Dibizid-m

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIBIZIDE-M (DIBIZIDE-M)

Composition:

Active substances: metformin hydrochloride and glipizide;

1 tablet contains 500 mg of metformin hydrochloride and 5 mg of glipizide;

Excipients: microcrystalline cellulose, corn starch, povidone, talc, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A).

Pharmaceutical form. Tablets.

Main physicochemical properties: white, oval-shaped tablets with a score line on one side.

Pharmacotherapeutic group. Combination of oral hypoglycemic agents.

ATC code A10B D02.

Pharmacological Properties.

Pharmacodynamics.

Glyburide reduces elevated blood glucose levels in response to food by stimulating insulin secretion from pancreatic ß-cells. Extrapancreatic effects include reduction of gluconeogenesis and increased insulin sensitivity of liver and muscle cells. It also exhibits fibrinolytic activity.

Metformin acts as an antihyperglycemic agent by increasing insulin sensitivity of liver and peripheral tissues. It also exerts a beneficial effect on plasma lipid levels and enhances fibrinolytic activity. Metformin therapy does not cause body weight gain in patients.

Pharmacokinetics.

The pharmacokinetics are determined by the individual components of the drug (glyburide and metformin), which do not affect each other's pharmacokinetics.

Glyburide is rapidly and completely absorbed after oral administration. The maximum absorption period in the absence of food in the stomach is 1–2 hours. Food may delay absorption.

Distribution: 98% of the drug bound to plasma proteins is rapidly distributed. The drug and its metabolites are not detected in the brain or cerebrospinal fluid.

Glyburide pharmacokinetics are linear within the dose range of 5–60 mg. It is eliminated via hepatic biotransformation; less than 10% of the administered dose is excreted unchanged in urine and feces; biotransformation products are also excreted in urine (80%) and feces (10%). The elimination half-life is 2–4 hours.

Metformin bioavailability after oral administration is 50–60%. It is absorbed in the gastrointestinal tract over 6 hours and rapidly distributed into tissues. Renal elimination of metformin is biphasic. 95% of the absorbed dose is eliminated during the first phase with a half-life of 6 hours. The remainder is eliminated during the second phase with a half-life of 20 hours. Metformin does not bind to plasma proteins. 40–60% of the dose is excreted unchanged in urine and 30% in feces.

Clinical Characteristics.

Indications.

Non-insulin-dependent diabetes mellitus not controlled by diet and physical exercise, including patients with obesity and lipid metabolism disorders.

Contraindications.

Hypersensitivity to metformin, glipizide, or to any other component of the drug. Hypersensitivity to other sulfonylurea drugs or sulfonamides. Type 1 diabetes mellitus. Diabetic precoma or coma, diabetic ketoacidosis (in such cases insulin therapy is recommended). Moderate (Stage IIIb) or severe renal insufficiency or impaired renal function (creatinine clearance < 45 mL/min or eGFR < 45 mL/min/1.73 m²). Acute conditions associated with a risk of developing renal impairment, such as: dehydration, severe infections, shock. Conditions that may lead to tissue hypoxia (especially acute conditions or exacerbations of chronic diseases): decompensated heart failure, respiratory failure, recent myocardial infarction, shock. Hepatic insufficiency, acute alcohol intoxication, alcoholism. Treatment with miconazole. Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

When prescribing drugs that may cause hypoglycemia or hyperglycemia when used concomitantly (see below), the patient should be warned about the need for careful monitoring of blood glucose levels during treatment. Adjustment of the antidiabetic drug dosage may be necessary during and after treatment with these agents.

Medicinal products whose concomitant use may increase the risk of hypoglycemia.

Concomitant use contraindicated.

Miconazole enhances the hypoglycemic effect, potentially leading to symptoms of hypoglycemia and even coma.

Concomitant use not recommended.

Nonsteroidal anti-inflammatory drugs (e.g., systemic phenylbutazone) enhance the hypoglycemic effect of sulfonylureas (by displacing them from plasma protein binding and/or reducing their excretion). Alcohol increases the risk of hypoglycemic reactions (due to inhibition of compensatory mechanisms), which may lead to hypoglycemic coma. Alcohol consumption and use of alcohol-containing medications should be avoided. Acute alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, adherence to a low-calorie diet, or hepatic insufficiency. During treatment with Diabizid-M, alcohol and alcohol-containing medicinal products should be avoided.

Iodine-containing contrast agents. Intravenous administration of iodine-containing contrast agents may lead to renal insufficiency and, consequently, metformin accumulation and increased risk of lactic acidosis.

In patients with eGFR > 60 mL/min/1.73 m², metformin should be discontinued before or during the procedure and not restarted earlier than 48 hours after the procedure, only after re-evaluation of renal function and confirmation of no further deterioration in renal status (see section "Special precautions").

In patients with moderate renal insufficiency (eGFR 45–60 mL/min/1.73 m²), metformin should be discontinued 48 hours before administration of iodine-containing contrast agents and not restarted earlier than 48 hours after the procedure, only after re-evaluation of renal function and confirmation of no further deterioration in renal status.

Combinations requiring caution.

Concomitant use with any of the following drugs may in some cases lead to hypoglycemia due to enhanced hypoglycemic effect: other antidiabetic agents (insulins, acarbose, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists), β-blockers, fluconazole, ACE inhibitors (captopril, enalapril), H₂-receptor antagonists, MAO inhibitors, sulfonamides, clarithromycin, sympathomimetics, nonsteroidal anti-inflammatory drugs. Blood glucose levels should be monitored more frequently, especially at the beginning of treatment. Dosage adjustment of Diabizid-M may be necessary during and after discontinuation of such combination therapy.

Diuretics, particularly loop diuretics, may increase the risk of lactic acidosis due to potential reduction in renal function.

Combinations requiring caution.

Fluconazole increases the half-life of sulfonylureas, which may lead to symptoms of hypoglycemia.

Voriconazole. Although not well studied, voriconazole may increase plasma levels of sulfonylureas (e.g., tolbutamide, glipizide, glyburide), thus causing hypoglycemia.

Salicylates (acetylsalicylic acid) may enhance the hypoglycemic effect of Diabizid-M.

β-blockers. All β-blockers may mask certain symptoms of hypoglycemia (e.g., palpitations and tachycardia). Most non-cardioselective β-blockers increase the frequency and severity of hypoglycemia.

Angiotensin-converting enzyme (ACE) inhibitors.

Use of ACE inhibitors may enhance the hypoglycemic effect in diabetic patients receiving Diabizid-M.
Cimetidine.
Cimetidine use may be associated with decreased postprandial blood glucose levels in patients receiving glipizide.

The hypoglycemic effect of sulfonylureas may also generally be enhanced by monoamine oxidase inhibitors, quinolones, and drugs that strongly bind to plasma proteins, such as sulfonamides, chloramphenicol, probenecid, coumarins, and fibrates.

When such drugs are prescribed to a patient receiving glipizide, the patient should be closely monitored due to the potential for hypoglycemia.

Medicinal products whose concomitant use may increase the risk of hyperglycemia.

Concomitant use not recommended.

Danazol exerts a diabetogenic effect. If danazol cannot be avoided, the patient should be warned and encouraged to increase self-monitoring of blood and urine glucose levels. Adjustment of Diabizid-M dosage may be necessary during and after danazol treatment.

Combinations requiring caution.

Phenothiazines, when used in high doses (over 100 mg daily), increase blood glucose levels (due to reduced insulin release).

Glucocorticoids (for systemic and local use: intra-articular, topical, and rectal preparations) and tetraCorticotropin increase blood glucose levels with possible development of ketoacidosis (by reducing carbohydrate tolerance).

Sympathomimetics: ritodrine, salbutamol, terbutaline increase blood glucose levels via β₂-agonist effects.

Progestogens. High doses of progestogens may have a diabetogenic effect. Warn the patient and increase self-monitoring of blood and urine glucose. Dosage adjustment of Diabizid-M may be necessary during and after treatment with neuroleptics, corticosteroids, or progestogens.

Other drugs that may cause hyperglycemia and lead to loss of blood glucose control include thiazides and other diuretics, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, calcium channel blockers, and isoniazid.

Special precautions for use.

Lactic acidosis is a very rare but serious metabolic complication (with high mortality if urgent treatment is not provided), which may result from metformin accumulation. Cases of lactic acidosis have been reported in patients with diabetes and renal impairment or acute worsening of kidney function. Caution is required in situations where renal function may be impaired, for example, in cases of dehydration (severe diarrhea or vomiting), or at the beginning of treatment with antihypertensive agents, diuretics, or nonsteroidal anti-inflammatory drugs (NSAIDs). If such conditions occur, temporary discontinuation of the drug is necessary.

Other risk factors should be considered to prevent the development of lactic acidosis: poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol consumption, hepatic insufficiency, or any condition associated with hypoxia (decompensated heart failure, acute myocardial infarction).

Lactic acidosis may present as muscle cramps, gastrointestinal disturbances, abdominal pain, and severe asthenia. Patients should immediately inform their physician if such reactions occur, especially if they previously tolerated the drug well. In such cases, temporary discontinuation of the drug is necessary until the situation is clarified. Therapy should be resumed only after individual benefit-risk assessment and evaluation of renal function.

Diagnosis. Lactic acidosis is characterized by acidotic dyspnea, abdominal pain, and hypothermia, with possible progression to coma. Diagnostic criteria include laboratory-confirmed reduction in blood pH, elevated serum lactate concentration above 5 mmol/L, increased anion gap, and elevated lactate/pyruvate ratio. In case of lactic acidosis development, immediate hospitalization is required (see section "Overdose"). Physicians must inform patients about the risk and symptoms of lactic acidosis.

Cardiac function. Patients with heart failure have a higher risk of hypoxia and renal impairment. Metformin may be used in patients with stable chronic heart failure under regular monitoring of cardiac and renal function. The drug is contraindicated in patients with acute or unstable heart failure (see section "Contraindications").

Iodine-containing contrast agents. Intravenous administration of contrast agents for radiological procedures may cause renal impairment and, consequently, metformin accumulation and increased risk of lactic acidosis. In patients with eGFR > 60 mL/min/1.73 m², the drug should be discontinued before or during the procedure and not restarted earlier than 48 hours after the procedure, only after re-evaluation of renal function and confirmation of no further deterioration in kidney status (see section "Interaction with other medicinal products and other forms of interaction").

In patients with moderate renal impairment (eGFR 45–60 mL/min/1.73 m²), the drug should be discontinued 48 hours before administration of iodine-containing contrast agents and not restarted earlier than 48 hours after the procedure, only after re-evaluation of renal function and confirmation of no further deterioration in kidney status (see section "Interaction with other medicinal products and other forms of interaction").

Surgical procedures. The drug (metformin) should be discontinued 48 hours before elective surgery performed under general, spinal, or epidural anesthesia, and not restarted earlier than 48 hours after surgery or until oral nutrition is restored, and only after confirmation of normal renal function.

Other precautions. Patients must adhere to a diet with balanced carbohydrate intake throughout the day. Patients with excess body weight should continue a low-calorie diet. Regular monitoring of carbohydrate metabolism parameters is required.

Metformin may reduce serum vitamin B12 levels. The risk of low vitamin B12 levels increases with higher metformin doses, longer treatment duration, and/or presence of known risk factors for vitamin B12 deficiency. In case of suspected vitamin B12 deficiency (e.g., anemia or neuropathy), serum vitamin B12 levels should be monitored. Patients with risk factors for vitamin B12 deficiency may require periodic monitoring of vitamin B12 levels. Metformin therapy should be continued as long as it is tolerated and not contraindicated, with appropriate corrective treatment for vitamin B12 deficiency provided according to current clinical guidelines.

Hypoglycemia. The drug containing glipizide should be prescribed only to patients able to eat regularly (including breakfast). Regular carbohydrate intake is essential, as the risk of hypoglycemia increases if meals are delayed, inadequate, or low in carbohydrates. Hypoglycemia is more likely with low-calorie diets, prolonged or intense physical exertion, alcohol consumption, or concomitant use of hypoglycemic agents.

Hypoglycemia may occur during treatment with sulfonylurea drugs (see section "Adverse reactions"). Sometimes hypoglycemia may be severe and prolonged. In such cases, hospitalization and glucose administration for several days may be necessary.

To reduce the risk of hypoglycemic episodes, individual patient characteristics must be considered, clear instructions provided, and dosage carefully selected.

Factors increasing the risk of hypoglycemia:

• Patient noncompliance or inability to follow physician recommendations (especially in elderly patients);
• Inadequate or irregular eating, missed meals, fasting periods, or dietary changes;
• Imbalance between physical activity and carbohydrate intake;
• Renal impairment;
• Severe hepatic impairment;
• Drug overdose;
• Certain endocrine disorders: thyroid dysfunction, hypopituitarism, and adrenal insufficiency;
• Concomitant use of certain medicinal products (see section "Interaction with other medicinal products and other forms of interaction").

Renal and hepatic impairment. The pharmacokinetics and/or pharmacodynamics of glipizide may be altered in patients with hepatic impairment or severe renal insufficiency. Hypoglycemic episodes in such patients may be prolonged and require appropriate treatment.

Patients and their family members should be informed about risk factors and conditions that may predispose to hypoglycemia, symptoms of hypoglycemia (see section "Adverse reactions"), and methods of their management.

Patients must be informed about the importance of adhering to dietary recommendations, regular physical activity, and regular blood glucose monitoring.

Since metformin is excreted by the kidneys, creatinine clearance (can be estimated from plasma creatinine using the Cockcroft-Gault formula) or eGFR must be assessed before starting and regularly during treatment:

• In patients with normal renal function – at least once a year;
• In patients with creatinine clearance at the lower limit of normal and elderly patients – at least 2–4 times a year.

If creatinine clearance is < 45 mL/min (eGFR < 45 mL/min/1.73 m²), use of the drug is contraindicated (see section "Contraindications").

Renal function decline in elderly patients is common and often asymptomatic. Caution is required in situations where renal function may be impaired, such as dehydration or initiation of treatment with antihypertensive agents, diuretics, or NSAIDs. In such cases, renal function should also be evaluated before starting treatment.

Worsening glycemic control in patients receiving antidiabetic agents may be caused by concomitant therapy affecting glipizide metabolism, infection, fever, trauma, or surgery. In some cases, insulin therapy may be necessary.

The hypoglycemic efficacy of any oral antidiabetic agent, including glipizide, may change over time. This may result from disease progression or reduced response to treatment. This phenomenon is known as secondary failure, distinct from primary failure, where the drug is ineffective from the start of treatment. Before concluding secondary failure, appropriate dose and dietary adherence must be verified.

Laboratory parameters. Glycated hemoglobin (or fasting blood glucose) is recommended for assessing blood glucose control. Self-monitoring of blood glucose by patients may also be useful.

In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, sulfonylurea drugs may cause hemolytic anemia. Since glipizide belongs to the sulfonylurea class, caution is advised, and alternative therapy from another class should be considered for patients with G6PD deficiency.

Use during pregnancy or breastfeeding.

Use of Dibizid-M is contraindicated during pregnancy or breastfeeding.

Pregnancy. Uncontrolled diabetes during pregnancy (gestational or pre-existing) increases the risk of congenital anomalies and perinatal mortality. Limited data on metformin use in pregnant women do not indicate an increased risk of congenital anomalies. Preclinical studies have not shown adverse effects on pregnancy, embryonic or fetal development, labor, or postnatal development. In planning pregnancy or if pregnancy occurs, insulin therapy is recommended instead of drugs containing metformin and glipizide to maintain blood glucose levels as close to normal as possible, minimizing the risk of fetal malformations.

Experience with glipizide use during pregnancy is limited, as are data on other sulfonylureas. Animal studies have not shown teratogenic effects of glipizide.

Breastfeeding. Metformin is excreted in breast milk, but no adverse effects have been observed in breastfed newborns/infants. However, due to insufficient safety data, breastfeeding is not recommended during metformin therapy. The decision on discontinuing breastfeeding should consider the benefits of breastfeeding and the potential risk of adverse effects to the infant.

There are no data on the passage of glipizide or its metabolites into breast milk. Dibizid-M is contraindicated during breastfeeding due to the potential risk of neonatal hypoglycemia. Risk to newborns and infants cannot be excluded.

Fertility. Metformin did not affect fertility in animals when administered at doses of 600 mg/kg/day, nearly three times the maximum recommended human daily dose based on body surface area.

No effects of glipizide on fertility or reproductive performance in male or female rats were observed in preclinical studies.

Ability to affect reaction speed when driving or operating machinery.

When using Dibizid-M, considering the possibility of hypoglycemic episodes (tremor, anxiety, decreased blood pressure), patients must be aware of hypoglycemia symptoms and exercise caution when driving or operating machinery, especially when optimal glycemic control has not been achieved, for example, during transition from other medications or irregular drug intake.

Dosage and Administration

The dose for adults is determined individually by a physician. The initial dose is 0.5–1 tablet per day. The dose should be gradually increased, if necessary, up to 1–2 tablets once or twice daily, but not exceeding 4 tablets per day, taken before meals.

After 10–15 days of treatment, the dose should be adjusted according to the results of blood serum glucose measurements. Gradual dose escalation helps reduce gastrointestinal side effects.

When switching to treatment with Dibizid-M, the previous antidiabetic agent must be discontinued.

Children

The safety and efficacy of the drug in children have not been established; therefore, the drug should not be prescribed to this age group of patients.

Overdose

When the drug was administered at a metformin dose of 85 g, hypoglycemia was not observed. However, in this case, lactic acidosis developed. A significant overdose of metformin or concomitant risk factors may lead to the development of lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital setting. Hemodialysis is the most effective measure for removing lactate and metformin from the body.

Overdose with sulfonylurea agents has not been well studied. However, overdose with sulfonylurea agents (glipizide) may cause hypoglycemia.

Symptoms of mild hypoglycemia (without loss of consciousness and without neurological symptoms) should be corrected by carbohydrate intake (sugar), adjustment of the dose of the glucose-lowering agent, and/or dietary changes. Close monitoring of the patient should continue until the physician is confident that the patient is safe.

Severe hypoglycemia leading to coma, convulsions, or other neurological disturbances requires immediate medical attention and urgent hospitalization.

In case of diagnosed hypoglycemic coma or suspected coma development, the patient should be promptly administered 50 ml of concentrated glucose solution (50%) intravenously, followed by continuous infusion of a less concentrated glucose solution (10%) at a rate sufficient to maintain blood glucose levels above 1 g/L. Continuous monitoring of the patient is required. Depending on the patient's condition, the physician decides on further monitoring.

Glipizide is highly bound to plasma proteins, so dialysis is ineffective.

Side effects.

The most common adverse reactions at the beginning of treatment are nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These symptoms usually resolve spontaneously in most cases. To prevent the occurrence of these adverse effects, a gradual increase in dosage is recommended, along with administration of the daily dose in two divided doses.

If a hypoglycemic episode is severe or prolonged and the patient's condition is temporarily controlled by sugar intake, immediate medical assistance or even hospitalization is required.

Adverse effects are classified by frequency of occurrence as follows:

very common (> 1/10), common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10000 and < 1/1000), very rare (< 1/10000).

Metabolic disorders.

Common: decreased levels/vitamin B12 deficiency (see section "Special precautions").

Very rare: lactic acidosis (see section "Special precautions").

Nervous system disorders.

Common: taste disturbances.

Gastrointestinal disorders.

Very common: gastrointestinal disturbances such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite. These adverse effects most often occur at the beginning of treatment and usually resolve spontaneously in most cases. To prevent gastrointestinal adverse effects, a gradual increase in dosage is recommended, along with administration of the daily dose in two divided doses during or after meals.

Very rare: constipation.

Hepatobiliary disorders.

Uncommon: cholestatic jaundice. If cholestatic jaundice occurs, treatment with the drug should be discontinued. These adverse effects usually resolve after discontinuation of the drug.

Very rare: liver function test abnormalities or hepatitis, which completely resolve after discontinuation of the drug. Increased levels of liver enzymes (ALT, AST, alkaline phosphatase), hepatitis (isolated cases).

Skin and subcutaneous tissue disorders.

Uncommon: eczema.

Very rare: skin reactions including erythema, pruritus, urticaria, allergic dermatitis, morbilliform rash, maculopapular rash, photosensitization.

Blood and lymphatic system disorders: hematologic disorders occur rarely and may include hemolytic anemia, thrombocytopenia, leukopenia, pancytopenia, agranulocytosis. These effects usually resolve after discontinuation of treatment.

Eye disorders: transient visual disturbances, particularly at the beginning of treatment, may occur due to changes in blood glucose levels. Diplopia, decreased visual acuity.

Nervous system disorders.

Uncommon: dizziness, somnolence, tremor.

Very rare: headache, confusion.

Reactions characteristic of the sulfonylurea class of drugs: cases of erythrocytopenia, agranulocytosis, hemolytic anemia, pancytopenia, allergic vasculitis, hyponatremia, increased liver enzymes, and even impaired liver function (e.g., with cholestasis and jaundice), hepatitis with regression after discontinuation of sulfonylurea drugs or, in isolated cases, with subsequent life-threatening liver failure.

Congenital, familial and genetic disorders.

Frequency unknown: porphyria.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25°C in a dry, child-resistant place.

Packaging. 10 tablets per blister; 6 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. Micro Labs Limited.

Manufacturer's address and location of business.

92, Sipcot Industrial Complex, Hosur, Tamil Nadu, IN-635 126, India.