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

Composition:

Active substance: glimepiride;

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

Excipients:

tablets of 2 mg: lactose monohydrate, sodium starch glycolate (type A), povidone, microcrystalline cellulose, magnesium stearate, yellow iron oxide (E 172), indigo carmine aluminium lake (E 132);

tablets of 3 mg: lactose monohydrate, sodium starch glycolate (type A), povidone, microcrystalline cellulose, magnesium stearate, yellow iron oxide (E 172);

tablets of 4 mg: lactose monohydrate, sodium starch glycolate (type A), povidone, microcrystalline cellulose, magnesium stearate, indigo carmine aluminium lake (E 132).

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 2 mg: green elongated tablets, biconvex with a break line on both sides. Upper imprint*: NMM and Company logo; lower imprint*: Company logo and NMM;

tablets of 3 mg: pale-yellow elongated tablets, biconvex with a break line on both sides. Upper imprint*: NMN and Company logo; lower imprint*: Company logo and NMN;

tablets of 4 mg: light-blue elongated tablets, biconvex with a break line on both sides. Upper imprint*: NMO and Company logo; lower imprint*: Company logo and NMO.

The tablet can be divided along the break line into equal doses.

* The order of imprint symbols and spatial arrangement of the stamp may vary.

Pharmacotherapeutic group. Antidiabetic agents, excluding insulin. Sulfonylureas, urea derivatives. ATC code A10B B12.

Pharmacological Properties

Pharmacodynamics

Glimepiride is an orally active hypoglycemic agent belonging to the sulfonylurea group. It can be used in insulin-independent diabetes mellitus.

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

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

Insulin release. Sulfonylurea agents regulate insulin secretion by closing ATP-dependent potassium channels located in the beta-cell membrane of the pancreas. 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, thereby triggering insulin release through exocytosis.

Glimepiride binds rapidly and specifically to a protein in the beta-cell membrane associated with the ATP-dependent potassium channel, although its binding site differs from the conventional sulfonylurea binding site.

Extrapancreatic activity. Extrapancreatic effects include, for example, improved peripheral tissue sensitivity to insulin 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 in isolated muscle and fat cells may correlate with drug-induced lipogenesis and glycogenesis.

Glimepiride inhibits hepatic glucose production by increasing intracellular concentrations of fructose-2,6-bisphosphate, which in turn suppresses gluconeogenesis.

General characteristics. In healthy volunteers, the minimal effective oral dose was 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 or immediately before a meal. In patients with diabetes, adequate metabolic control over 24 hours can be achieved with once-daily dosing.

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

Combination with metformin. One study demonstrated improved metabolic control with combination therapy using glimepiride compared to metformin monotherapy in patients whose diabetes was inadequately 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; however, with combination therapy, a lower average insulin dose was required.

Special patient categories. Children, including adolescents. 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 the rate of absorption. Maximum plasma concentration (Cmax) is reached approximately 2.5 hours after oral administration (mean value is 0.3 µg/mL following repeated 4 mg daily dose). There is a linear relationship between dose and Cmax, as well as between dose and AUC (area under the concentration-time curve).

Distribution. Glimepiride has a low volume of distribution (approximately 8.8 L), roughly equivalent to the distribution volume of albumin, a high degree of plasma protein binding (>99%), and 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.

Metabolism and elimination. The mean terminal half-life at plasma concentrations corresponding to repeated dosing regimens is approximately 5 to 8 hours. A slight increase in half-life was observed after administration of high doses.

After a single radiolabeled dose of glimepiride, 58% of radioactivity was recovered in urine and 35% in feces. The unchanged drug was not detected in urine. Two metabolites were identified in urine and feces, most likely formed via hepatic metabolism (main enzyme CYP2C9), one being a hydroxy derivative and the other a 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 pharmacokinetics after single and repeated once-daily dosing showed no significant differences. Interindividual variability was very low. No clinically relevant accumulation was observed.

Special patient categories. Pharmacokinetic parameters in men and women, as well as in young 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, likely due to faster elimination resulting from reduced protein binding. Renal excretion of both metabolites was impaired. Overall, increased risk of drug accumulation in these patients is not expected.

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

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

Preclinical safety data. Effects observed during 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, and reproductive toxicity studies. Adverse effects identified in the latter (including studies on embryotoxicity, teratogenicity, and developmental toxicity) were considered consequences of drug-induced hypoglycemic effects 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.

Amaryl**®** is not indicated for the treatment of insulin-dependent diabetes, diabetic ketoacidosis, or diabetic coma. The use of this medication is contraindicated in patients with severe impairment of renal or hepatic function. In cases of severe renal or hepatic dysfunction, patients must be switched to insulin therapy.

Amaryl**®** must not be administered to patients with hypersensitivity to glimepiride or to any excipient contained in the formulation, as well as to other sulfonylurea derivatives or sulfonamide drugs (risk of developing hypersensitivity reactions).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Amaryl**®** with certain medications may either reduce or enhance the hypoglycemic effect of glimepiride. Therefore, other medications should be taken only with the consent (or upon prescription) 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.

The following types of interactions are supported by clinical experience with Amaryl**®** and other sulfonylurea derivatives.

Potentiation of glucose-lowering effect, and thus, in some cases, hypoglycemia, may occur when glimepiride is used concomitantly with the following drugs: phenylbutazone, azapropazone, and oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic agents (such as metformin), certain long-acting sulfonamides, tetracyclines, salicylates and p-aminosalicylic acid, MAO inhibitors, anabolic steroids and androgens, quinolone antibiotics and clarithromycin, chloramphenicol, probenecid, coumarin anticoagulants, miconazole, fenfluramine, disopyramide, pentoxifylline (high parenteral doses), fibrates, troglitazone, ACE inhibitors, fluconazole, fluoxetine, allopurinol, sympatholytics, cyclophosphamide, ifosfamide, and trophosphamide.

Reduced glucose-lowering effect, and consequently, increased blood glucose levels, may occur when patients are concomitantly taking the following medications: estrogens and progestogens; saluretics, thiazide diuretics; thyroid-stimulating agents, glucocorticoids; phenothiazine derivatives, chlorpromazine; adrenaline and sympathomimetics; nicotinic acid (high doses) and its derivatives; laxatives (prolonged use); phenytoin, diazoxide; glucagon, barbiturates, and rifampicin; acetazolamide.
H2-receptor antagonists, beta-blockers, clonidine, and reserpine may either potentiate or reduce the 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.

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

Glimepiride may either increase or decrease the effect of coumarin derivatives.

Colesevelam 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 colesevelam. Therefore, glimepiride should be taken at least 4 hours before colesevelam.

Special precautions for use.

Amaryl**®** should be taken shortly before or during a meal.

In case of irregular eating habits or missed meals, treatment with Amaryl**®** may cause hypoglycemia. Possible symptoms of hypoglycemia include headache, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, increased motor activity, aggression, difficulty concentrating, anxiety, slowed reaction time, depressive mood, confusion, speech and visual disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, convulsions, somnolence, 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, arterial hypertension, palpitations, angina pectoris, and cardiac arrhythmias.

The clinical picture of a severe hypoglycemic episode may resemble that of a stroke.

Symptoms of hypoglycemia can almost always be rapidly relieved by immediate ingestion of carbohydrates (sugar). Artificial sweeteners are ineffective.

Based on experience with other sulfonylurea derivatives, although initial measures to correct hypoglycemia may be effective, hypoglycemia may recur.

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

Factors predisposing to the development of hypoglycemia include:

unwillingness or (particularly in elderly patients) inability of the patient to cooperate with the physician;
inadequate food intake, irregular eating, skipping meals, or periods of fasting;
dietary imbalances;
mismatch between physical exertion and carbohydrate intake;
alcohol consumption, especially when combined with skipped meals;
impaired renal function;
severe hepatic impairment;
overdose of Amaryl**®**;
certain decompensated endocrine disorders affecting carbohydrate metabolism or hypoglycemia 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").

Treatment with Amaryl**®** requires regular monitoring of blood and urine glucose levels. Additionally, measurement of glycated hemoglobin is recommended.

During treatment with Amaryl**®**, liver function tests and hematological parameters (especially leukocyte and platelet counts) should be monitored regularly.

In stressful situations (e.g., trauma, unplanned surgery, infections accompanied by fever), temporary transition to insulin therapy may be necessary.

Experience with the use of Amaryl**®** 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.

Treatment of patients with glucose-6-phosphate dehydrogenase deficiency with sulfonylurea agents may lead to the development of 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. Alternative non-sulfonylurea agents should be considered for these patients.

Amaryl**®** contains lactose monohydrate. This medicinal product should not be used in patients with rare hereditary galactose intolerance, 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, careful monitoring of blood glucose levels in pregnant women is essential to avoid teratogenic risk.

Pregnant women with diabetes should be switched to insulin therapy. Women with diabetes should inform their physician about planned pregnancy to allow timely 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 reproductive toxicity of the drug, likely related to the pharmacological action of glimepiride (hypoglycemia).

Therefore, glimepiride must not be used at any time 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 period.

It is unknown whether the drug is excreted in human breast milk. In rats, glimepiride is excreted in breast milk. Since other sulfonylurea derivatives are excreted in breast milk and considering the risk of hypoglycemia in breastfed infants, breastfeeding is not recommended during treatment with glimepiride.

Effect on ability to drive and use machines.

Studies on the effect of the medicinal product on the ability to drive and operate machinery have not been conducted.

The ability to concentrate and reaction speed may be impaired due to hypoglycemia or hyperglycemia, or, for example, due to visual disturbances. This may pose risks in situations where such abilities are particularly important (e.g., driving a car or operating machinery).

Patients should be warned not to allow hypoglycemia to occur while driving. This is especially important for individuals who have poor or no awareness of the warning signs of hypoglycemia, or who experience frequent hypoglycemic episodes. Careful consideration should be given to whether driving or operating machinery is appropriate under such circumstances.

Dosage and Administration

The drug is intended for oral administration.

Successful diabetes management 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 using insulin.

The dosage depends on blood and urine glucose test results.

The initial dose is 1 mg (1/2 of a 2 mg tablet) of glimepiride daily. If this dose adequately controls the disease, it should be used for maintenance therapy.

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

Doses exceeding 4 mg daily provide additional benefit only in individual cases. The maximum recommended dose is 6 mg of Amaryl® daily.

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

While maintaining the previous metformin dosage, glimepiride therapy should be initiated at a low dose, which can then be gradually increased up to the maximum daily dose, based on the desired level of metabolic control. Combination therapy must be conducted under strict medical supervision.

If the maximum daily dose of Amaryl® does not provide adequate glycemic control, insulin therapy may be initiated as needed. While maintaining the previous glimepiride dosage, insulin treatment should begin with a low dose, which can then be increased based on the desired level of metabolic control.

Combination therapy must be conducted under strict medical supervision.

Typically, a single daily dose of glimepiride is sufficient. It should be taken shortly before or during a substantial breakfast, or—if breakfast is omitted—shortly before or during the first main meal of the day. Errors in drug administration, such as missing a dose, should never be corrected by taking a higher dose subsequently. The tablet should be swallowed whole, without chewing, with liquid.

If a hypoglycemic reaction occurs with 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; therefore, during treatment, the requirement for glimepiride may decrease. To avoid hypoglycemia, the dose should be gradually reduced or therapy discontinued altogether. Re-evaluation of dosage may also be necessary if the patient experiences changes in body weight or lifestyle, or if other factors affecting the risk of hypo- or hyperglycemia are present.

Switching from other oral hypoglycemic agents to Amaryl®.

Switching from other oral hypoglycemic agents to Amaryl® is generally possible. When switching, the potency and elimination half-life of the previous agent should be considered. In some cases, especially when the previous antidiabetic agent has a long elimination half-life (e.g., chlorpropamide), it is recommended to wait several days before starting Amaryl® to reduce the risk of hypoglycemic reactions due to additive effects of the two agents.

The recommended initial dose is 1 mg of glimepiride daily. As noted above, the dose may be gradually increased according to the patient's response.

Switching from insulin to Amaryl®.

In exceptional cases, patients with type 2 diabetes mellitus receiving insulin therapy may be candidates for switching to Amaryl®. This transition must be performed under strict medical supervision.

Children. Currently, there is a lack of evidence-based data on the use of glimepiride in patients under 8 years of age. Limited data exist for children aged 8 to 17 years regarding the use of glimepiride as monotherapy (see sections "Pharmacodynamics" and "Pharmacokinetics"). The available data on the safety and efficacy of the drug in children are insufficient; therefore, its use is not recommended in this patient population.

Overdose.

Overdose may lead to hypoglycemia, lasting from 12 to 72 hours, which may recur after initial improvement. Symptoms may appear up to 24 hours after drug administration. Typically, such patients should be monitored in a clinical setting. 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.

Treatment of overdose. Treatment primarily involves preventing further drug absorption. This may be achieved by inducing vomiting, followed by ingestion of water or soda containing activated charcoal (an adsorbent) and sodium sulfate (a 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 as 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 ingestion of Amaryl® in infants and young children, the glucose dose must be carefully adjusted to prevent dangerous hyperglycemia, and blood glucose levels must be closely monitored.

Adverse Reactions

Based on the experience with Amaryl® and other sulfonylurea derivatives, the following adverse reactions have been observed in clinical trials, listed 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 (cannot be estimated from available data).

Blood and lymphatic system disorders.

Rare: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, erythropenia, hemolytic anemia, and pancytopenia, which are usually reversible upon discontinuation of the drug.
Frequency not known: severe thrombocytopenia with platelet count less than 10,000/µL and thrombocytopenic purpura.

Immune system disorders.

Very rare: leukocytoclastic vasculitis, moderate hypersensitivity reactions that may progress to severe forms, accompanied by dyspnea, hypotension, and sometimes shock.
Frequency not known: possible cross-allergy with sulfonylurea derivatives, sulfonamides, or related compounds.

Metabolism and nutrition disorders.

Rare: hypoglycemia.

These hypoglycemic reactions typically occur immediately, may be severe, and are not always easily corrected. The occurrence of such reactions, as with other hypoglycemic agents, depends on individual factors such as dietary habits and dosage (see section "Special precautions" for details).

Eye disorders.

Frequency not known: transient visual disturbances may occur, especially at the beginning of treatment, due to changes in blood glucose levels.

Gastrointestinal disorders.

Very rare: nausea, vomiting, diarrhea, abdominal distension, abdominal discomfort, abdominal pain, which rarely necessitate discontinuation of treatment.

Hepatobiliary disorders.

Frequency not known: increased levels of liver enzymes.
Very rare: liver function abnormalities (e.g., with cholestasis or jaundice), hepatitis, and hepatic failure.

Skin and subcutaneous tissue disorders.

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

Investigations.

Very rare: decreased serum sodium levels.

Reporting of 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 are encouraged to report any suspected adverse reactions via national reporting systems.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

No. 30 (15x2): 15 tablets in a blister, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

SANOFI S.R.L. / SANOFI S.R.L.

Manufacturer's address and location of operations.

S.S. 17 KM 22, SCOPPITO (AQ), 67019, Italy / S.S. 17 KM 22, SCOPPITO (AQ), 67019, Italy

Marketing Authorization Holder.

LLC "Sanofi-Aventis Ukraine", Ukraine / Sanofi-Aventis Ukraine LLC, Ukraine.