Diapyrid®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIAPIRIDE® (DIAPIRIDE)

Composition:

Active substance: glimepiride;

1 tablet contains 2 mg or 3 mg or 4 mg of micronized glimepiride, calculated as 100% substance;

Excipients:

2 mg tablet: lactose monohydrate (200), microcrystalline cellulose 101, sodium starch glycolate (type A), povidone (25), iron oxide yellow (E 172), indigocarmine (E 132), magnesium stearate;

3 mg tablet: lactose monohydrate (200), microcrystalline cellulose 101, sodium starch glycolate (type A), povidone (25), iron oxide yellow (E 172), magnesium stearate;

4 mg tablet: lactose monohydrate (200), microcrystalline cellulose 101, sodium starch glycolate (type A), povidone (25), indigocarmine (E 132), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

2 mg tablets: tablets from pale green to green in color, round-shaped, with flat surface, beveled edges and a score line. Speckles may be present on the tablet surface;

3 mg tablets: tablets from pale yellow to yellow in color, round-shaped, with flat surface, beveled edges and a score line. Speckles may be present on the tablet surface;

4 mg tablets: tablets from pale blue to blue in color, round-shaped, with flat surface, beveled edges and a score line. Speckles may be present on the tablet surface.

Pharmacotherapeutic group. Antihyperglycemic 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 type 2 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 pronounced extrapancreatic effects, which are also characteristic of other sulfonylurea agents.

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 causes depolarization of the beta cell and, via opening of calcium channels, leads to increased calcium influx into the cell, which in turn results in insulin release by 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 binding site of sulfonylurea agents.

Extrapancreatic activity. Extrapancreatic effects include, for example, improved insulin sensitivity in 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 inhibits glucose production in the liver by increasing intracellular concentrations of fructose-2,6-bisphosphate, which in turn suppresses gluconeogenesis.

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 clinically significant difference in glimepiride action was observed between administration 30 minutes before or immediately before a meal. In patients with diabetes, adequate metabolic control over 24 hours was achieved with once-daily dosing.

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

Use in combination with metformin. Improved metabolic control has been demonstrated with combination therapy using glimepiride compared to metformin monotherapy in patients whose diabetes is not adequately controlled with maximum doses of metformin.

Use in combination with insulin. Data on the use of the drug 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. This combination has achieved the same degree of metabolic control as insulin monotherapy, but with a lower average insulin dose required.

Special patient populations. Children, including adolescents. In a 24-week active-controlled clinical trial (glimepiride up to 8 mg daily or metformin up to 2000 mg daily), both glimepiride and metformin led to a statistically 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 compared to adult patients with type 2 diabetes were identified. There are no data on long-term efficacy and safety of the drug in pediatric use.

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 multiple daily doses of 4 mg). 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 very 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 crosses into 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 multiple dosing regimens is approximately 5 to 8 hours. After administration of high doses, a slight increase in half-life was observed.

Following 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 to 6 hours and 5 to 6 hours, respectively.

Comparison of pharmacokinetics after single-dose and repeated once-daily administration 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 young and elderly subjects (aged 65 years and older), 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, no additional risk of drug accumulation is expected in these patients.

Pharmacokinetic parameters in patients who underwent biliary tract surgery were similar to those in healthy volunteers.

Children, including adolescents. A pharmacokinetic, safety, and tolerability study after a single 1 mg dose of glimepiride administered in the fed state in children with type 2 diabetes demonstrated that mean values of AUC(0-last), Cmax, and t1/2 (half-life) were similar to those previously observed 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 hypoglycemic effects induced by the drug in pregnant females and offspring.

Clinical characteristics.

Indications.

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

Contraindications.

The medicinal product Diapirid® is not indicated for the treatment of insulin-dependent diabetes mellitus type I, diabetic ketoacidosis, or diabetic coma. The use of the drug is contraindicated in patients with severe impairment of renal or hepatic function. In case of severe renal or hepatic dysfunction, the patient should be switched to insulin therapy.

Diapirid® 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-containing drugs (risk of developing hypersensitivity reactions).

Interaction with other medicinal products and other forms of interactions.

Concomitant use of Diapirid® with certain medicinal products may result in either reduced or enhanced hypoglycemic effect of glimepiride. Therefore, other drugs should be taken only with physician’s consent (or prescription). 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 of in vivo interaction studies have shown that fluconazole, one of the most potent inhibitors of CYP2C9, increases the AUC of glimepiride approximately two-fold. Clinical experience with Diapirid® and other sulfonylurea derivatives supports the existence of such types of interactions.

Potentiation of glucose-lowering effect, and thus, in some cases, hypoglycemia, may occur when the following drugs are taken concomitantly with glimepiride: phenylbutazone, azapropazone and oxyphenbutazone, sulfinpyrazone, insulin and oral antidiabetic agents, certain long-acting sulfonamides, metformin, tetracyclines, salicylates and para-aminosalicylic acid, MAO inhibitors, anabolic steroids and androgenic hormones, quinolone antibiotics and clarithromycin, chloramphenicol, probenecid, coumarin anticoagulants, miconazole, fenfluramine, disopyramide, pentoxifylline (high parenteral doses), fibrates, troglitazone.

Reduced glucose-lowering effect and, consequently, increased blood glucose levels may occur when the patient is taking concomitantly the following medicinal products: 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.

Adrenergic counter-regulatory symptoms of hypoglycemia may be reduced or absent under the influence of sympatholytic agents such as beta-blockers, clonidine, guanethidine, and reserpine.

Alcohol intake may unpredictably enhance or diminish the hypoglycemic action 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 administration.

Special precautions for use.

The medicinal product Diapirid**®** should be taken shortly before or during a meal.

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

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

Hypoglycemic symptoms can almost always be rapidly relieved by immediate carbohydrate intake (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 treatment and sometimes hospitalization.

Factors contributing 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, missed meals, or periods of fasting;
• dietary imbalances;
• mismatch between physical exertion and carbohydrate intake;
• alcohol consumption, especially in combination with missed meals;
• impaired renal function;
• severe impairment of liver function;
• overdose of Diapirid**®**;
• certain decompensated endocrine disorders affecting carbohydrate metabolism or hypoglycemia counter-regulation (e.g., certain thyroid disorders or deficiency of the anterior pituitary or adrenal cortex);
• concomitant use of certain other medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

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

During treatment with Diapirid**®**, 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 indicated.

Experience with the use of Diapirid**®** 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 (G6PD) deficiency with sulfonylurea drugs 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.

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

This medicinal product contains less than 1 mmol/dose of sodium, i.e., essentially "sodium-free".

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 monitoring 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 for 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, likely related to the pharmacological effect of glimepiride (hypoglycemia). Therefore, glimepiride must not be used during pregnancy (see section "Contraindications"). 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 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 glimepiride therapy.

Ability to influence reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive vehicles or 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 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 develop 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.

Dosage and Administration

The medication 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 insulin.

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

The initial dose is 1 mg (½ of a 2 mg tablet) of glimepiride per day. If this dose achieves adequate disease control, it should be maintained during ongoing therapy.

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

Doses exceeding 4 mg per day provide improved efficacy only in individual cases. The maximum recommended dose is 6 mg of Diapirid® per day.

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 should be started at a low dose and gradually increased, as needed, 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 Diapirid® does not provide adequate glycemic control, concomitant insulin therapy may be initiated, if necessary. While maintaining the previous glimepiride dosage, insulin therapy should be started at 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, a single daily dose of glimepiride is sufficient. It is recommended to take the dose shortly before or during a substantial breakfast. If breakfast is not consumed, the dose should be taken shortly before or during the first main meal of the day. Errors in medication use, such as missing a scheduled dose, should never be corrected by taking a higher dose at the next administration. 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 dietary management alone.

Improved diabetes control is often associated with increased insulin sensitivity, so the requirement for glimepiride may decrease during treatment. 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 arise.

Switching from other oral hypoglycemic agents to Diapirid®

Switching from other oral hypoglycemic agents to Diapirid® is generally feasible. The potency and half-life of the previous agent should be considered during the transition. In some cases, particularly when the prior antidiabetic agent has a long half-life (e.g., chlorpropamide), it is recommended to wait several days before initiating Diapirid® to reduce the risk of hypoglycemic reactions due to additive effects of the two agents.

The recommended initial dose is 1 mg of glimepiride per day. As noted above, the dose may be gradually increased based on the patient's response to the medication.

Switching from insulin to Diapirid®®

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

Children

There is currently no clinical evidence supporting the use of glimepiride in patients under 8 years of age. Limited data exist regarding the use of glimepiride as monotherapy in children aged 8 to 17 years (see sections "Pharmacodynamics" and "Pharmacokinetics"). Due to insufficient data on safety and efficacy in pediatric patients, the medication is not recommended for use in this patient population.

Overdose

Overdose may lead to hypoglycemia, which can last from 12 to 72 hours and may recur after initial improvement. Symptoms may appear up to 24 hours after drug absorption. Patients with overdose typically require clinical observation. Nausea, vomiting, and epigastric pain may occur. Hypoglycemia may be accompanied by neurological symptoms such as restlessness, tremor, visual disturbances, coordination disorders, drowsiness, coma, and seizures.

Treatment of overdose. The primary goal of treatment is to prevent further drug absorption. Induce vomiting, followed by administration of water or lemonade 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 required. Glucose administration should be initiated as soon as possible: if necessary, start with 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 Diapirid® in infants and young children, the glucose dose must be carefully adjusted to avoid dangerous hyperglycemia, and blood glucose levels should be closely monitored.

Adverse Reactions

Based on the experience with the medicinal product Diapirid® and other sulfonylurea derivatives, the following adverse reactions have been observed during 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, mild hypersensitivity reactions which may progress to severe forms and be accompanied by dyspnea, hypotension, and sometimes shock.
Frequency not known: possible cross-allergy with sulfonamides, sulfonylureas, or related compounds.

Metabolism and nutrition disorders:
Rare: hypoglycemia. These hypoglycemic reactions usually 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 warnings and precautions for use" for details). The clinical picture of a severe hypoglycemic attack may resemble that of stroke.

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, abdominal distension, 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 abnormalities (e.g., cholestasis or jaundice), hepatitis, and liver failure.

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

Laboratory findings:
Very rare: decreased serum sodium levels.

Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions through national reporting systems.

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach and sight of children.

Packaging.
10 tablets in a blister. 3 or 6 blisters in a carton.

Prescription status. Prescription only.

Manufacturer.
JSC "Farmak".

Manufacturer's address and location of operations.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.