INSUPRID

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INSUPRID (INSUPRID)

Composition:

Active substance: glimepiride;

1 tablet contains 2 mg, 3 mg, or 4 mg of glimepiride;

Excipients: microcrystalline cellulose; lactose monohydrate; sodium croscarmellose; sodium starch glycolate (type A); povidone; magnesium stearate.

Pharmaceutical form. Tablets.

Basic physico-chemical properties: elongated tablets, white to almost white, with a break line on both sides.

Pharmacotherapeutic group

Antidiabetic agents, excluding insulin. Sulfonylurea derivatives, urea derivatives. ATC code A10B B12.

Pharmacological Properties

Pharmacodynamics

Glimepiride is a hypoglycemic agent belonging to the sulfonylurea group. It is active orally and can be used in the treatment of type 2 diabetes mellitus.

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

As with other sulfonylurea agents, this effect is based on increasing the sensitivity of pancreatic cells to the physiological stimulation by glucose. In addition, glimepiride exerts a pronounced extrapancreatic effect, which is also characteristic of other sulfonylurea agents.

General characteristics

In healthy volunteers, the minimal effective oral dose is approximately 0.6 mg. The effect of glimepiride is dose-dependent and reproducible. The physiological response to acute physical stress, i.e., reduced insulin secretion, is preserved under the influence of glimepiride.

No significant difference in the effect of glimepiride was observed between administration 30 minutes before food intake or immediately before meals. In patients with diabetes mellitus, adequate metabolic control over 24 hours was achieved with once-daily administration.

Although the hydroxylated metabolite caused a slight but significant reduction in blood glucose levels in healthy volunteers, this represents only a minor component of the overall effect of glimepiride.

Effect on insulin release

Sulfonylurea agents regulate insulin secretion by closing ATP-dependent potassium channels located in the membrane of pancreatic beta cells. Closure of the potassium channel leads to depolarization of the beta cell and, via opening of calcium channels, results in increased calcium influx into the cell, which in turn triggers insulin release through exocytosis.

Glimepiride binds with high affinity to a membrane protein of the beta cell associated with the ATP-dependent potassium channel; however, its binding site differs from the conventional sulfonylurea binding site.

Extrapancreatic activity

Extrapancreatic effects include, for example, improved insulin sensitivity of peripheral tissues and reduced hepatic insulin clearance.

Glucose utilization by peripheral tissues (muscle and adipose tissue) occurs via specific transport proteins located in the cell membrane. Glucose transport into these tissues is limited by the rate of glucose utilization. Glimepiride rapidly increases the number of active glucose-transporting molecules in the plasma membranes of muscle and adipose cells, thereby stimulating 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 suppresses hepatic glucose production by increasing intracellular concentrations of fructose-2,6-bisphosphate, which in turn inhibits gluconeogenesis.

Combination with metformin

In one study, improved metabolic control was demonstrated with concomitant therapy with glimepiride compared to metformin monotherapy in patients whose diabetes was not adequately controlled with maximum doses of metformin.

Combination with insulin

Data on the use of glimepiride in combination with insulin are limited. In patients whose diabetes is not adequately controlled with maximum doses of glimepiride, concomitant insulin therapy may be initiated. In two studies, this combination achieved metabolic control comparable to insulin monotherapy, but with a lower mean insulin dose required during combination therapy.

Special patient populations

In a 24-week active-controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2,000 mg daily), 285 children (aged 8–17 years) with type 2 diabetes were enrolled.

Both glimepiride and metformin led to a significant reduction in HbA1c compared to baseline (glimepiride – 0.95 (SE 0.41); metformin – 1.39 (SE 0.40)). However, glimepiride did not demonstrate superior efficacy compared to metformin in terms of mean change in HbA1c from baseline. The difference between the two treatments was 0.44% in favor of metformin. The upper limit (1.05) of the 95% confidence interval for this difference was not below the 0.3% non-inferiority margin.

No new safety concerns with glimepiride treatment in children were identified compared to adult patients with type 2 diabetes. Long-term efficacy and safety data in children are lacking.

Pharmacokinetics

Absorption

After oral administration, glimepiride has 100% bioavailability. Food intake does not significantly affect absorption, but slightly slows its rate. Maximum plasma concentrations (Cmax) of glimepiride are reached approximately 2.5 hours after oral administration (mean value is 0.3 µg/mL following repeated 4 mg daily doses). A linear relationship exists between dose and Cmax, as well as between dose and AUC (area under the concentration-time curve).

Distribution

Glimepiride has a very low volume of distribution (approximately 8.8 L), nearly equal to the distribution volume of albumin, a high degree of plasma protein binding (>99%), and low clearance (approximately 48 mL/min).

In animals, glimepiride crosses into breast milk. Glimepiride crosses the placenta. Penetration across the blood-brain barrier is low.

Metabolism

Two metabolites are found in urine and feces, most likely formed via hepatic metabolism (main enzyme CYP2C9), one being a hydroxy derivative and the other a carboxy derivative.

Elimination

After administration of a single radiolabeled dose of glimepiride, 58% of the radioactivity was recovered in urine and 35% in feces. Unchanged drug was not detected in urine.

The mean terminal elimination half-life (t1/2) at plasma concentrations corresponding to repeated dosing is approximately 5 to 8 hours. A slight increase in half-life was observed after administration of higher doses.

Terminal t1/2 values for the hydroxy and carboxy metabolites were 3 to 6 hours and 5 to 6 hours, respectively.

Comparison of pharmacokinetics after single and multiple once-daily doses of glimepiride revealed no significant differences. Inter-individual variability was very low. No clinically relevant accumulation was observed.

Special patient populations

Pharmacokinetic parameters in men and women, as well as in younger and elderly individuals (over 65 years), were similar.

In patients with reduced creatinine clearance, a trend toward increased glimepiride clearance and decreased mean plasma concentration was observed, most likely due to enhanced elimination resulting from reduced plasma protein binding. Renal excretion of both metabolites was impaired. Overall, accumulation of the drug is not expected in these patients.

Pharmacokinetic parameters in five non-diabetic patients who underwent biliary surgery were similar to those in healthy volunteers.

Children (including adolescents)

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

Preclinical safety data

Effects observed in preclinical studies occurred at exposure levels substantially exceeding the maximum exposure levels in humans, indicating their limited relevance to clinical practice, or were due to the pharmacodynamic action of the drug (hypoglycemia). These findings were obtained within traditional safety pharmacology studies, repeated-dose toxicity studies, genotoxicity tests, carcinogenic potential studies, and reproductive toxicity studies. Adverse effects identified in the latter studies (including embryotoxicity, teratogenicity, and developmental toxicity) were considered to be consequences of the hypoglycemic effects induced by the drug in pregnant females and offspring.

Clinical Characteristics

Indications

Type 2 diabetes mellitus in adults when blood glucose levels cannot be controlled by diet, physical exercise, and weight reduction alone.

Contraindications

• Hypersensitivity to glimepiride, other sulfonylurea derivatives, other sulfonamide agents, or to any of the excipients (risk of developing hypersensitivity reactions);
• insulin-dependent type 1 diabetes mellitus;
• diabetic ketoacidosis, diabetic coma;
• severe impairment of renal or hepatic function (in cases of severe renal or hepatic dysfunction, patients should be switched to insulin therapy).

Interaction with other medicinal products and other forms of interaction

Concomitant use of glimepiride with certain medicinal products may either reduce or enhance its hypoglycemic effect. Therefore, other medicinal products should be taken only with the consent (or as prescribed) of a physician.

Glimepiride is metabolized via cytochrome P450 2C9 (CYP2C9). It is known that co-administration of inducers (e.g., rifampicin) or inhibitors of CYP2C9 (e.g., fluconazole) may alter this metabolism. In vivo interaction studies have shown that fluconazole, one of the most potent inhibitors of CYP2C9, approximately doubles the AUC of glimepiride. Such types of interactions are supported by clinical experience with glimepiride and other sulfonylurea derivatives.

Phenylbutazone, azapropazone, oxyphenbutazone, sulfinpyrazone, insulin, and oral antidiabetic agents (such as metformin), certain long-acting sulfonamides, tetracyclines, salicylates, and p-aminosalicylic acid, anabolic steroids and male sex hormones, quinolone antibiotics, clarithromycin, chloramphenicol, probenecid, coumarin anticoagulants, miconazole, fenfluramine, disopyramide, pentoxifylline (high parenteral doses), fibrates, troglitazone, ACE inhibitors, fluconazole, fluoxetine, allopurinol, sympatholytics, cyclo-, tro-, and ifosfamide, MAO inhibitors.

Concomitant use of glimepiride with these agents may potentiate its effect, thereby lowering blood glucose levels (hypoglycemia may occur in some cases).

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

Concomitant use of glimepiride with these agents may reduce its effect, thereby increasing blood glucose levels.

H2-receptor antagonists, beta-blockers, clonidine, reserpine.

Concomitant use of glimepiride with these agents may either enhance or reduce the blood glucose-lowering effect. Under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine, and reserpine, the symptoms of adrenergic counter-regulation during hypoglycemia may be diminished or absent.

Coumarin derivatives.

Concomitant use of glimepiride with these agents may either enhance or reduce the effect of coumarin derivatives.

Cholestyramine.

Cholestyramine binds to glimepiride and reduces its absorption from the gastrointestinal tract. No interactions were observed when glimepiride was administered at least 4 hours prior to cholestyramine. Therefore, glimepiride should be taken at least 4 hours before cholestyramine.

Alcohol consumption may unpredictably enhance or diminish the hypoglycemic effect of glimepiride.

Special precautions for use

The medicinal product should be taken shortly before or during meals.

During treatment with the medicinal product, liver function tests and haematological parameters (especially leukocyte and platelet counts) should be monitored regularly.

In stress situations (e.g. trauma, unplanned surgical interventions, infections accompanied by fever), temporary transition of the patient to insulin may be indicated.

Hypoglycaemia risk

Irregular eating patterns or missed meals during treatment with glimepiride may cause hypoglycaemia.

Possible symptoms of hypoglycaemia include headache, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, increased motor activity, aggression, difficulty concentrating, anxiety and delayed reaction time, depressive mood, confusion, speech and visual disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, epileptic seizures, drowsiness and loss of consciousness up to coma, shallow breathing and bradycardia. In addition, signs of adrenergic counter-regulation may occur, such as sweating, cold and clammy skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias.

The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Symptoms of hypoglycaemia can almost always be rapidly relieved by immediate intake of carbohydrates (sugar). Artificial sweeteners are ineffective. Based on experience with other sulphonylurea derivatives, hypoglycaemia may recur despite initial successful management.

Severe or prolonged hypoglycaemia, which is only temporarily relieved by usual amounts of sugar, requires immediate treatment and sometimes hospitalization.

Factors contributing to the development of hypoglycaemia include:

• unwillingness or (especially in elderly patients) inability of the patient to cooperate with the physician;
• undernutrition, irregular eating patterns or missed meals, or periods of fasting;
• dietary irregularities;
• imbalance between physical exertion and carbohydrate intake;
• alcohol consumption, particularly in combination with missed meals;
• impaired renal function;
• severe impairment of liver function;
• glimepiride overdose;
• certain decompensated endocrine disorders affecting carbohydrate metabolism or hypoglycaemia counter-regulation (e.g. certain thyroid disorders, hypopituitarism or adrenal insufficiency);
• concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

During treatment with the medicinal product, regular monitoring of blood and urine glucose levels is required. Additionally, measurement of glycated haemoglobin is recommended.

Patients with severe renal or hepatic impairment

Experience with glimepiride in patients with severe hepatic impairment or in patients undergoing dialysis is lacking. Patients with severe renal or hepatic impairment should be switched to insulin therapy.

Patients with glucose-6-phosphate dehydrogenase deficiency

Treatment of such patients with sulphonylurea drugs may lead to the development of haemolytic anaemia. Since glimepiride belongs to the sulphonylurea class of drugs, the medicinal product should be used with caution in patients with glucose-6-phosphate dehydrogenase deficiency. Alternative agents not containing sulphonylurea should be prescribed for these patients.

Precautions related to excipients

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

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Risk associated with diabetes mellitus.

Abnormal blood glucose levels during pregnancy may increase the risk of congenital malformations and perinatal mortality. Blood glucose levels in pregnant women should be carefully controlled to avoid teratogenic risk.

Pregnant women with diabetes mellitus should be switched to insulin. Women with diabetes should inform their physician about any planned pregnancy to allow adjustment of treatment and transition to insulin.

Risk associated with glimepiride.

There are no data on the use of glimepiride in pregnant women. Animal studies indicate that glimepiride has reproductive toxicity, likely related to its pharmacological effect (hypoglycaemia). The medicinal product is contraindicated during pregnancy. If a patient taking glimepiride plans a pregnancy or becomes pregnant, she should be switched to insulin therapy as soon as possible.

Breastfeeding

It is unknown whether glimepiride passes into human breast milk. In animals, glimepiride is excreted in breast milk. Since other sulphonylurea derivatives are excreted in breast milk and considering the risk of hypoglycaemia in breastfed infants, breastfeeding is not recommended during treatment with this medicinal product.

Ability to influence reaction speed while driving or operating machinery

Studies on the effect of glimepiride on the ability to drive or operate machinery have not been conducted.

The ability to concentrate and reaction speed may be reduced due to hypoglycaemia or hyperglycaemia or, for example, due to impaired vision. This may pose a risk in situations where such abilities are particularly important (e.g. driving a car or operating machinery).

Patients should be warned not to allow hypoglycaemia to develop while driving or operating machinery. This is particularly important for individuals who poorly recognize or are unable to recognize early warning symptoms of hypoglycaemia, and for those who experience frequent hypoglycaemic episodes. The necessity of driving or operating machinery under such circumstances should be seriously reconsidered.

Dosage and Administration

The medicinal product is intended for oral administration.

Successful treatment of diabetes mellitus depends on the patient adhering to an appropriate diet, regular physical activity, and consistent monitoring of blood and urine glucose levels. Failure to follow the prescribed diet cannot be compensated by taking tablets or insulin.

The dosage is determined based on blood and urine glucose test results.

The initial dose of glimepiride is 1 mg once daily (½ of a 2 mg tablet).

If this dose achieves adequate disease control, it should be maintained for maintenance therapy.

If glycemic control is not optimal, the dose should be increased stepwise to 2, 3, or 4 mg daily (at intervals of 1–2 weeks). For different treatment regimens, the medicinal product is available in various strengths.

A dose exceeding 4 mg daily provides better results only in individual cases. The maximum recommended dose is 6 mg of the medicinal product per day.

Concomitant use with metformin

If the maximum daily dose of metformin does not provide adequate glycemic control, combination therapy with glimepiride may be initiated.

While maintaining the previous metformin dosage, glimepiride therapy should begin with a low dose, which can then be gradually increased up to the maximum daily dose, depending on the desired level of metabolic control.

Combination therapy must be conducted under close medical supervision.

Concomitant use with insulin

If the maximum daily dose of the medicinal product does not provide adequate glycemic control, concomitant insulin therapy may be initiated when necessary. While maintaining the previous glimepiride dosage, insulin therapy should begin with a low dose, which can then be gradually increased based on the desired level of metabolic control.

Combination therapy must be conducted under close medical supervision.

Typically, one daily dose of glimepiride is sufficient. It should be taken shortly before or during a substantial breakfast, or, if breakfast is skipped, shortly before or during the first main meal of the day. Errors in medication use, such as missing a dose, should never be corrected by taking a higher dose next time. The tablet should be swallowed whole with liquid, without chewing.

If a patient experiences a hypoglycemic reaction to a 1 mg daily dose of glimepiride, this indicates that diabetes may be controlled by diet alone.

Improved glycemic control is often accompanied by increased insulin sensitivity, so during treatment the need for glimepiride may decrease. To avoid hypoglycemia, the dose should be gradually reduced or the medication discontinued altogether. A reassessment of dosage may also be necessary if the patient's body weight or lifestyle changes, or if other factors affecting the risk of hypo- or hyperglycemia arise.

Switching from other oral hypoglycemic agents to glimepiride

Switching from other oral hypoglycemic agents to Insuprid is generally feasible.

When switching, the potency and half-life of the previous agent should be considered. In some cases, especially when the previous antidiabetic agent has a long half-life (e.g., chlorpropamide), it is recommended to wait several days before starting glimepiride to reduce the risk of hypoglycemic reactions due to additive effects. The recommended initial dose of the medicinal product is 1 mg daily. As mentioned above, the dose may be gradually increased according to the patient's response.

Switching from insulin to glimepiride

In exceptional cases, insulin replacement with glimepiride may be indicated for patients with type 2 diabetes mellitus. Such a switch should be performed under close medical supervision.

Children

Currently, there is a lack of evidence regarding the use of glimepiride in patients under 8 years of age. Limited evidence exists for the use of glimepiride as monotherapy in children aged 8 to 17 years (see section "Pharmacological properties"). Available data on the safety and efficacy of the medicinal product in children are insufficient; therefore, it is not recommended for use in this patient population.

Overdose

Symptoms

Overdose may lead to hypoglycemia lasting from 12 to 72 hours, and symptoms may recur even after initial improvement. Symptoms may appear up to 24 hours after glimepiride absorption. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia is often accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, coordination disorders, drowsiness, coma, and seizures. Hospital observation is generally recommended for such patients.

Treatment

Treatment primarily involves preventing further absorption of the drug. This can be achieved by inducing vomiting, followed by drinking water or soda containing activated charcoal (adsorbent) and sodium sulfate (laxative). If a large amount of glimepiride has been ingested, gastric lavage is indicated, followed by administration of activated charcoal and sodium sulfate. In cases of severe overdose, hospitalization in an intensive care unit is necessary. Glucose administration should be initiated as soon as possible: if necessary, initially by a single intravenous injection of 50 mL of a 50% glucose solution, followed by infusion of a 10% glucose solution, with continuous monitoring of blood glucose levels. Further treatment is symptomatic.

When treating hypoglycemia caused by accidental glimepiride ingestion in infants and young children, the glucose dose must be carefully adjusted to avoid dangerous hyperglycemia, and monitoring should include careful observation of plasma glucose levels.

Adverse Reactions

Adverse reactions are listed below by organ system classes in decreasing order of frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); frequency not known (frequency cannot be estimated from the available data).

Blood and lymphatic system disorders:

Rare – thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, hemolytic anemia, pancytopenia (usually reversible after discontinuation of glimepiride); frequency not known – severe thrombocytopenia (with platelet count less than 10,000/µL), thrombocytopenic purpura.

Immune system disorders:

Very rare – leukocytoclastic vasculitis, moderate hypersensitivity reactions which may progress to severe forms, accompanied by dyspnea, hypotension and sometimes shock; frequency not known – possible cross-allergy with sulfonamides, sulfonamide derivatives or related substances.

Metabolism and nutrition disorders:

Rare – hypoglycemia.

Such hypoglycemic reactions usually occur immediately, may be severe and are not always easily corrected. The occurrence of such reactions, as with treatment with other hypoglycemic agents, depends on individual factors such as dietary habits and dosage (see section "Dosage and Administration").

Eye disorders:

Frequency not known – transient visual disturbances, particularly at the beginning of treatment, caused by changes in blood glucose levels.

Gastrointestinal disorders:

Very rare – nausea, vomiting, diarrhea, sensation of fullness and discomfort in the abdomen, abdominal pain, which rarely lead to the need to discontinue treatment.

Hepatobiliary disorders:

Very rare – liver function abnormalities (e.g., cholestasis or jaundice), hepatitis, hepatic failure; frequency not known – increased levels of liver enzymes.

Skin and subcutaneous tissue disorders:

Frequency not known – hypersensitivity reactions may occur, including pruritus, rash, urticaria and photosensitivity.

Laboratory findings:

Very rare – decreased plasma sodium levels.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25 °C. Keep out of the reach and sight of children.

Packaging

15 tablets in a blister; 2 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

UORLID MEDITSIN ILACH SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey /
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder

LLC "WORLD MEDICINE", Ukraine /
WORLD MEDICINE, LLC, Ukraine.