Glimepiride Tablets Instructions

Date of approval: Month of year
Date of revision: January
Glimepiride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Glimepiride Tablets
Trade name: Jiaheluo
English Name: Glimepiride Tablets
Hanyu Pinyin: Geliemeiniao 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: 490.62
Properties]: This product is a white tablet or coloring shaped 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 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】1mg; 2mg
Dosage]
Dosage
In principle, the dose of Glimepiride Tablets should be adjusted according to the target blood glucose level. The dose of Glimepiride tablets must be the lowest dose sufficient to achieve the target metabolic control.
During the treatment with Glimepiride Tablets, blood glucose and urine glucose levels must be measured regularly. In addition, regular measurement of glycated 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 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
In patients with well-controlled diabetes, the usual daily dose is 1mg to 4mg Glimepiride 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 to be taken immediately before breakfast or, if breakfast is skipped, 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 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 tablets is a long-term treatment.
-Change from other oral hypoglycemic agents to glimepiride tablets
There is no clear dose relationship between Glimepiride tablets and other oral diabetes treatment medications. When replacing other oral hypoglycemic agents with Glimepiride tablets, the same initial dose as starting with 1 mg per day is recommended. 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 tablets
With some exceptions, patients with type 2 diabetes treated with insulin may be switched to glimepiride tablets.
Replacement of insulin with glimepiride tablets should be done under close monitoring by a physician.
Dosage
This product is to be taken orally.
-Special Populations
Renal insufficiency
There is limited information regarding the use of Glimepiride Tablets in patients with renal insufficiency. Patients with impaired renal function may be more sensitive to the hypoglycemic effect of Glimepiride Tablets (see [Pharmacokinetics]).
[Adverse Reactions] According to foreign literature
-Systemic disorders.
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.
Hematological changes during the course of Glimepiride tablets treatment: rare, thrombocytopenia, in disseminated cases there may be leukopenia, erythrocytopenia, granulocyte deficiency, hemolytic anemia and holocytopenia.
-Metabolic and nutritional disorders.
Due to the hypoglycemic effect of glimepiride 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, decreased concentration, impaired alertness and responsiveness, depression, confusion, speech disturbances, aphasia, visual disturbances, tremor, local paresthesia, abnormal sensation, 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 profuse sweating, moist skin, anxiety, tachycardia, hypertension, palpitations, angina and arrhythmias may be present.
The clinical phenomena of severe hypoglycemic episodes may be similar to strokes.
When hypoglycemia is corrected, these symptoms almost always resolve.
-Ocular abnormalities.
Temporary visual impairment may result, especially at the beginning of treatment, due to changes in blood glucose. The cause may be a temporary change in tightness leading to a change in lens refraction, depending on the blood glucose level.
-Gastrointestinal disturbances.
Occasionally, gastrointestinal symptoms such as nausea, vomiting and diarrhea, epigastric pressure or feeling of 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 tablets.
[Contraindications].
This product should not be used for the following conditions.
-People who are hypersensitive 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
No experience has been accumulated regarding the use of Glimepiride tablets in patients with severe hepatic impairment and dialysis patients. For patients with severe hepatic impairment, insulin should be used instead, and more importantly, optimal metabolic control should be achieved.
[Caution].
Warning
Under stressful conditions (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 testing is particularly necessary.
Factors that predispose to hypoglycemia include.
-Unwillingness or inability to cooperate (most often seen in older patients)
-Malnutrition, 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
-Renal impairment
-Severe liver impairment
-Overdose of glimepiride 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)
-In combination with certain other drugs (see [Drug Interactions])
-Treatment with glimepiride 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 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 the reverse regulation of adrenaline in the body (see [Adverse Reactions]) may be mild or non-existent.
Almost all of these hypoglycemic symptoms disappear after immediate oral administration of carbohydrates (glucose or sucrose).
It is known from other sulfonylureas that hypoglycemia can recur despite successful control of hypoglycemia at the beginning. 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 initiation or change in therapy, or when glimepiride tablets are taken irregularly. This may affect, for example, the ability to drive or operate machinery.
[For pregnant and lactating women].
Pregnancy.
Glimepiride tablets are contraindicated during pregnancy. Otherwise there is a risk of fetal harm. Patients who are pregnant must be switched to insulin. 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 tablets are contraindicated in breastfeeding women. If necessary, patients must switch to insulin or stop breastfeeding.
[Pediatric Dosage].
There is a lack of information on the safety and efficacy of this product in children.
According to foreign literature, a trial evaluating the pharmacokinetics, safety and tolerability of glimepiride 1 mg administered as a single dose 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 Use].
Use as directed by your physician.
Drug Interactions]
Based on experience with glimepiride 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, tetracycline family, 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, phenothiazines, epinephrine and other sympathomimetic drugs, niacin (at high doses), laxatives (when used chronically), phenytoin, diazoxide, hyperglycemia, 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 tablets in some unpredictable manner.
Glimepiride may enhance or diminish the effect of coumarin derivatives.
Drug Overdose]
Acute overdose and prolonged treatment with excessive doses of glimepiride may result in life-threatening severe hypoglycemia. Once an overdose of Glimepiride 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, 0.5mg to 1mg doses of glucagon intravenously, subcutaneously or intramuscularly may be considered as an alternative.
Especially in the treatment of hypoglycemia after accidental administration of glimepiride 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 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 properties
Glimepiride lowers blood glucose levels in both healthy individuals and patients with type 2 diabetes, mainly by stimulating insulin release from pancreatic b-cells. This effect is mainly based on increasing the responsiveness of pancreatic islet b cells to physiological concentrations of glucose. When an equivalent reduction in blood glucose was achieved, the administration of low doses of glimepiride to animals and healthy volunteers resulted in a smaller release of insulin compared to glibenclamide. This fact suggests that glimepiride also has significant extra-pancreatic (insulin-sensitizing and insulinomimetic) effects.
In addition, glimepiride has less effect on the cardiovascular system than other sulfonylureas. It reduces platelet aggregation (animal and in vitro data) and leads to a significant reduction in atherosclerotic plaque formation (animal data).
 Insulin release.
Like all other sulfonylureas, glimepiride regulates insulin secretion by interacting with the pancreatic b-cell membrane ATP-dependent potassium channel. Unlike other sulfonylureas, glimepiride binds specifically to a 65 kDa protein in the β-cell membrane. This interaction of glimepiride with its binding protein determines the possibility of ATP-dependent opening or closing of potassium channels.
Glimepiride closes potassium channels and induces b-cell depolarization, while opening voltage-sensitive calcium channels, leading to an influx of calcium ions into the cell and, ultimately, an increase in intracellular calcium concentration, which stimulates insulin release through cytokinesis.
The binding and separation of glimepiride from its binding protein is more rapid and frequent than that of glibenclamide. Therefore, it can be hypothesized that this high exchange rate characteristic of glimepiride with binding proteins is responsible for its significant sensitizing effect on glucose and protection against beta-cell desensitization and premature depletion.
Insulin sensitizing effect: Glimepiride enhances the normal action of insulin on peripheral glucose uptake (human and animal data).
Insulinomimetic effect: Glimepiride mimics the effects of insulin on peripheral glucose uptake and hepatic glucose output.
Peripheral glucose uptake occurs via transfer into muscle and adipocytes, and glimepiride directly increases the number of glucose transfer molecules in the plasma membrane of muscle and adipocytes. Glimepiride increases the activity of glycosyl-phosphatidylinositol-specific phospholipase C. As a result, cellular cAMP levels are reduced, leading to decreased protein kinase A activity; thereby stimulating glucose metabolism.
Glimepiride inhibits hepatic glucose production by increasing the intracellular concentration of fructose 2,6-diphosphate, as fructose 2,6-diphosphate inhibits glucose xenobiogenesis.
Effects on platelet aggregation and atherosclerotic plaque formation: Glimepiride reduces platelet aggregation both in vitro and in vivo. This effect may result from the selective inhibition of cyclooxygenase, which is responsible for the formation of thromboxane A, an important endogenous platelet aggregation factor.
Glimepiride significantly reduced the formation of atherosclerotic plaques in animals. The underlying mechanism remains to be elucidated.
Cardiovascular effects: Through ATP-sensitive potassium channels (see above), sulfonylureas also affect the cardiovascular system. Glimepiride has significantly fewer effects on the cardiovascular system compared to traditional sulfonylureas (animal data). This may be explained by the specific nature of its interaction with ATP-sensitive potassium channel binding proteins.
 Pharmacodynamic properties
The minimum effective oral dose in healthy individuals is approximately 0.6 mg. The effects of glimepiride are dose dependent and reproducible. The physiological response of reduced insulin secretion during intense exercise persists in the presence of glimepiride.
There was no significant difference in the therapeutic effect of glimepiride, whether administered 30 minutes before or immediately before a meal. Once daily dosing is sufficient to control the metabolism of diabetic patients for 24 hours. In addition, good metabolic control was achieved in 12 of 16 patients with renal insufficiency (creatinine clearance of 4 to 79 ml/min) in a clinical study.
Although the hydroxyl metabolites of glimepiride caused a small but significant reduction in serum glucose in healthy subjects, this was only a small part of the overall effect of the drug.
 Clinical effectiveness
A 24-week controlled clinical trial was conducted in 285 randomized pediatric patients (aged 8-17 years) with type 2 diabetes (glimepiride up to 8 mg per day or metformin up to 2000 mg per day). Both glimepiride and metformin showed a significant reduction in HbA1c from baseline.
No significant differences were observed between treatment groups. Glimepiride did not show non-inferiority to metformin.
After glimepiride treatment, no new safety events were observed in children compared to adults with type 2 diabetes. No long-term efficacy and safety data are available for pediatric patients.
Preclinical Toxicology Studies.
Long-term toxicity.
Decreased serum glucose levels and pancreatic b-cell degranulation were observed in chronic and subchronic toxicity tests in rats, mice and dogs. These reactions are usually reversible and are considered pharmacodynamically relevant to the product. A chronic toxicity study in dogs found cataracts in two dogs in the high dose administration group (320 mg/kg body weight). However, in vitro bovine crystal studies and rat studies showed no cataractogenic or synergistic cataractogenic toxicity with glimepiride.
Carcinogenicity.
Rat studies suggest no potential carcinogenic toxicity of this product. Due to the chronic stimulation of b-cells by this product, mice tests revealed an increased incidence of islet cell hyperplasia and islet cell adenoma.
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 cesarean section. Deformities of the humerus, femur, shoulder, and hip joints were observed in the natural born offspring of dams given high doses of this product. Oral administration during late gestation and/or lactation in dams 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 observed. 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 may be pharmacodynamic-related reactions to high doses of the drug, rather than toxicities specific to the drug itself.
 [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) is reached approximately 2.5 hours after oral administration (309 ng/ml for multiple doses of 4 mg daily), and there is 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), high protein binding (>99%), and low clearance (approximately 48 ml/min).
Glimepiride is secreted into the milk of animals.
The mean serum half-life is related to serum concentrations at multiple dose administrations and is approximately 5 to 8 hours. A slightly prolonged 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 titration trial of multiple dosing in 16 patients with NIDDM 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 tightly closed, below 25℃.
Package
1mg: aluminum-plastic packaging, 12 tablets/plate/box, 2×12 tablets/plate/box, 3×12 tablets/plate/box, 4×12 tablets/plate/box, 5×12 tablets/plate/box.
2mg: aluminum-plastic packaging, 10 tablets/plate/box, 2×10 tablets/plate/box, 3×10 tablets/plate/box, 4×10 tablets/plate/box, 5×10 tablets/plate/box.
【Validity】12 months
【Execution standard
Approval number】1mg: State medicine quanzhi H20010571
2mg：Guohuazhongzhi H20061256
Manufacturer
Company Name: Shandong Xinhua Pharmaceutical Co.
Address: No. 14, East Road, Zhangdian District, Zibo City, Shandong Province
Postal code: 255005
Telephone number: 0533-2166666
Fax number: 0533-2184991
Web address: www.xhzy.com