Dimaril®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIMARYLÒ (DIMARYL)

Composition:

Active substance: glimepiride;

1 tablet contains 2.0 mg, 3.0 mg, or 4.0 mg of glimepiride, calculated as 100% substance;

Excipients:

tablets of 2.0 mg: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); povidone; indigocarmine lake (E 132); yellow iron oxide (E 172); magnesium stearate;

tablets of 3.0 mg: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); povidone; yellow iron oxide (E 172); magnesium stearate;

tablets of 4.0 mg: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (type A); povidone; indigocarmine lake (E 132); magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 2.0 mg: elongated, biconvex tablets with a score line on both sides, light green to green in color, with slightly uneven surface coloration; presence of specks of more intense color is acceptable;

tablets of 3.0 mg: elongated, biconvex tablets with a score line on both sides, light yellow in color, with slightly uneven surface coloration; presence of specks of more intense color is acceptable;

tablets of 4.0 mg: elongated, biconvex tablets with a score line on both sides, pale blue to blue in color, with slightly uneven surface coloration; presence of specks of more intense color is acceptable.

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

Pharmacological Properties.

Pharmacodynamics.

Glibenclamide is an oral hypoglycemic agent belonging to the sulfonylurea group. Glibenclamide can be used in type 2 diabetes mellitus.

Glibenclamide 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, glibenclamide exerts a pronounced extrapancreatic effect, which is also characteristic of other sulfonylurea drugs.

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 exocyt游戏副本

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

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

Interaction with other medicinal products and other forms of interaction.

Concomitant administration of Diamaril**®** with certain medications may either reduce or enhance the hypoglycemic effect of glimepiride. Therefore, other medications should be taken only with the consent (or 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. Results from in vivo interaction studies have shown that fluconazole, one of the most potent inhibitors of CYP2C9, increases the AUC of glimepiride approximately twofold. Clinical experience with Diamaril and other sulfonylurea derivatives supports the existence of such interactions.

Potentiation of glucose-lowering effect, and consequently, hypoglycemia in some cases, may occur when glimepiride is used concomitantly with the following agents: phenylbutazone, azapropazone and oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic agents, certain long-acting sulfonamides, metformin, 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, trofosfamide, and ifosfamide.

Reduced glucose-lowering effect, and consequently, increased blood glucose levels, may be observed when the patient is concurrently taking the following medications: estrogens and progestogens; thiazide diuretics and saluretics; thyroid-stimulating agents, glucocorticoids; phenothiazine derivatives, chlorpromazine; epinephrine and sympathomimetics; nicotinic acid (high doses) and its derivatives; laxatives (with 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.

Dimarel® should be taken shortly before or during a meal.

In cases of irregular eating habits or missed meals, treatment with Dimarel® may cause hypoglycemia. Possible symptoms of hypoglycemia include headache, intense hunger, nausea, vomiting, fatigue, drowsiness, sleep disturbances, increased motor activity, aggression, difficulty concentrating, anxiety, delayed reaction time, depressive mood, confusion, speech disorders and visual disturbances, aphasia, tremor, paresis, sensory disturbances, dizziness, helplessness, loss of self-control, delirium, seizures, 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 attack may resemble that of a stroke.

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

Based on experience with other sulfonylurea derivatives, it is known that despite initial effectiveness of measures to correct hypoglycemia, it may recur.

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

Factors predisposing to the development of hypoglycemia include:

• unwillingness or (especially 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, particularly in combination with skipped meals;
• impaired renal function;
• severe impairment of liver function;
• overdose of Dimarel®;
• 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 Dimarel® requires regular monitoring of blood and urine glucose levels. Additionally, measurement of glycated hemoglobin (HbA1c) is recommended.

Liver function tests and hematological parameters (particularly white blood cell and platelet counts) should be monitored regularly during treatment with Dimarel®.

In stressful situations (e.g., trauma, unplanned surgical procedures, infections accompanied by fever), temporary conversion to insulin therapy may be indicated.

Experience with the use of Dimarel® in patients with severe hepatic dysfunction or in patients undergoing dialysis is lacking. Patients with severe renal or hepatic impairment should be switched to insulin therapy.

Treatment with sulfonylurea drugs in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may lead to hemolytic anemia. Since glimepiride belongs to the sulfonylurea class of drugs, it should be used with caution in patients with G6PD deficiency. Alternative non-sulfonylurea agents should be considered for such patients.

Dimarel® tablets contain less than 5 g of lactose monohydrate (2.0 mg tablets – 146.019 mg; 3.0 mg tablets – 145.019 mg; 4.0 mg tablets – 144.019 mg). Therefore, if a patient has known sugar intolerance, consultation with a physician is advised before taking this medicinal product.

This medicinal product should not be used in patients with the rare hereditary conditions of 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 blood glucose control 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 any 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 due to the pharmacological effect of glimepiride (hypoglycemia). Therefore, glimepiride must not be used 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 glimepiride passes into human breast milk. In rats, glimepiride is excreted in breast milk. Since other sulfonylurea derivatives are known to pass into breast milk and considering the risk of hypoglycemia in breastfed infants, breastfeeding is not recommended during glimepiride therapy.

Ability to affect reaction speed when driving or operating machinery.
No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted.

The ability to concentrate and reaction speed may be reduced due to hypoglycemia or hyperglycemia, 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 hypoglycemia to occur while driving. This is especially important for individuals who poorly or not at all recognize early warning symptoms of hypoglycemia, and for those who experience frequent hypoglycemic episodes. Serious consideration should be given to whether driving or operating machinery is appropriate under such circumstances.

Method of Administration and Dosage.

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 insulin.

The dosage depends on the results of blood and urine glucose analyses.

The initial dose is 1 mg (1/2 tablet of 2 mg) of glimepiride daily. If this dose achieves adequate disease control, it should be used for maintenance therapy.

If glycemic control is not optimal, the dose should be increased stepwise to 2, 3, or 4 mg of glimepiride daily, with intervals of 1–2 weeks between dose adjustments.

Doses exceeding 4 mg daily provide better results only in individual cases. The maximum recommended dose is 6 mg of Diamirel® daily.

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

Without changing 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.

If the maximum daily dose of Diamirel® does not provide adequate glycemic control, insulin therapy may be initiated if necessary. Without changing 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 close 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, must never be corrected by taking a higher dose subsequently. The tablet should be swallowed whole, without chewing, with liquid.

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

Improved diabetes control is associated with increased insulin sensitivity; therefore, during treatment, the need for glimepiride may decrease. To avoid hypoglycemia, the dose should be gradually reduced or therapy discontinued altogether. Dose adjustments may also be necessary if the patient's body weight or lifestyle changes, or if other factors that increase the risk of hypo- or hyperglycemia are present.

Switching from other oral hypoglycemic agents to Diamirel®.

Patients can usually be switched from other oral hypoglycemic agents to Diamirel®. When switching, the potency and half-life of the previous agent should be taken into account. In some cases, especially when the antidiabetic agent has a long half-life (e.g., chlorpropamide), it is recommended to wait several days before starting Diamirel® 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 mentioned above, the dose may be gradually increased according to the patient's response to the drug.

Switching from insulin to Diamirel®.

In exceptional cases, patients with type 2 diabetes who are taking insulin may be candidates for switching to Diamirel**®**. This transition must be conducted under close medical supervision.

Children. Currently, there is insufficient evidence regarding the use of glimepiride in patients under 8 years of age. Limited data exist on the use of glimepiride as monotherapy in children aged 8 to 17 years. Due to insufficient data on safety and efficacy in pediatric patients, the drug is not recommended for use 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 absorption. Affected patients should generally be observed 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 absorption of the drug. To achieve this, vomiting should be induced, followed by ingestion of water or lemonade 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 required. Glucose administration should be initiated as soon as possible: if necessary, initially 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 Diamirel® in infants and young children, the glucose dose must be carefully adjusted to avoid dangerous hyperglycemia, with close monitoring of blood glucose levels.

Side effects.

Based on the experience of using Dimaryl® and other sulfonylurea derivatives, the following adverse reactions have been observed during clinical trials, listed below by organ system classes in decreasing order of frequency: very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000; 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 generally 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 which may progress to severe forms, accompanied by dyspnea, hypotension, and sometimes shock.

Frequency not known: possible cross-allergy with sulfonylurea derivatives, sulfonamides, or related substances.

Metabolism and nutrition disorders.

Rare: hypoglycemia.

Such hypoglycemic reactions occur predominantly acutely, 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 drug dosage (see section "Special precautions" for details).

Eye disorders.

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

Gastrointestinal disorders.

Very rare: nausea, vomiting, diarrhea, bloating, abdominal discomfort, abdominal pain, which rarely lead to the necessity of discontinuing treatment.

Hepatobiliary disorders.

Frequency not known: increased levels of liver enzymes.

Very rare: liver function disorders (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 authorization of the medicinal product by regulatory authorities is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report all suspected adverse reactions via national reporting systems.

Shelf life.

3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets per blister. 3, 5, or 6 blisters per carton.

Prescription status.

Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.