcr); (Group I, CLcr = 77.7 mL/min, n = 5), (Group II, CLcr = 27.4 mL/min, n = 3), and (Group III, CLcr = 9.4 mL/ min, n = 7). Glimepiride was well tolerated in all 3 groups. In patients with low creatinine clearance, there was a trend toward increased glimepiride clearance and decreased mean plasma concentrations, most likely due to more rapid clearance resulting from lower protein binding. Renal clearance of both metabolites was impaired. A 3-month trial of multiple dose titration in 16 type 2 diabetic patients with renal insufficiency, using doses ranging from 1-8 mg per day, yielded results consistent with those observed after a single dose. All patients with a CLcr below 22 mL/min had their blood glucose levels adequately controlled using a dose of only 1 mg per day. Overall, there was no risk of additional drug accumulation in this group of patients.
Whether glimepiride is dialyzable remains unclear.
The pharmacokinetics of this product in 5 non-diabetic post-biliary surgery patients were similar to those in healthy subjects.
Storage】Store under 25℃ in an airtight place.
Package】Aluminum-aluminum package, (1) 1mg: 12 tablets/plate; (2) 2mg: 12 tablets/plate.
Expiration date】18 months
【Execution standard
Approval number】1mg: State medicine quantification H20100183; 2mg: State medicine quantification H20100182
[Drug Marketing License Holder
Name: Shiyapharm Group Ouyi Pharmaceutical Co.
Registered address: No. 88 Yangzi Road, Shijiazhuang Economic and Technological Development Zone
Postal Code: 052165
Telephone number: 0311-87886158, 0311-67163660
Fax number: 0311-87171665
Manufacturer
Company name: Shiyapharm Group Ouyi Pharmaceutical Co.
Address: No. 88 Yangzi Road, Shijiazhuang Economic and Technological Development Zone
Postal Code: 052165
Telephone number: 0311-87886158, 0311-67163660
Fax number: 0311-87171665