Altar 4 mg tablets 4 mg blister No. 30

Instructions for use Altar 4 mg tablets 4 mg blister No. 30

Composition

active ingredient: glimepiride;

1 tablet contains glimepiride 4 mg;

Excipients: lactose monohydrate, corn starch, sodium starch glycolate (type A), povidone, polysorbate 80, yellow iron oxide (E 172), talc, magnesium stearate.

Dosage form

Pills.

Main physicochemical properties: yellow capsule-shaped tablets with a flat beveled edge and a score line on one side.

The tablet can be divided into equal doses.

Pharmacotherapeutic group

Oral hypoglycemic drugs. 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 non-insulin-dependent diabetes mellitus.

Glimepiride works primarily by stimulating the release of insulin from pancreatic beta cells.

As with other sulfonylureas, this effect is associated with an increase in the sensitivity of pancreatic beta cells to physiological glucose stimulation. In addition, glimepiride is likely to have a pronounced extrapancreatic effect, theoretically inherent in other sulfonylureas.

Insulin release. Sulfonylureas regulate insulin secretion by closing the ATP-dependent potassium channel in the beta cell membrane. Closing the potassium channel induces depolarization of the beta cell and, by opening the calcium channel, leads to increased calcium influx into the cell. This 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 differs from the usual sulfonylurea binding site.

Extrapancreatic activity. Extrapancreatic effects include, for example, increased sensitivity of peripheral tissues to insulin and decreased hepatic insulin uptake.

The absorption of glucose from the blood by muscle and adipose peripheral tissues is carried out with the participation of special transport proteins located in the cell membrane. The transport of glucose into these tissues is the rate-limiting step in glucose utilization. Glimepiride very quickly increases the number of active glucose-transporting molecules on the plasma membranes of muscle and adipose cells, which leads to stimulation of glucose uptake.

Glimepiride increases the activity of glycosylphosphatidylinositol-specific phospholipase C, which may correlate with drug-induced lipogenesis and glycogenesis in isolated muscle and fat cells.

Glimepiride inhibits glucose formation in the liver 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 action of glimepiride is dose-dependent and reproducible. The physiological response to sudden physical exertion, i.e. a decrease in insulin secretion, is maintained under the action of glimepiride.

There was no significant difference in the effect of glimepiride depending on whether the drug was given 30 minutes before a meal or immediately before a meal. In patients with diabetes, good metabolic control over 24 hours can be achieved with a single daily dose.

Although the hydroxymetabolite of glimepiride causes a small but statistically significant decrease in serum glucose levels in healthy subjects, this represents only a minor part of the overall effect of the drug.

Combination therapy with metformin: One study demonstrated improved metabolic control with concomitant glimepiride therapy compared with metformin monotherapy in patients inadequately controlled on the maximum daily dose of metformin.

Combination therapy with insulin. Data on combination therapy with insulin are limited. In patients inadequately controlled with the maximum dose of glimepiride, concomitant insulin therapy may be initiated. In two studies, this combination achieved similar improvements in metabolic control as insulin monotherapy; however, a lower mean insulin dose was required with combination therapy.

Children: A 24-week active-controlled clinical trial (glimepiride up to 8 mg/day or metformin up to 2000 mg/day) was conducted in 285 children aged 8 to 17 years with type 2 diabetes.

Both glimepiride and metformin resulted in significant reductions in HbA1c from baseline (glimepiride 0.95 (SD 0.41); metformin 1.39 (SD 0.40)). However, glimepiride was not superior to metformin in terms of mean change from baseline in HbA1c. The treatment difference was 0.44% in favour of metformin. The upper limit (1.05) of the 95% confidence interval for the difference was not lower than the 0.3% non-inferiority margin.

No new safety concerns have been identified in children following glimepiride treatment compared to adult patients with type 2 diabetes. There are no data on long-term efficacy and safety in children.

Absorption. The bioavailability of glimepiride after oral administration is complete. Food intake does not significantly affect absorption, only slightly reduces the rate of absorption. The maximum serum concentration (Cmax) after oral administration of the drug is reached after approximately 2.5 hours (on average 0.3 μg/ml with multiple doses of 4 mg per day), and there is a linear relationship between dose and Cmax and dose and area under the concentration-time curve (AUC).

Distribution: Glimepiride has a very low volume of distribution (approximately 8.8 L), which approximately corresponds to the volume of distribution of albumin, a high degree of protein binding (> 99%) and a low clearance (approximately 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 mean terminal elimination half-life at serum drug concentrations consistent with multiple dosing is approximately 5–8 hours. A slight increase in half-life was observed after high doses.

After a single dose of radiolabeled glimepiride, radioactivity was recovered in urine (58%) and feces (35%). Unchanged substance was not detected in urine. Two metabolites, most likely formed as a result of hepatic metabolism (primarily CYP2C9), were identified in both urine and feces: the hydroxy derivative and the carboxy derivative. After oral administration of glimepiride, the terminal half-lives of these metabolites were 3–6 hours and 5–6 hours, respectively. Comparison of single and multiple once-daily dosing revealed no significant differences in pharmacokinetics, and interindividual variability was very low. No significant accumulation was observed.

Special patient groups. In men and women, as well as in young and elderly patients (65 years and older), the pharmacokinetics are similar. In patients with reduced creatinine clearance, there was a tendency for glimepiride clearance to increase and mean serum concentrations to decrease, most likely due to more rapid elimination due to lower protein binding. Renal excretion of the two metabolites was impaired. It is considered that there is generally no additional risk of accumulation in such patients.

Pharmacokinetics in five non-diabetic patients after biliary tract surgery were similar to those in healthy subjects.

Children: A study investigating the pharmacokinetics, safety and tolerability of a single dose of 1 mg glimepiride in the fed state in 30 children (4 children aged 10 to 12 years and 26 children aged 12 to 17 years) with type 2 diabetes demonstrated that mean AUC(0-last), Cmax and t1/2 were similar to those in adults.

Preclinical safety data

Effects observed in preclinical studies occurred only at exposures well in excess of the maximum human exposure, indicating little relevance to clinical practice, or were due to the pharmacodynamic action of the drug (hypoglycemia). This finding is based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and reproductive toxicity. Adverse effects observed recently (including embryotoxicity, teratogenicity, and developmental toxicity) were considered to be due to the hypoglycemic effects of the drug in dams and pups.

Indication

Treatment of type 2 diabetes mellitus in adults when diet, exercise and weight loss alone are not sufficient to control blood glucose levels.

Contraindication

Hypersensitivity to glimepiride, to any of the excipients or to other sulfonylurea or sulfonamide derivatives. Insulin-dependent diabetes. Diabetic coma. Diabetic ketoacidosis. Severe renal or hepatic impairment. In case of severe renal or hepatic impairment, a switch to insulin is necessary.

Interaction with other medicinal products and other types of interactions

When glimepiride is used simultaneously with some other drugs, both strengthening and weakening of its hypoglycemic effect are possible, therefore other drugs should be used only with the permission of a doctor (or on prescription). Glimepiride is metabolized by cytochrome P450 2C9 (CYP2C9). It is known that its metabolism is affected by the simultaneous use of CYP2C9 inducers (e.g. rifampicin) or CYP2C9 inhibitors (e.g. fluconazole). The results of an in vivo interaction study show that fluconazole, one of the strongest CYP2C9 inhibitors, increases the AUC of glimepiride approximately 2-fold.

Experience with the use of glimepiride with other sulfonylurea derivatives indicates the existence of the following interactions.

phenylbutazone, azapropazone, oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic drugs such as metformin, some long-acting sulfonamides, tetracyclines, salicylates and para-aminosalicylic acid, monoamine oxidase inhibitors (MAOIs), anabolic steroid drugs and male sex hormones, antibacterial agents - quinolone derivatives and clarithromycin, chloramphenicol, probenecid, coumarin-type anticoagulants, miconazole, fenfluramine, disopyramide, pentoxifylline (parenterally in high doses), fibrates, tritoqualine, ACE (angiotensin-converting enzyme) inhibitors, fluoxetine, allopurinol, sympatholytic agents, cyclophosphamide, trofosfamide, ifosfamide, fluconazole.

Weakening of the blood sugar-lowering effect of glimepiride and, accordingly, increased blood glucose levels are possible with simultaneous use with the following substances:

estrogens and progestogens, saluretics, thiazide diuretics, thyroid-stimulating and glucocorticoid agents, phenothiazine derivatives, chlorpromazine, adrenaline and sympathomimetic agents, nicotinic acid (in high doses) and its derivatives, laxatives (with prolonged use), phenytoin, diazoxide, glucagon, barbiturates and rifampicin, acetazolamide.

H2-receptor blockers, b-blockers, clonidine and reserpine can either enhance or weaken the hypoglycemic effect.

Under the influence of sympatholytic drugs such as β-blockers, clonidine, guanethidine and reserpine, the symptoms of compensatory adrenergic regulation of hypoglycemia may be weakened or absent.

Alcohol consumption may unpredictably enhance or weaken the antidiabetic effect of glimepiride.

Glimepiride can both enhance and weaken 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.

Application features

Altar® should be taken immediately before or during meals.

If meals are taken irregularly or skipped, glimepiride treatment may lead to hypoglycemia. Possible symptoms of hypoglycemia include: headache, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disorders, agitation, aggression, impaired concentration, anxiety, increased reaction time, depression, confusion, speech and vision disorders, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, cerebral 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, clammy skin, anxiety, tachycardia, hypertension, palpitations, 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 sugar substitutes are ineffective.

Other sulfonylureas are known to cause hypoglycemia to recur despite successful initial measures.

Severe or prolonged hypoglycemia that is only temporarily controlled by regular amounts of sugar requires immediate treatment and occasionally hospitalization.

The following factors may contribute to the development of hypoglycemia: the patient's unwillingness or inability to cooperate with the doctor (most often in elderly patients); insufficient, irregular nutrition, skipping meals or periods of fasting; inconsistency between physical activity and carbohydrate intake; changes in diet; alcohol consumption, especially in combination with skipping meals; impaired renal function; serious impaired liver function; overdose with glimepiride; some uncompensated endocrine diseases that affect carbohydrate metabolism or counterregulation of hypoglycemia (for example, certain thyroid disorders, insufficiency of the anterior pituitary or adrenal cortex); simultaneous administration of certain other drugs (see section "Interaction with other drugs and other types of interactions").

Treatment with glimepiride requires regular monitoring of blood and urine sugar levels.

In addition, it is recommended to determine the level of glycosylated hemoglobin.

During treatment with glimepiride, it is necessary to regularly monitor liver function and blood parameters (especially the number of leukocytes and platelets).

In a stressful situation (e.g. trauma, urgent surgery, infectious diseases with fever, etc.), a temporary switch to insulin may be indicated.

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylureas may cause hemolytic anemia. Since glimepiride belongs to the sulfonylurea class of drugs, it should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency and alternative non-sulfonylurea drugs should be considered.

This medicinal product contains lactose monohydrate and should not be used in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Ability to influence reaction speed when driving vehicles or other mechanisms

No studies have been conducted on the effect on reaction speed when driving vehicles or other mechanisms.

As a result of hypoglycemia or hyperglycemia or, for example, as a result of visual impairment, the patient's ability to concentrate and react may be impaired. This may be a risk in situations where this ability is of particular importance (e.g. driving a car or operating machinery). Patients should be advised to take precautions to avoid hypoglycemia while driving. This is particularly important for those who have no or limited understanding of the warning symptoms of hypoglycemia or who have frequent episodes of hypoglycemia. In such circumstances, the advisability of driving a car or operating machinery should be considered.

Use during pregnancy or breastfeeding

Pregnancy

Risk associated with diabetes mellitus. Abnormal blood glucose levels during pregnancy may be associated with an increased incidence of congenital malformations and perinatal mortality. Therefore, blood glucose levels should be carefully monitored during pregnancy to avoid teratogenic risk.

In such circumstances, insulin must be used. Patients with diabetes who are planning a pregnancy should inform their doctor so that treatment can be adjusted and a switch to insulin can be made.

Risk associated with glimepiride. There are no data on the use of glimepiride in pregnant women. Animal experiments have shown reproductive toxicity, which was probably related to the pharmacological action of glimepiride (hypoglycemia).

Therefore, glimepiride should not be used throughout pregnancy.

If a patient taking glimepiride plans to become pregnant or pregnancy is already diagnosed, insulin therapy should be started as soon as possible.

Breastfeeding period

It is not known whether glimepiride is excreted in human milk. In rats, glimepiride is excreted in breast milk. Since other sulfonylureas are excreted in human milk and there is a risk of hypoglycemia in breast-fed infants, breast-feeding is not recommended during treatment with glimepiride.

Method of administration and doses

The medicine is intended for oral use.

The key to successful diabetes treatment is a proper diet, regular physical activity, and periodic testing of blood and urine glucose levels. Oral antidiabetic drugs or insulin cannot compensate for the patient's failure to adhere to the recommended diet.

The dosage is determined by the doctor based on the results of blood and urine sugar tests.

The initial dose of glimepiride is 1 mg* per day. Once adequate control is achieved, this dose should be used for maintenance therapy.

Tablets with appropriate strengths are available for different dosage regimens. If glycemic control is inadequate, the dosage should be gradually increased, based on this control, with an interval of approximately 1–2 weeks between each step, to 2, 3* or 4 mg glimepiride per day.

Dosages higher than 4 mg glimepiride per day give better results only in exceptional cases. The maximum recommended daily dose of glimepiride is 6 mg.

In patients inadequately controlled with the maximum daily dose of metformin, concomitant therapy with glimepiride can be initiated.

While maintaining the metformin dosage, glimepiride therapy should be initiated at a low dose, which should then be increased up to the maximum daily dose depending on the desired level of metabolic control. Combination therapy should be initiated under close medical supervision.

In patients not adequately controlled with the maximum daily dose of glimepiride, concomitant insulin therapy may be initiated if necessary. While maintaining the glimepiride dose, insulin treatment should be initiated at a low dose and increased depending on the desired level of metabolic control. Combination therapy should be initiated under close medical supervision.

A single daily dose of glimepiride is usually sufficient. It is recommended to take this dose immediately before or during a substantial breakfast or, if there is none, immediately before or during the first main meal. If a dose is missed, the condition should not be corrected by increasing the next dose. The tablets should be swallowed whole with liquid.

During treatment, as improved diabetic control is associated with greater insulin sensitivity, the need for glimepiride may decrease. Therefore, to prevent hypoglycemia, temporary dose reduction or discontinuation of treatment should be considered. Dosage adjustment may also be necessary if the patient's weight or lifestyle changes or if other factors that increase the risk of hypo- or hyperglycemia arise.

Switching from other oral antidiabetic drugs to glimepiride.

In general, switching from other oral antidiabetic agents to glimepiride is possible. When switching to glimepiride, the potency and half-life of the previous drug should be taken into account. In some cases, especially when using antidiabetic agents with a long half-life (e.g. chlorpropamide), it is recommended to wait a washout period of several days to minimize the risk of hypoglycemic reactions due to the additive effect of the two agents.

The recommended starting dose of glimepiride is 1 mg* per day. The dosage of glimepiride can be increased gradually based on the response to the drug, as described above.

* Use glimepiride at the appropriate dosage.

Switching from insulin to glimepiride.

In exceptional cases, if patients with type 2 diabetes mellitus are receiving insulin therapy, a switch to glimepiride may be indicated. The switch should be carried out under close medical supervision.

Children

The safety and efficacy of Oltar® in children under 8 years of age have not been established. For children aged 8 to 17 years, there are limited data on glimepiride monotherapy (see sections 5.1 and 5.2).

There is insufficient data on safety and efficacy in children, so this use is not recommended.

Overdose

Overdose may cause hypoglycemia lasting 12 to 72 hours, which may recur after initial relief. Symptoms may be absent for 24 hours after administration. Hospital observation is generally recommended. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia may be accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, incoordination, drowsiness, coma, and convulsions.

Treatment of overdose. First of all, treatment consists in preventing absorption by inducing vomiting, followed by drinking water or lemonade with activated charcoal (adsorbent) and sodium sulfate (laxative). When taking large amounts of the drug, 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 indicated. Glucose administration should be started as soon as possible, if necessary - in the form of a bolus intravenous injection of 50 ml of a 50% solution followed by an infusion of a 10% solution with careful monitoring of the glucose concentration in the blood. Further treatment should be symptomatic.

In particular, when treating hypoglycemia in infants and young children caused by accidental ingestion of Oltar®, the glucose dose should be carefully controlled to avoid the possibility of developing dangerous hyperglycemia. Blood glucose levels should be closely monitored.

Adverse reactions

Based on experience with glimepiride and other sulfonylureas, the following adverse reactions have been listed below by system organ class and in decreasing order of frequency: very common: ≥ 1/10; common: ≥ 1/100 - < 1/10; uncommon: ≥ 1/1000 - < 1/100; rare: ≥ 1/10000 - < 1/1000; very rare: < 1/10000; frequency unknown (cannot be estimated from the available data).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after a medicinal product has been authorised plays an important role. This allows for continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

2 years.

Do not use the drug after the expiration date indicated on the package.

Storage conditions

Store at a temperature not exceeding 30 ° C. Store in the original packaging. Keep out of the reach of children.

Packaging

30 tablets in a blister; 1 blister in a cardboard box.

Vacation category

According to the recipe.

Producer

A. Menarini Manufacturing Logistics and Services S.r.L.

Location of the manufacturer and its business address

Via Campo di Pile, 67100 L'Aquila (AC), Italy.