Instructions Diapirid tablets 3 mg blister No. 30
Composition
active ingredient: glimepiride;
1 tablet contains glimepiride 2 mg or 3 mg or 4 mg in terms of 100% substance;
excipients:
2 mg tablet: lactose monohydrate, microcrystalline cellulose 102, sodium starch glycolate (type A), povidone (25), yellow iron oxide (E 172), indigo carmine (E 132), magnesium stearate;
3 mg tablet: lactose monohydrate, microcrystalline cellulose 102, sodium starch glycolate (type A), povidone (25), yellow iron oxide (E 172), magnesium stearate;
4 mg tablet: lactose monohydrate, microcrystalline cellulose 102, sodium starch glycolate (type A), povidone (25), indigo carmine (E 132), magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
2 mg tablets: pale green to green, round tablets with a flat surface with beveled edges and a score. The presence of inclusions on the surface of the tablets is allowed;
3 mg tablets: pale yellow to yellow, round tablets with a flat surface with beveled edges and a score. The tablets may have inclusions on their surface;
4 mg tablets: pale blue to blue tablets, round in shape with a flat surface with beveled edges and a score. The presence of inclusions on the surface of the tablets is allowed.
Pharmacotherapeutic group
Hypoglycemic agents, except insulins. Sulfonamides, urea derivatives. ATX code A10B B12.
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 glucose stimulation. 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 sulfonylureas.
Extrapancreatic activity. Extrapancreatic effects include, for example, improved sensitivity of peripheral tissues to insulin and reduced hepatic insulin utilization.
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 rate of the glucose utilization step. Glimepiride very quickly increases the number of active molecules that transport glucose 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 may 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. In 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. a decrease in 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 effect of the drug.
Use in combination with metformin: Improved metabolic control has been demonstrated with concomitant glimepiride therapy compared to metformin monotherapy in patients whose diabetes is not adequately controlled with maximum doses of metformin.
Special populations: 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 not shown to be superior to metformin in terms of mean change from baseline in HbA1c. The treatment difference between the two 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 margin.
No new safety concerns have been identified in children with glimepiride compared to adult patients with type 2 diabetes. Long-term efficacy and safety data are not available in children.
Pharmacokinetics.
Absorption. After oral administration, glimepiride is 100% bioavailable. Food intake has no significant effect on absorption, but only slightly slows down the rate of absorption. Maximum serum concentrations (Cmax) are reached approximately 2.5 hours after oral administration (mean 0.3 μg/ml after multiple daily doses of 4 mg). There is a linear relationship between dose and Cmax, as well as dose and AUC (area under the concentration-time curve).
Distribution: Glimepiride has a very low volume of distribution (about 8.8 l), which is approximately equal to the volume of distribution of albumin, a high degree of binding to plasma proteins (more than 99%) and a low clearance (about 48 ml/min).
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 terminal elimination half-life at plasma concentrations consistent with multiple dosing is approximately 5 to 8 hours. A slight increase in half-life has been observed following high doses.
After a single dose of radiolabeled glimepiride, 58% of the radioactivity was recovered in the urine and 35% in the feces. No unchanged drug was recovered in the urine. Two metabolites, most likely resulting from hepatic metabolism (primarily CYP2C9), were recovered 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 half-lives of these metabolites were 3 to 6 and 5 to 6 hours, respectively.
Comparison of pharmacokinetics after single and multiple once-daily dosing revealed no 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 (aged 65 years and over), were similar. In patients with reduced creatinine clearance, there was a tendency for glimepiride clearance to increase and its mean plasma concentrations to decrease, most likely due to more rapid elimination due to a lower degree of 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: A study investigating the pharmacokinetics, safety and tolerability of a single dose of 1 mg glimepiride in the fed state in children with type 2 diabetes demonstrated that mean AUC(0-last), Cmax and t1/2 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 action of the drug (hypoglycemia). These results were obtained within the framework of conventional safety pharmacology studies, repeated dose toxicity studies, genotoxicity, carcinogenic potential and reproductive toxicity tests. 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 offspring.
Indication
Type 2 diabetes in adults, if blood sugar levels cannot be controlled by diet, exercise and weight loss alone.
Contraindication
Diapirid® should not be taken by patients with hypersensitivity to glimepiride or any of the excipients included in the preparation, to sulfonylurea derivatives or other sulfonamide drugs (risk of hypersensitivity reactions).
Interaction with other medicinal products and other types of interactions
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 prescription) of a doctor. Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). It is known that due to the simultaneous use of inducers (e.g. rifampicin) or inhibitors of CYP2C9 (e.g. fluconazole) this metabolism may change. The results of an in vivo interaction study showed that fluconazole, one of the strongest inhibitors of CYP2C9, increases the AUC of glimepiride approximately twice. The existence of these types of interactions is evidenced by experience with the use of 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, tetracyclines, salicylates and para-aminosalicylic acid, 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, glucocorticoids; phenothiazine derivatives, chlorpromazine; adrenaline and sympathomimetics; nicotinic acid (high doses) and its derivatives; laxatives (long-term use); phenytoin, diazoxide; glucagon, barbiturates and rifampicin; acetazolamide.
H2-receptor antagonists, beta-blockers, clonidine and reserpine may lead to both potentiation and attenuation of the blood glucose-lowering effect.
Under the influence of sympatholytics, such as beta-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.
Application features
Diapirid® should be taken shortly before or during meals.
There may be an increased risk of hypoglycemia in the first weeks of treatment, so particularly careful monitoring is necessary.
In case of irregular meals or skipping meals, treatment with Diapirid® may cause hypoglycemia. Possible symptoms of hypoglycemia include headache, intense hunger, nausea, vomiting, 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 disturbances, 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 counterregulation may be present, such as sweating, cold and clammy skin, anxiety, tachycardia, arterial hypertension, increased heart rate, angina pectoris and cardiac arrhythmias.
The clinical presentation of a severe hypoglycemic attack may resemble that of a stroke.
Symptoms of hypoglycemia can almost always be quickly resolved by immediate consumption of carbohydrates (sugar). Artificial sweeteners are ineffective.
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 or periods of fasting;
- dietary violations;
- mismatch between physical activity and carbohydrate consumption;
- alcohol consumption, especially in combination with skipping meals;
- kidney dysfunction;
- severe liver dysfunction;
- overdose with Diapirid®;
- simultaneous use of certain other medicines (see section "Interaction with other medicines and other types of interactions").
Treatment with Diapirid® 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 Diapirid® 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 sulfonylureas 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. They should be prescribed alternative drugs that do not contain sulfonylureas.
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.
Use during pregnancy or breastfeeding
Pregnancy. Risk associated with diabetes. Abnormal blood glucose levels during pregnancy may increase the risk of congenital malformations and perinatal mortality. Therefore, the blood glucose level of a pregnant woman should be carefully monitored 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 so that treatment can be adjusted and insulin can be switched.
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 used during pregnancy. If a patient taking glimepiride plans to become pregnant or becomes pregnant, she should be transferred to insulin therapy as soon as possible.
Breastfeeding period.
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 women during lactation. If necessary, the patient should switch to insulin or completely stop breastfeeding.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted to study the effect of the drug on the ability to drive vehicles and operate machinery.
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 car or operating machinery).
Patients should be warned not to allow hypoglycemia to develop while driving. This is especially true for those who have poor or no ability to recognize the warning signs of hypoglycemia and those who have frequent hypoglycemic episodes. It is necessary to seriously consider whether to drive or operate machinery under these circumstances.
Method of administration and doses
Successful treatment of diabetes depends on patients following an appropriate diet, regular physical activity, and constant monitoring of blood and urine glucose levels. Failure to follow a diet cannot be compensated for by taking pills or insulin.
The dosage depends on the results of blood and urine glucose tests.
The initial dose is 1 mg (½ 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 not optimal, the dose should be increased to 2, 3 or 4 mg glimepiride per day gradually (at intervals of 1-2 weeks).
A dose of more than 4 mg per day gives better results only in some cases. The maximum recommended dose is 6 mg of Diapirid® per day.
If the maximum daily dose of metformin does not provide adequate glycemic control, the patient can be started on concomitant therapy with glimepiride.
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. Mistakes in taking the drug, for example, forgetting to take another dose, can never be corrected by taking a higher dose next time. The tablet should be swallowed without chewing, with liquid.
If a patient has a hypoglycemic reaction to taking glimepiride at a dose of 1 mg per day, this means that diabetes can be controlled only by following a diet.
Improved diabetes control is accompanied by increased insulin sensitivity, so during the course of treatment the need for glimepiride may decrease. In order to avoid hypoglycemia, the dose should be gradually reduced or therapy should be discontinued. The need for dosage adjustment may also arise if the patient's body weight or lifestyle changes or other factors that increase the risk of hypo- or hyperglycemia occur.
Switching from oral hypoglycemic agents to Diapirid®.
It is usually possible to switch from other oral hypoglycemic agents to Diapiride®. When switching, the potency and half-life of the previous agent should be taken into account. In some cases, especially if the antidiabetic agent has a long half-life (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 increased gradually, taking into account the reactions 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 the close supervision of a physician.
Children
Existing data on the safety and efficacy of the drug in children are insufficient, therefore its use in this category of patients is not recommended.
Overdose
Overdose may result in hypoglycemia, which lasts from 12 to 72 hours and may recur after initial relief. Symptoms may appear 24 hours after absorption of the drug. Clinical observation is generally recommended for such patients. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia may often be accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, incoordination, drowsiness, coma, and convulsions.
Overdose treatment. Treatment consists primarily of preventing 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 is taken, gastric lavage is indicated, followed by the use of activated charcoal and sodium sulfate. In case of severe overdose, hospitalization in the intensive care unit 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, constantly monitoring the blood glucose level. 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.
Adverse reactions
Blood and lymphatic system disorders: thrombocytopenia, thrombocytopenic purpura, leukopenia, granulocytopenia, agranulocytosis, erythropenia, hemolytic anemia and pancytopenia, which are usually reversible after drug withdrawal.
On the part of the immune system: leukocytoclastic vasculitis, moderate hypersensitivity reactions that may progress to severe forms, accompanied by shortness of breath, decreased 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 dietary habits and dose (for details see section 4.4). The clinical presentation of a severe hypoglycaemic attack may resemble that of a stroke.
Gastrointestinal: 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, abnormal liver function (e.g. cholestasis or jaundice), hepatitis and hepatic failure.
Skin and subcutaneous tissue disorders: Allergic and pseudoallergic reactions may occur, including itching, rash, urticaria, and photosensitivity.
Laboratory indicators: decreased serum sodium levels.
Expiration date
3 years.
Do not use the drug after the expiration date indicated on the package.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
10 tablets in a blister. 3 or 6 blisters in a pack.
Vacation category
According to the recipe.
Producer
PJSC "Farmak".
Location of the manufacturer and its business address
Ukraine, 04080, Kyiv, Frunze St., 74.
