Pharmacological properties
Pharmacodynamics. Glimepiride is an orally active hypoglycemic agent belonging to the sulfonylurea group. It can be used in type 2 diabetes mellitus.
Glimepiride acts primarily by stimulating the release of insulin from pancreatic beta cells.
As with other sulfonylureas, this effect is based on an increase in the sensitivity of pancreatic cells to physiological stimulation by glucose. In addition, glimepiride has a pronounced extrapancreatic effect, which is also characteristic of other sulfonylureas.
Insulin release. Sulfonylureas regulate insulin secretion by closing the ATP-dependent potassium channel located in the membrane of the pancreatic beta cell. Closing the potassium channel causes depolarization of the beta cell and, by opening calcium channels, leads to an increase in calcium influx into the cell, which in turn leads to insulin release by exocytosis.
Glimepiride binds with a high rate of substitution to a beta-cell membrane protein associated with the ATP-dependent potassium channel, but the location of its binding site differs from the usual binding site of sulfonylurea drugs.
Extrapancreatic activity. Extrapancreatic effects include, for example, improving the sensitivity of peripheral tissues to insulin and reducing insulin utilization by the liver.
The utilization of blood glucose by peripheral tissues (muscle and adipose tissue) occurs with the help of special transport proteins located in the cell membrane. The transport of glucose into these tissues is limited by the speed of the glucose utilization step. Glimepiride very quickly increases the number of active glucose-transporting molecules on the plasma membranes of muscle and adipose tissue cells, which leads to stimulation of glucose uptake.
Glimepiride increases the activity of glycosylphosphatidylinositol-specific phospholipase C, with which drug-induced lipogenesis and glycogenesis can be correlated in isolated muscle and fat cells.
Glimepiride inhibits hepatic glucose production by increasing intracellular concentrations of fructose-2,6-bisphosphate, which in turn inhibits gluconeogenesis.
General characteristics. For healthy individuals, the minimum effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute exercise, i.e., decreased insulin secretion, is maintained under glimepiride.
No significant difference in the effect of glimepiride was found when the drug was taken 30 minutes before a meal or immediately before a meal. In patients with diabetes, adequate metabolic control over 24 hours was ensured when the drug was taken once a day.
Although the hydroxylated metabolite causes a small but significant decrease in blood glucose levels in healthy individuals, this is only a minor component of the overall action of the drug.
Use in combination with metformin. Improved metabolic control has been demonstrated with combination therapy with glimepiride compared to metformin monotherapy in patients whose diabetes is not adequately controlled with maximum doses of metformin.
Use in combination with insulin. Data on the use of the drug in combination with insulin are limited. In patients whose diabetes is not adequately controlled with maximum doses of glimepiride, concomitant insulin treatment may be initiated. This combination has been shown to achieve the same improvement in metabolic control as insulin monotherapy; however, a lower average insulin dose is required with combination therapy.
Special patient groups. Children, including adolescents. In a 24-week active-controlled clinical trial (glimepiride up to 8 mg/day or metformin up to 2000 mg/day), both glimepiride and metformin significantly reduced HbA1c from baseline (glimepiride 0.95 (SD = 0.41); metformin 1.39 (SD = 0.40)). However, glimepiride was shown to be more effective than metformin in terms of mean change from baseline in HbA1c. The difference between the two treatments was 0.44% in favour of metformin. The upper limit (1.05) of the 95% confidence interval for this difference was not lower than the 0.3% non-inferiority limit.
No new safety data were identified from glimepiride treatment in children compared to adult patients with type 2 diabetes. There are no data on the long-term efficacy and safety of the drug in children.
Pharmacokinetics
Absorption. After oral administration, glimepiride has 100% bioavailability. Food intake has no significant effect on absorption, but only slightly slows down the rate of absorption. C max in blood plasma is achieved ≈2.5 h after oral administration of the drug (average value is 0.3 μg / ml when taking a multiple daily dose of 4 mg). There is a linear relationship between dose and C max, as well as dose and AUC.
In animals, glimepiride is excreted in breast milk. Glimepiride crosses the placenta. Penetration across the blood-brain barrier is low.
Biotransformation and elimination. The mean basal T½ at plasma drug concentrations consistent with multiple dosing is ≈5-8 hours. A slight increase in T½ was observed after high doses.
After a single dose of radiolabeled glimepiride, 58% of the radioactive substance was recovered in the urine and 35% in the feces. No unchanged substance was detected in the urine. Two metabolites, most likely resulting from hepatic metabolism (primary enzyme CYP 2C9), were detected in the urine and feces, one of which is a hydroxy derivative and the other a carboxy derivative. After oral administration of glimepiride, the terminal T½ of these metabolites was 3-6 h and 5-6 h, respectively.
Comparison of pharmacokinetics after a single dose and multiple once-daily dosing did not reveal any significant differences. Interindividual variability was very low. No significant accumulation was observed.
Special patient groups. Pharmacokinetic parameters in men and women, as well as in young and elderly subjects (65 years), were similar. In patients with reduced creatinine clearance, there was a tendency for glimepiride clearance to increase and its mean plasma concentration to decrease, which is most likely due to more rapid elimination due to less protein binding. Renal excretion of both metabolites was impaired. In general, no additional risk of drug accumulation is expected in these patients.
Pharmacokinetic parameters in patients who underwent biliary tract surgery were similar to those in healthy volunteers.
Children, including adolescents: Pharmacokinetic, safety and tolerability studies following a single dose of 1 mg glimepiride in the fed state in children with type 2 diabetes mellitus demonstrated that mean AUC (0-last), C max and T ½ were similar to those previously observed in adults.
Preclinical safety data. The effects observed in preclinical studies occurred at exposure levels well in excess of the maximum human exposure levels, indicating little relevance to clinical practice, or were due to the pharmacodynamic effects of the drug (hypoglycemia). These results were obtained in conventional safety pharmacology studies, repeated dose toxicity studies, genotoxicity, carcinogenic potential, and reproductive toxicity. Adverse effects observed in the latter (which included embryotoxicity, teratogenicity, and developmental toxicity) were considered to be due to the hypoglycemic effects of the drug in dams and pups.
Indication
Type 2 diabetes in adults, if blood glucose levels cannot be maintained by diet, exercise and weight loss alone.
Application
Successful treatment of diabetes depends on the patient's adherence to an appropriate diet, regular physical activity, and constant monitoring of blood and urine glucose levels. Failure to adhere to a diet by patients cannot be compensated by taking pills or insulin.
The dosage depends on the results of blood and urine glucose tests.
The initial dose is 1 mg (1/2 tablet of 2 mg) of glimepiride per day. If this dose allows to achieve disease control, it should be used for maintenance therapy.
If glycemic control is suboptimal, the dose should be increased to 2, 3 or 4 mg glimepiride per day gradually (at intervals of 1-2 weeks).
A dose of 4 mg/day gives better results only in some cases. The maximum recommended dose is 6 mg of Diapiride per day.
If the maximum daily dose of metformin does not provide adequate glycemic control, concomitant therapy with glimepiride can be initiated.
Following the previous metformin dosage, glimepiride should be started at a low dose, which can then be gradually increased to the maximum daily dose, focusing on the desired level of metabolic control. Combination therapy should be carried out under close medical supervision.
If the maximum daily dose of Diapiride does not provide adequate glycemic control, concomitant insulin therapy may be initiated if necessary. Following the previous glimepiride dosage, insulin treatment should be initiated at a low dose, which can then be increased based on the desired level of metabolic control.
Combination therapy should be carried out under the close supervision of a physician.
Usually one dose of glimepiride per day is sufficient. It is recommended to take it shortly before or during a hearty breakfast or, if there is no breakfast, shortly before or during the first main meal. Errors in taking the drug, for example, forgetting to take another dose, can never be corrected by taking the next increased dose. The tablet should be swallowed without chewing, with liquid.
Improved diabetes control is accompanied by increased insulin sensitivity, so during the course of treatment the need for glimepiride may decrease. To avoid hypoglycemia, the dose should be gradually reduced or therapy should be discontinued. The need to revise the dosage may also arise if the patient's body weight, lifestyle or other factors increase the risk of hypo- or hyperglycemia.
Switching from oral hypoglycemic agents to Diapiride
It is usually possible to switch from other oral hypoglycemic agents to Diapiride. During such a switch, the potency and T½ of the previous agent should be taken into account. In some cases, especially if the antidiabetic agent has a long T½ (e.g. chlorpropamide), it is recommended to wait a few days before starting Diapiride. This will reduce the risk of hypoglycemic reactions due to the additive effect of the two agents.
The recommended starting dose is 1 mg glimepiride per day. As mentioned above, the dose can be gradually increased based on the response to the drug.
Switching from insulin to Diapiride.
In exceptional cases, patients with type 2 diabetes mellitus who are taking insulin may be advised to switch to Diapiride. Such a transition should be carried out under close medical supervision.
Contraindication
Diapirid is not intended for the treatment of insulin-dependent diabetes mellitus type 1, diabetic ketoacidosis, diabetic coma. The use of the drug is contraindicated in patients with severe renal or hepatic impairment. In case of severe renal or hepatic impairment, the patient must be transferred to insulin.
Diapiride should not be taken by patients with hypersensitivity to glimepiride or any auxiliary ingredient included in the composition of the drug, to sulfonylurea derivatives or other sulfonamide drugs (risk of developing hypersensitivity reactions).
Pregnancy or breastfeeding (see Use during pregnancy or breastfeeding).
Side effects
Based on experience with sulfonylureas, the following adverse reactions were observed in clinical trials, listed by system organ class:
Blood and lymphatic system disorders: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, hemolytic anemia and pancytopenia, usually reversible after drug withdrawal. During post-marketing surveillance, cases of severe thrombocytopenia with platelet count <10,000/μL and thrombocytopenic purpura were reported.
On the part of the immune system: leukocytoclastic vasculitis, moderate hypersensitivity reactions, which may develop into serious forms and be accompanied by shortness of breath, a drop in blood pressure and sometimes shock, cross-allergy with sulfonylureas, sulfonamides or related substances.
Metabolic and nutritional disorders: hypoglycaemia. Such hypoglycaemic reactions are usually immediate, may be severe and may not always be easily corrected. The occurrence of such reactions, as with other hypoglycaemic agents, depends on individual factors such as eating habits and dose (see Precautions). The clinical presentation of a severe hypoglycaemic attack may resemble that of a stroke.
On the part of the organ of vision: transient visual disturbances, especially at the beginning of treatment, are caused by changes in blood sugar levels.
Gastrointestinal tract: nausea, vomiting, diarrhea, feeling of heaviness and discomfort in the abdomen, abdominal pain, which rarely lead to the need to discontinue treatment.
Hepatobiliary disorders: increased liver enzymes, liver function abnormalities (e.g. cholestasis or jaundice), hepatitis and hepatic failure.
Skin and subcutaneous tissue disorders: hypersensitivity reactions including pruritus, rash, urticaria and photosensitivity.
Changes in laboratory parameters: decreased plasma sodium levels.
Special instructions
Diapiride should be taken shortly before or during meals.
In the first weeks of treatment, the risk of hypoglycemia may increase, so particularly careful monitoring is necessary.
In case of irregular meals or skipping meals, treatment with Diapiride may cause hypoglycemia. Possible symptoms of hypoglycemia include headache, intense hunger, nausea, vomiting, increased fatigue, apathy, drowsiness, sleep disorders, increased motor activity, aggression, impaired concentration, anxiety and delayed reaction time, depression, confusion, speech and visual disorders, aphasia, tremor, paresis, sensory disorders, dizziness, helplessness, loss of self-control, delirium, central convulsions, drowsiness and loss of consciousness up to coma, shallow breathing and bradycardia. In addition, signs of adrenergic repulsion may be observed, such as sweating, cold and clammy skin, anxiety, tachycardia, arterial hypertension, palpitations, angina pectoris and arrhythmias.
The clinical presentation of a severe hypoglycemic attack may resemble that of a stroke.
From the experience of using other sulfonylureas, it is known that, despite the initial effectiveness of measures to eliminate hypoglycemia, it may occur again.
Severe or prolonged hypoglycemia, which is only temporarily resolved by ordinary amounts of sugar, requires immediate treatment, sometimes hospitalization.
Factors contributing to the development of hypoglycemia include:
unwillingness or (especially in old age) inability of the patient to cooperate with the doctor; malnutrition, irregular eating or skipping meals, fasting period; dietary violations; inconsistency between physical activity and carbohydrate intake; alcohol consumption, especially in combination with skipping meals; impaired renal function; severe liver dysfunction; overdose with Diapirid; certain decompensated endocrine diseases affecting carbohydrate metabolism or hypoglycemia regulation (for example, in certain disorders of the thyroid gland and insufficiency of the anterior pituitary or adrenal cortex); simultaneous use of certain other drugs (see Interaction with other drugs).
Treatment with Diapiride requires regular monitoring of blood and urine glucose levels. In addition, it is recommended to determine the content of glycosylated hemoglobin.
During treatment with Diapirid, liver function tests and hematological parameters (especially leukocyte and platelet counts) should be regularly monitored.
In stressful situations (e.g. trauma, unplanned surgery, infections accompanied by fever), temporary transfer of the patient to insulin may be indicated.
There is no experience with the use of Diapiride in patients with severe hepatic impairment or patients on dialysis. Patients with severe renal or hepatic impairment should be switched to insulin. Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylurea drugs may lead to the development of hemolytic anemia. Since glimepiride belongs to the sulfonylurea class of drugs, it should be prescribed with caution to patients with glucose-6-phosphate dehydrogenase deficiency. Alternative drugs that do not contain sulfonylurea are indicated for them.
Diapirid contains lactose monohydrate. This medicine should not be taken by patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
This medicinal product contains less than 1 mmol sodium/dose, i.e. essentially sodium-free.
Use during pregnancy and breastfeeding
Pregnancy. Risk associated with diabetes. Abnormal blood glucose levels during pregnancy may increase the risk of congenital malformations and perinatal mortality. Therefore, blood glucose levels should be carefully monitored during pregnancy to avoid teratogenic risk.
A pregnant woman with diabetes should be switched to insulin. Women with diabetes should inform their doctor about a planned pregnancy in order to adjust their treatment and switch to insulin.
Risk associated with glimepiride. There are no data on the use of glimepiride in pregnant women. According to the results of animal experiments, the drug has reproductive toxicity, probably related to the pharmacological action of glimepiride (hypoglycemia). Therefore, glimepiride should not be taken during the entire period of pregnancy (see Side effects). If a patient taking glimepiride plans to become pregnant or becomes pregnant, she should be transferred to insulin therapy as soon as possible.
Breastfeeding. To avoid the drug Diapiride entering the mother's breast milk and possible harmful effects on the child, this drug should not be taken by breastfeeding women. If necessary, the patient should switch to insulin or completely stop breastfeeding (see Side effects).
Children: There is insufficient data on the safety and efficacy of the drug in children, so its use in this category of patients is not recommended.
Effects on the ability to drive and use machines. No studies have been conducted on the effects of the drug on the ability to drive and use machines.
The ability to concentrate and react may be impaired due to hypoglycaemia or hyperglycaemia or, for example, due to impaired vision. This may pose a risk in situations where this ability is particularly important (e.g. driving a vehicle or operating machinery).
Patients should be warned not to allow themselves to develop hypoglycemia while driving. This is especially true for those who have poor or no ability to recognize the symptoms of hypoglycemia and those who have frequent attacks of hypoglycemia. It is necessary to seriously consider whether it is advisable to drive a vehicle or operate machinery under these circumstances.
The simultaneous use of Diapiride with certain drugs can cause both weakening and strengthening of the hypoglycemic effect of glimepiride. Therefore, other drugs should be taken only with the consent (or as prescribed) of a doctor. Glimepiride is metabolized by CYP 2C9. It is known that due to the simultaneous use of inducers (for example, rifampicin) or inhibitors of CYP 2C9 (for example, fluconazole), this metabolism may change. The results of an in vivo interaction study showed that fluconazole, one of the strongest inhibitors of CYP 2C9, increases the AUC of glimepiride approximately twice. The existence of these types of interactions is evidenced by the experience of using Diapiride and other sulfonylurea derivatives.
Potentiation of the blood glucose-lowering effect, and therefore in some cases hypoglycemia, may occur when glimepiride is taken simultaneously with the following drugs: phenylbutazone, azapropazone and oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic drugs, some long-acting sulfonamides, metformin, tetracycline, salicylates and PAS, MAO inhibitors, anabolic steroids and male sex hormones, quinolone antibiotics and clarithromycin, chloramphenicol, probenecid, coumarin anticoagulants, miconazole, fenfluramine, disopyramide, pentoxifylline (high doses parenterally), fibrates, tritoqualine, ACE inhibitors, fluconazole, fluoxetine, allopurinol, sympatholytics, cyclo-, tro- and ifosfamides.
Weakening of the blood glucose-lowering effect and, accordingly, an increase in this level may occur when the patient simultaneously takes the following medications: estrogens and progestogens; saluretics, thiazide diuretics; drugs that stimulate thyroid function; corticosteroids; phenothiazine derivatives, chlorpromazine; adrenaline and sympathomimetics; nicotinic acid (high doses) and its derivatives; laxatives (long-term use); phenytoin, diazoxide; glucagon, barbiturates and rifampicin; acetazolamide.
H 2 receptor antagonists, β-blockers, clonidine and reserpine can lead to both potentiation and weakening of the blood glucose-lowering effect.
Under the influence of sympatholytics, such as β-blockers, clonidine, guanethidine and reserpine, the manifestations of adrenergic feedback regulation of hypoglycemia may be reduced or disappear.
Alcohol consumption may increase or decrease the hypoglycemic effect of glimepiride in an unpredictable manner.
Glimepiride is capable of both increasing and decreasing the effects of coumarin derivatives.
Colesevelam binds to glimepiride and reduces its absorption from the gastrointestinal tract. No interactions were observed when glimepiride was taken at least 4 hours before colesevelam. Therefore, glimepiride should be taken at least 4 hours before colesevelam.
Overdose
Overdose can lead to hypoglycemia, which lasts from 12 to 72 hours and may recur after the first improvement. Symptoms may appear 24 hours after absorption of the drug. As a rule, observation in the clinic is recommended for such patients. Nausea, vomiting and pain in the epigastric region may occur. Hypoglycemia can often be accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, impaired coordination, drowsiness, coma and convulsions.
Treatment of overdose consists primarily in preventing the absorption of the drug. To do this, it is necessary to induce vomiting, and then drink water or lemonade with activated charcoal (adsorbent) and sodium sulfate (laxative). If a large amount of glimepiride has been taken, gastric lavage is indicated, followed by the use of activated charcoal and sodium sulfate. In case of severe overdose, hospitalization in intensive care and resuscitation departments is necessary. Glucose administration should be started as soon as possible: if necessary, first a single intravenous injection of 50 ml of a 50% solution, and then an infusion of a 10% solution with constant monitoring of blood glucose levels.
Further treatment is symptomatic.
When treating hypoglycemia caused by accidental ingestion of Diapiride in infants and young children, the glucose dose should be adjusted especially carefully due to the possibility of dangerous hyperglycemia, and its control should be carried out by careful monitoring of blood glucose levels.
Storage conditions
In the original packaging at a temperature not exceeding 25 °C.
