Diamerid^® (Tablets) Instructions for Use

ATC Code

A10BB12 (Glimepiride)

Active Substance

Glimepiride (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Oral hypoglycemic drug

Pharmacotherapeutic Group

Hypoglycemic agent for oral administration of the third-generation sulfonylurea group

Pharmacological Action

An oral hypoglycemic drug – a derivative of sulfonylurea of the third generation.

Glimepiride acts mainly by stimulating the secretion and release of insulin from pancreatic beta-cells (pancreatic action).

As with other sulfonylurea derivatives, this effect is based on an increased response of pancreatic beta-cells to physiological glucose stimulation, with the amount of insulin secreted being significantly less than with traditional sulfonylurea derivatives.

The minimal stimulatory effect of glimepiride on insulin secretion also ensures a lower risk of hypoglycemia.

In addition to this, Glimepiride has an extrapancreatic action – the ability to improve the sensitivity of peripheral tissues (muscle, adipose) to the action of endogenous insulin, to reduce insulin uptake by the liver; it inhibits glucose production in the liver.

Glimepiride selectively inhibits COX and reduces the conversion of arachidonic acid to thromboxane A2, which promotes platelet aggregation, thus exerting an antiplatelet effect.

Glimepiride helps normalize lipid levels, reduces the concentration of malondialdehyde in the blood, which leads to a significant decrease in lipid peroxidation; this contributes to the antiatherogenic effect of the drug.

Glimepiride increases the level of endogenous alpha-tocopherol, the activity of catalase, glutathione peroxidase and superoxide dismutase, which helps reduce the severity of oxidative stress in the patient’s body, which is constantly present in type 2 diabetes mellitus.

Pharmacokinetics

Absorption

After multiple administration of glimepiride at a daily dose of 4 mg, C_max in blood serum is reached in approximately 2.5 hours and is 432 ng/ml; there is a linear relationship between the dose and C_max, as well as between the dose and AUC. When taken orally, the bioavailability of glimepiride is about 100%. Food intake does not have a significant effect on absorption, except for a slight delay in the rate of absorption.

Distribution

Glimepiride is characterized by a very low V_d (about 8.8 L), approximately equal to the V_d of albumin, a high degree of binding to plasma proteins (more than 99%) and a low clearance (about 48 ml/min).

Glimepiride penetrates into breast milk and through the placental barrier. The drug poorly penetrates the blood-brain barrier.

Elimination

After a single oral dose of glimepiride, 58% is excreted by the kidneys and 35% through the intestines. No unchanged substance was detected in the urine. T_1/2 at plasma drug concentrations in serum corresponding to multiple doses is 5-8 hours. After administration of high doses, T_1/2 increases somewhat.

Pharmacokinetics in special clinical cases

In patients with impaired renal function, there is a tendency towards an increase in the clearance of glimepiride and a decrease in its mean serum concentrations, which is probably due to faster elimination of the drug due to its lower binding to plasma proteins. Thus, there is no additional risk of drug accumulation in this category of patients.

Indications

• Type 2 diabetes mellitus when previously prescribed diet and physical exercise are ineffective.

If monotherapy with glimepiride is ineffective, it is possible to use it as part of combination therapy with metformin or insulin.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally. The initial and maintenance doses of glimepiride are set individually based on the results of regular blood glucose monitoring.

Initial dose and dose titration

At the beginning of treatment, the drug is prescribed at a dose of 1 mg once a day. When the optimal therapeutic effect is achieved, it is recommended to take this dose as a maintenance dose.

If glycemic control is not achieved, the daily dose should be gradually increased under regular blood glucose monitoring (at intervals of 1-2 weeks) to 2 mg, 3 mg or 4 mg per day. Doses above 4 mg/day are effective only in exceptional cases. The maximum recommended daily dose is 6 mg.

Time and frequency of administration of the daily dose is determined by the doctor, taking into account the patient’s lifestyle. The daily dose is prescribed in a single dose immediately before or during a substantial breakfast, or the first main meal. The tablets should be taken whole, without chewing, with a sufficient amount of liquid (about half a glass). It is not recommended to skip a meal after taking Diamerid^®.

Duration of treatment

Treatment with Diamerid^® is long-term, under the control of blood glucose levels.

Use in combination with metformin

If glycemic control is not achieved in patients taking metformin, concomitant therapy with Diamerid^® may be initiated. While maintaining the dose of metformin at the same level, treatment with Diamerid^® is started at the minimum dose, and then gradually increased depending on the desired level of glycemic control, up to the maximum daily dose. Combination therapy should be carried out under careful medical supervision.

Use in combination with insulin

In cases where glycemic control cannot be achieved by taking the maximum dose of Diamerid^® as monotherapy or in combination with the maximum dose of metformin, a combination of glimepiride with insulin is possible. In this case, the last prescribed dose of glimepiride remains unchanged. At the same time, insulin therapy should be started at the minimum dose, with a possible subsequent gradual increase in its dose under the control of blood glucose concentration. Combined treatment requires mandatory medical supervision.

Transfer of a patient from another oral hypoglycemic drug to Glimepiride

When transferring a patient from another oral hypoglycemic drug to Diamerid^®, the initial daily dose of the latter should be 1 mg (even if the patient is transferred to Diamerid^® from the maximum dose of another oral hypoglycemic drug). Any increase in the dose of Diamerid^® should be carried out step by step in accordance with the above recommendations. The efficacy, dose and duration of action of the hypoglycemic drug used should be taken into account. In some cases, especially when taking hypoglycemic drugs with a long half-life, it may be necessary to temporarily (for several days) discontinue treatment to avoid an additive effect that increases the risk of hypoglycemia.

Transfer of a patient from insulin to Glimepiride

In exceptional cases, during insulin therapy in patients with type 2 diabetes mellitus, with compensation of the disease and preserved secretory function of pancreatic beta-cells, it is possible to replace insulin with glimepiride. The transfer should be carried out under close medical supervision. In this case, the transfer of the patient to Diamerid^® begins with a minimum dose of 1 mg.

Adverse Reactions

Metabolism: development of hypoglycemic reactions is possible. These reactions mainly occur shortly after taking the drug, can be severe and protracted and are not always easy to control. The development of these symptoms depends on individual factors, such as dietary habits and dosing.

Organ of vision: during treatment (especially at the beginning) transient visual disturbances may be observed, due to changes in blood glucose concentration.

Digestive system: nausea, vomiting, feeling of heaviness or discomfort in the epigastrium, abdominal pain, diarrhea, very rarely leading to discontinuation of treatment; increased activity of liver enzymes, cholestasis, jaundice, hepatitis (up to the development of liver failure).

Hematopoietic system: thrombocytopenia (from moderate to severe), leukopenia, hemolytic or aplastic anemia, erythrocytopenia, granulocytopenia, agranulocytosis and pancytopenia.

Allergic reactions: urticaria (itching, skin rash) may occur. Such reactions are usually moderate, but can progress, accompanied by a drop in blood pressure, shortness of breath, up to the development of anaphylactic shock. If urticaria appears, you should immediately consult a doctor. Cross-allergy with other sulfonylurea derivatives, sulfonamides or other sulfonamides is possible; the development of allergic vasculitis is also possible.

Dermatological reactions in some cases – photosensitivity, late cutaneous porphyria.

Other: in some cases – headache, asthenia, hyponatremia.

Contraindications

• Type 1 diabetes mellitus;
• Diabetic ketoacidosis, diabetic precoma and coma;
• Conditions accompanied by impaired food absorption and the development of hypoglycemia (including infectious diseases);
• Leukopenia;
• Severe liver dysfunction;
• Severe renal impairment (including patients on hemodialysis);
• Pregnancy;
• Lactation period;
• Lactose intolerance, lactase deficiency, glucose-galactose malabsorption;
• Children under 18 years of age;
• Hypersensitivity to the components of the drug;
• Hypersensitivity to other sulfonylurea derivatives or sulfonamide drugs (risk of hypersensitivity reactions).

Use with caution in conditions requiring the patient to be switched to insulin therapy (including extensive burns, severe multiple injuries, major surgical interventions, as well as in cases of impaired absorption of food and drugs from the gastrointestinal tract – intestinal obstruction, gastric paresis).

Use in Pregnancy and Lactation

Glimepiride is contraindicated for use during pregnancy. In case of planned pregnancy or if pregnancy occurs, the woman should be switched to insulin therapy.

Since Glimepiride is excreted in breast milk, it should not be prescribed during lactation. In this case, it is necessary to switch to insulin therapy or stop breastfeeding.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

Use in Renal Impairment

Contraindicated in severe renal impairment (including patients on hemodialysis).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

Diamerid^® should be taken at the recommended doses and at the prescribed time. Errors in the use of the drug, for example, missing a dose, should never be corrected by taking a higher dose later. The doctor and the patient should discuss in advance the measures to be taken in case of such errors (for example, missing a dose of the drug or a meal) or in situations where it is impossible to take the next dose of the drug at the set time. The patient should immediately inform the doctor in case of taking too high a dose of the drug.

The development of hypoglycemia in a patient after taking Diamerid^® at a dose of 1 mg/day indicates the possibility of glycemic control solely through diet.

When compensation of type 2 diabetes mellitus is achieved, sensitivity to insulin increases. In this regard, during treatment, the need for glimepiride may decrease. To avoid the development of hypoglycemia, it is necessary to temporarily reduce the dose or discontinue Diamerid^®. Dose adjustment should also be carried out when the patient’s body weight, lifestyle changes, or when other factors appear that contribute to an increased risk of hypo- or hyperglycemia.

Adequate diet, regular and sufficient physical exercise and, if necessary, weight loss are just as important for achieving optimal blood glucose control as regular intake of glimepiride.

Clinical symptoms of hyperglycemia are: increased frequency of urination, intense thirst, dry mouth and dry skin.

During the first weeks of treatment, the risk of developing hypoglycemia may increase, which requires particularly careful monitoring of the patient. During treatment with Diamerid^®, hypoglycemia may develop with irregular meals or skipping meals. Factors contributing to the development of hypoglycemia include

• Unwillingness or (especially in the elderly) insufficient ability of the patient to cooperate with the doctor;
• Inadequate, irregular nutrition, skipping meals, fasting, changing the usual diet;
• Imbalance between physical activity and carbohydrate intake;
• Alcohol consumption, especially in combination with skipping a meal;
• Impaired renal function;
• Severe liver dysfunction;
• Overdose of glimepiride;
• Some uncompensated endocrine diseases affecting carbohydrate metabolism (for example, thyroid dysfunction, pituitary insufficiency or adrenal cortex insufficiency);
• Concomitant use of certain other medicines.

The doctor should be informed about the above factors and about episodes of hypoglycemia, as they require particularly strict monitoring of the patient. In the presence of such factors that increase the risk of hypoglycemia, the dose of glimepiride or the entire treatment regimen should be adjusted. This should also be done in case of intercurrent illness or changes in the patient’s lifestyle.

Symptoms of hypoglycemia may be smoothed out or completely absent in elderly patients, in patients with autonomic neuropathy or those receiving concomitant treatment with beta-blockers, clonidine, reserpine, guanethidine. Hypoglycemia can almost always be quickly controlled by immediate intake of carbohydrates (glucose or sugar, for example, in the form of a lump of sugar, sweet fruit juice or tea). In this regard, the patient should always carry at least 20 g of glucose (4 lumps of sugar). Sugar substitutes are not effective in treating hypoglycemia.

From experience with other sulfonylurea drugs, it is known that despite the initial success in controlling hypoglycemia, its recurrence is possible. In this regard, continuous and careful monitoring of the patient is necessary. Severe hypoglycemia requires immediate treatment under medical supervision, and under certain circumstances, hospitalization of the patient.

If a patient with diabetes is treated by different doctors (for example, during a hospital stay after an accident, illness on weekends), he must be sure to inform them about his disease and previous treatment.

During treatment with Diamerid^®, regular monitoring of liver function and peripheral blood picture (especially the number of leukocytes and platelets) is required.

In stressful situations (for example, with trauma, surgical intervention, infectious diseases accompanied by fever), it may be necessary to temporarily transfer the patient to insulin therapy.

There is no experience with the use of glimepiride in patients with severe hepatic and renal impairment or patients on hemodialysis. Patients with severe renal and hepatic impairment should be switched to insulin therapy.

During treatment with glimepiride, regular monitoring of blood glucose concentration, as well as the concentration of glycated hemoglobin, is necessary.

Certain adverse reactions (severe hypoglycemia, serious changes in blood picture, severe allergic reactions, liver failure) may, under certain circumstances, pose a threat to the patient’s life. In case of development of undesirable or severe reactions, the patient should immediately inform the attending physician and in no case continue taking the drug without his recommendation.

Effect on ability to drive vehicles and operate machinery

At the beginning of treatment, when switching from one drug to another, or with irregular intake of Diamerid^®, a decrease in concentration and speed of psychomotor reactions of the patient, caused by hypo- or hyperglycemia, may occur. This may adversely affect the ability to drive a car or operate various machines and mechanisms. Patients should be advised to take measures to prevent the development of hypoglycemia and hyperglycemia when driving vehicles and working with machinery. This is especially important for patients with absent or reduced severity of warning symptoms of developing hypoglycemia or those suffering from frequent episodes of hypoglycemia. In these cases, the advisability of performing such work should be considered.

Overdose

Symptoms after oral intake of glimepiride in a high dose, hypoglycemia may develop, lasting from 12 hours to 72 hours, which may recur after initial restoration of blood glucose concentration. In most cases, observation in a hospital setting is recommended.

Symptoms of hypoglycemia: increased sweating, feeling of anxiety, tachycardia, increased blood pressure, palpitations, pain in the heart area, arrhythmia, headache, dizziness, sharp increase in appetite, nausea, vomiting, apathy, drowsiness, restlessness, aggressiveness, impaired concentration, depression, confusion, tremor, paresis, sensory disturbances, central genesis convulsions. Sometimes the clinical picture of hypoglycemia may resemble a stroke. The development of coma is possible.

Treatment: induction of vomiting, plenty of fluids with activated charcoal (adsorbent) and sodium picosulfate (laxative). If a large amount of the drug is taken, gastric lavage is indicated, followed by intake of sodium picosulfate and activated charcoal. Administration of dextrose should be started as soon as possible, if necessary – intravenously as a bolus of 50 ml of a 40% solution, followed by infusion of a 10% solution, with careful monitoring of blood glucose concentration. Subsequently, symptomatic therapy is carried out.

Drug Interactions

Concomitant use of glimepiride with certain drugs can cause either an enhancement or a weakening of the hypoglycemic effect of the drug. Therefore, other medications should be taken only after consultation with a doctor.

Enhancement of the hypoglycemic effect and the associated possible development of hypoglycemia may be observed with the concomitant use of glimepiride with insulin, metformin, or other oral hypoglycemic drugs, ACE inhibitors, allopurinol, anabolic steroids and androgens, chloramphenicol, coumarin derivatives, cyclophosphamide, trophosphamide and isophosphamide, fenfluramine, fibrates, fluoxetine, sympatholytics (guanethidine), MAO inhibitors, miconazole, pentoxifylline (with parenteral administration in high doses), phenylbutazone, azapropazone, oxyphenbutazone, probenecid, quinolone antibiotics, salicylates and aminosalicylic acid, sulfinpyrazone, some long-acting sulfonamides, tetracyclines, tritoqualine, fluconazole.

Weakening of the hypoglycemic effect and the associated increase in blood glucose concentration may be observed with the concomitant use of glimepiride with acetazolamide, barbiturates, corticosteroids, diazoxide, saluretics, thiazide diuretics, epinephrine and other sympathomimetic agents, glucagon, laxatives (with long-term use), nicotinic acid (in high doses) and nicotinic acid derivatives, estrogens and progestogens, phenothiazine derivatives, including chlorpromazine, phenytoin, rifampicin, thyroid hormones, lithium salts.

H₂-histamine receptor blockers, clonidine, and reserpine can either potentiate or weaken the hypoglycemic effect of glimepiride.

Under the influence of beta-blockers, clonidine, guanethidine, and reserpine, a weakening or absence of clinical signs of hypoglycemia is possible.

While taking glimepiride, an enhancement or weakening of the effect of coumarin derivatives may be observed.

When used concomitantly with drugs that inhibit bone marrow hematopoiesis, the risk of myelosuppression increases.

Single or chronic alcohol consumption can either enhance or weaken the hypoglycemic effect of glimepiride.

Storage Conditions

The drug should be stored out of the reach of children, in a dry, light-protected place at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.