Maninil® 5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MANINIL® 5 (MANINIL® 5)

Composition:

Active substance: glibenclamide;

1 tablet contains 5 mg of glibenclamide;

Excipients: lactose monohydrate, potato starch, gelatin, magnesium stearate, talc, Ponceau 4R (E 124).

Pharmaceutical form. Tablets.

Main physicochemical properties: flat, parallel-sided tablets of pink color with beveled edges and a dividing line on one side. The tablet can be divided into equal doses.

Pharmacotherapeutic group. Alimentary system and metabolism. Antidiabetic medicinal products. Hypoglycemic agents, excluding insulin. Sulfonylurea derivatives. Glibenclamide. ATC code A10BB01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Maninil® 5 exerts a hypoglycemic effect due to increased insulin secretion by pancreatic β-cells, both in individuals with normal metabolism and in patients with insulin-independent diabetes mellitus (type 2, IIDD). This effect is glucose concentration-dependent in the environment surrounding the β-cells.

At very high blood glucose concentrations, where glucose-induced stimulation of insulin secretion is maximal, additional large-scale insulin release following glyburide administration is not expected. The clinical relevance of this observation, made in healthy volunteers, for diabetic patients taking glyburide has not been established.

Inhibition of glucagon release by pancreatic α-cells has been described, as well as extrapancreatic effects (insulin receptor replication, increased insulin sensitivity in peripheral tissues); however, their clinical significance has not been established.

Pharmacokinetics.

Absorption

Maninil® 5 is rapidly and almost completely absorbed after oral administration. Concomitant food intake does not significantly affect glyburide absorption.

Distribution

Protein binding of Maninil® 5 to plasma albumin exceeds 98%.

Maximum serum concentration is reached within 2.5 hours and amounts to 100 ng/mL. After 8–10 hours, serum concentration decreases to 10–20 ng/mL, depending on the administered dose. The elimination half-life from serum after intravenous administration is approximately 2 hours, and after oral administration – 7 hours. However, some studies indicate that in diabetic patients it may be prolonged up to 8–10 hours.

Metabolism

Glyburide is completely metabolized in the liver. The main metabolite is 4-trans-hydroxyglyburide; a minor metabolite is 3-cis-hydroxyglyburide. Metabolites do not significantly contribute to the hypoglycemic effect of glyburide.

Elimination

Metabolites are excreted in approximately equal amounts in urine and bile, and elimination is completed within 45–72 hours.

In patients with impaired liver function, elimination of the active substance from plasma is delayed.

In patients with renal insufficiency, depending on the degree of renal impairment, biliary excretion of metabolites increases compensatorily. With moderate renal impairment (creatinine clearance ≥ 30 mL/min), total elimination remains unchanged; with severe renal impairment, accumulation is possible.

Preclinical safety data.

There are no data from chronic toxicity studies that would suggest previously unknown adverse reactions in humans.

Furthermore, no evidence of mutagenic potential was found in in vitro studies.

Regular long-term carcinogenicity studies have not been conducted.

In studies conducted in rats, mice, and rabbits, there were no indications of a teratogenic effect.

Clinical characteristics.

Indications.

Non-insulin-dependent diabetes mellitus (NIDDM, type 2) in adults, when other measures such as strict adherence to a diabetic diet, reduction of excess body weight, and adequate physical activity have not resulted in satisfactory blood glucose control.

Contraindications.

• Hypersensitivity to the active substance, ponzo 4R, or to any of the excipients listed in the section "Composition";
• hypersensitivity to other sulfonylurea drugs, sulfonamides, sulfonamide diuretics, and probenecid, since cross-reactions may occur;
• in the following conditions associated with diabetes mellitus requiring insulin therapy: insulin-dependent diabetes mellitus (type 1); complete secondary failure of glimepiride therapy in type 2 diabetes mellitus; metabolic acidosis; diabetic precoma or coma; post-pancreatectomy state;
• severe hepatic impairment;
• severe renal impairment;
• pregnancy and lactation period (also see section "Use in pregnancy or lactation");
• patients treated with bosentan must not take Maninil® 5.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of other medicinal products may enhance or reduce the effect of Maninil® 5. Therefore, other medicinal products should be taken only with the approval of the treating physician.

Glimepiride is metabolized primarily via CYP 2C9 and to a lesser extent via CYP 3A4. This should be taken into account when glimepiride is used concomitantly with inducers or inhibitors of CYP 2C9.

Hypoglycemic reactions as a manifestation of enhanced drug effect may occur during concomitant use with: oral antidiabetic agents and insulin, ACE inhibitors, anabolic steroids and androgens, antidepressants (such as fluoxetine and MAO inhibitors), quinolone derivatives, chloramphenicol, clarithromycin, clofibrate and its analogs, coumarin derivatives, disopyramide, fenfluramine, miconazole, fluconazole, para-aminosalicylic acid, pentoxifylline (when administered parenterally in high doses), perhexiline, pyrazolone derivatives, probenecid, salicylates, sulfinpyrazone, sulfonamides, sympatholytics (such as β-blockers), tetracyclines, troxiquetant, cytostatic agents such as cyclophosphamide.

Perception of symptoms heralding low blood glucose levels may be impaired during treatment with β-blockers, clonidine, guanethidine, and reserpine.

Hyperglycemic reactions as a manifestation of reduced drug effect may occur during concomitant use with: acetazolamide, β-blockers, barbiturates, diazoxide, diuretics, glucagon, isoniazid, corticosteroids, laxatives (in chronic abuse, see section "Special precautions"), nicotinic acid, phenothiazine derivatives, phenytoin, rifampicin, thyroid hormones, female sex hormones (progestogens, estrogens), sympathomimetics.

H2-receptor antagonists, clonidine, and reserpine may cause either reduction or enhancement of the hypoglycemic effect.

In individual cases, pentamidine may lead to severe hypoglycemia or hyperglycemia. The effect of coumarin derivatives may be enhanced or reduced.

In patients receiving glimepiride concomitantly with bosentan, increased incidence of elevated liver enzymes has been observed. Both glimepiride and bosentan inhibit the bile salt export pump protein, leading to intracellular accumulation of cytotoxic bile salts. Therefore, this combination should not be used (see section "Contraindications").

Glimepiride may increase plasma concentrations of cyclosporine and thus likely enhance its toxicity. Therefore, when both agents are used concomitantly, monitoring and dose adjustment of cyclosporine are recommended.

Colesevelam binds glimepiride and thereby reduces its absorption from the gastrointestinal tract. Glimepiride should be taken at least 4 hours before administration of colesevelam, as no interaction has been observed under these conditions.

Other types of interactions. Acute or chronic alcohol consumption may unpredictably enhance or reduce the hypoglycemic effect of Maninil® 5.

Special precautions for use.

The patient should be informed that if other disorders occur during therapy with Maninil® 5, they must immediately consult their treating physician. When changing physicians, patients should inform the new physician about their existing diabetes (e.g. during hospitalization, after an accident, or if illness occurs during vacation).

Hypoglycemia.

Patients should be made aware of the risk of hypoglycemia when undergoing treatment with glucose-lowering medicinal products.

Prolonged fasting, inadequate carbohydrate intake, unusual physical exertion, diarrhea, or vomiting are conditions associated with a high risk of decreased blood glucose levels (see section "Adverse reactions").

Patients with pronounced signs of cerebral sclerosis and those who do not adhere to medical recommendations generally have a higher risk of hypoglycemia.

Medicinal products acting on the central nervous system and β-adrenoreceptor blockers, as well as autonomic neuropathy, may mask the warning symptoms of hypoglycemia.

Despite initial success in treating hypoglycemia, recurrence is possible. Therefore, patients should remain under medical supervision. Severe hypoglycemia or prolonged episodes, which can only be temporarily controlled with usual amounts of sugar, require immediate treatment (see section "Overdose").

Hyperglycemia.

If the treatment regimen is not followed, if the hypoglycemic effect of Maninil® 5 is insufficient, or during particularly stressful situations, blood glucose levels may rise.

Symptoms of hyperglycemia may include intense thirst, dry mouth, frequent urination, itching and/or dry skin, fungal infections, or skin infections, as well as reduced performance.

In exceptional stressful situations (e.g. trauma, surgery, infectious diseases accompanied by elevated body temperature), metabolic control may deteriorate, resulting in hyperglycemia, which may necessitate temporary insulin therapy.

Laxatives.

Chronic abuse of laxatives may lead to impaired metabolism.

Alcohol.

Acute or chronic alcohol abuse may unpredictably enhance or reduce the hypoglycemic effect of Maninil® 5.

Impaired liver and kidney function and endocrine disorders.

Maninil® 5 should be used with particular caution in patients with impaired liver or kidney function or with reduced function of the thyroid gland, pituitary gland, or adrenal cortex.

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency).

In patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), treatment with sulfonylurea drugs may cause hemolytic anemia. Since glibenclamide belongs to the chemical class of sulfonylurea drugs, it should be used with caution in patients with G6PD deficiency, and consideration should be given to switching to non-sulfonylurea alternative agents.

Elderly patients.

Age 65 years and older has been identified as a risk factor for hypoglycemia in patients receiving sulfonylurea therapy. Hypoglycemia may be difficult to recognize in elderly patients. Initial and maintenance doses of glibenclamide should be carefully adjusted to minimize the risk of hypoglycemia (see section "Dosage and administration"). For this age group, sulfonylurea agents with a shorter duration of action should be preferred.

Maninil® 5 contains lactose.

If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

This medicinal product is contraindicated in patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy.

Maninil® 5 is contraindicated during pregnancy. Since oral antidiabetic agents do not control blood glucose levels as reliably as insulin, they are not suitable for the treatment of diabetes during pregnancy.

Insulin therapy is the treatment of choice during pregnancy. If possible, oral antidiabetic agents should be discontinued and replaced with insulin prior to planned conception.

Breastfeeding.

Since it is unknown whether Maninil® 5 passes into breast milk, it is contraindicated during breastfeeding.

Breastfeeding women should be treated with insulin to control diabetes or should discontinue breastfeeding.

Fertility.

There are no data on the effect of the active substance glibenclamide on fertility in humans.

Ability to affect reaction speed when driving or operating machinery.

During episodes of hypoglycemia or hyperglycemia, attention and reaction speed may be impaired, particularly at the beginning of treatment, after a change in therapy, or with irregular intake of glibenclamide. In situations where these abilities are particularly important (e.g. driving a vehicle or operating machinery), this may pose a risk. Therefore, patients should be advised to take preventive measures to avoid hypoglycemia while driving. This is especially important for patients with frequent episodes of hypoglycemia or with reduced or absent ability to perceive hypoglycemic warning symptoms. In such cases, the appropriateness of driving should be reassessed.

Method of Administration and Dosage.

Dosage.

Dose adjustment of Maninil® 5 should be performed only by a physician concurrently with dietary adjustments. The dosage depends on the patient's metabolic evaluation results (blood and urine glucose levels).

Treatment should be initiated with the lowest possible dose. This is particularly important for patients predisposed to hypoglycemia or with body weight below 50 kg. It should be noted that glyburide (glibenclamide) in Maninil® 5 is present in a non-micronized form. Therefore, the recommended doses of Maninil® 5 differ from those of medicinal products containing micronized glyburide.

Initiation of Treatment.

Dosage should be gradually increased, starting with the lowest possible dose:

• ½ (up to 1) tablet of Maninil® 5 (corresponding to 2.5–5 mg of glyburide) per day.

If metabolic control remains unsatisfactory, the dose should be gradually increased at intervals of several days to approximately one week, until reaching the required therapeutic daily dose, which is:

• a maximum of 3 tablets of Maninil® 5 (corresponding to 15 mg of glyburide) per day.

Switching from Other Glucose-Lowering Medicinal Products.

Switching from another oral antidiabetic agent to Maninil® 5 should be done cautiously, starting with:

• ½ (up to 1) tablet of Maninil® 5 (corresponding to 2.5–5 mg of glyburide) per day.

Dose Adjustment.

For elderly patients, debilitated individuals, or those with malnutrition, as well as patients with impaired renal or hepatic function, initial and maintenance doses should be reduced due to the risk of hypoglycemia. Additionally, dose adjustment should be considered in case of changes in body weight or lifestyle.

Combination with Other Hypoglycemic Medicinal Products.

In justified cases, patients intolerant to metformin may be prescribed thiazolidinediones (e.g., pioglitazone) in addition.

Maninil® 5 may also be combined with oral antidiabetic agents that do not stimulate insulin release (e.g., guar gum or acarbose).

At the onset of secondary failure of glyburide therapy, combined treatment with insulin may be attempted. When endogenous insulin secretion has completely ceased, insulin monotherapy is indicated.

Elderly Patients.

Patients aged 65 years and older: initial and maintenance doses of glyburide should be carefully adjusted to minimize the risk of hypoglycemia. Treatment should begin with the lowest possible dose and be gradually increased if necessary (see section "Special Warnings and Precautions for Use").

Method of Administration.

Tablets should be taken before meals, swallowed whole with sufficient liquid (preferably a glass of water).

For daily doses exceeding 2 tablets of Maninil® 5, it is recommended to divide the total dose into morning and evening doses in a 2:1 ratio.

It is important to take the medication at the same time every day. Missed doses, for example, if the patient forgets to take the tablets, should never be compensated by taking a higher dose.

The duration of treatment depends on the course of the disease. Metabolic status should be monitored at regular intervals as recommended.

In particular, blood and urine glucose concentrations should be regularly checked; additionally, HbA1c and/or fructosamine levels, as well as other parameters (e.g., blood lipid levels), are recommended to be monitored.

Children.

The safety and efficacy of Maninil® 5 in children have not been established. Therefore, this medicinal product should not be used for the treatment of children.

Overdose.

Acute, significant overdose of Maninil® 5, for example, prolonged use of slightly increased doses, may lead to severe, prolonged hypoglycemia that is life-threatening. Once overdose is suspected, careful monitoring is required until it is certain that the patient is no longer at risk. It should be noted that hypoglycemia and its clinical manifestations may recur even after temporary recovery. Significant overdose and severe reactions, such as loss of consciousness and other serious neurological disturbances, should be considered emergencies requiring immediate treatment and hospitalization.

Symptoms of Overdose.

In cases of intentional overdose, prolonged hypoglycemia with a tendency to relapse after several days of initially successful treatment may occur. In patients with impaired consciousness, hypoglycemic coma may rapidly develop, manifesting as loss of consciousness, tachycardia, moist skin, hyperthermia, motor agitation, hyperreflexia, paresis with a positive Babinski reflex.

Therapeutic Measures in Overdose.

See section "Adverse Reactions" for treatment of mild hypoglycemia.

In accidental intoxications and in contact with more vulnerable patients who do not have a predisposition to seizures, in addition to intravenous glucose administration, vomiting should first be induced or gastric lavage performed.

For patients in a comatose state, immediate intravenous administration of glucose is required (40–80 mL of 40% glucose solution as an injection, followed by infusion of 5–10% glucose solution).

Afterwards, 1 mg of glucagon may be additionally administered intramuscularly or intravenously. If the patient does not regain consciousness, this measure may be repeated, and intensive therapy may subsequently be required.

Particularly in children who have accidentally ingested Maninil® 5, glucose solution should be administered cautiously to avoid dangerous hyperglycemia; careful monitoring of blood glucose levels is required thereafter.

For patients who have ingested life-threatening amounts of Maninil® 5, detoxification by gastric lavage and administration of activated charcoal should be performed if the medicinal product was taken recently.

In cases of prolonged hypoglycemia, the patient must be observed for several days with regular monitoring of blood glucose levels and infusion therapy if necessary.

Adverse Reactions.

Adverse reactions were classified by frequency:

Very common (≥ 1/10)

Common (≥ 1/100, < 1/10)

Uncommon (≥ 1/1000, < 1/100)

Rare (≥ 1/10000, < 1/1000)

Very rare (< 1/10000)

Not known (frequency cannot be estimated from available data).

Hypoglycaemia.

Hypoglycaemia is the most common adverse reaction associated with glibenclamide therapy.

It may be prolonged in duration during glibenclamide treatment and may lead to severe hypoglycaemia with coma, which can be life-threatening. In cases of very subtle onset of hypoglycaemia, such as in autonomic neuropathy or during concomitant therapy with sympatholytic agents (see section "Interaction with other medicinal products and other forms of interaction"), typical warning symptoms of hypoglycaemia may be diminished or absent. The clinical picture of a severe hypoglycaemic attack may resemble that of a stroke.

Possible causes of hypoglycaemia are described in the section "Special precautions for use".

Hypoglycaemia is defined as a drop in blood glucose levels below approximately 50 mg/dL. Signs indicating an excessive drop in blood glucose levels for the patient or those around them may include sudden sweating, palpitations, tremor, hunger, nervousness, tingling sensation in the mouth, pallor of the skin, headache, drowsiness, sleep disturbances, anxiety, unsteadiness of movement, and reversible neurological symptoms (e.g. speech and visual disturbances, signs of paralysis or sensory disturbances).

If hypoglycaemia progresses, the patient may lose self-control and consciousness. Such patients typically have cold, clammy skin and may be prone to seizures.

A patient with diabetes can manage mild hypoglycaemia by consuming sugar or food or drinks containing high amounts of sugar. Therefore, patients should always carry 20 grams of glucose with them.

If hypoglycaemia cannot be promptly corrected, a physician must be contacted immediately.

Other adverse reactions.

Disorders of the blood and lymphatic system.

Rare: thrombocytopenia.

Very rare: leukopenia, erythropenica, granulocytopenia up to agranulocytosis, pancytopenia, haemolytic anaemia.

These blood count changes are usually reversible after discontinuation of the drug, but very rarely may be life-threatening.

Disorders of the immune system.

Very rare: cross-allergy with sulfonamides, derivatives of sulfonamides, and probenecid is possible.

Disorders of metabolism and nutrition.

Common: weight gain.

Very rare: hyponatremia, disulfiram-like reaction.

Disorders of the eye.

Very rare: transient visual disturbances and accommodation disorders, particularly at the beginning of treatment, due to changes in blood glucose concentration.

Disorders of the gastrointestinal tract.

Uncommon: nausea, feeling of fullness/bloating in the stomach, vomiting, abdominal pain, diarrhoea, belching, metallic taste.

These complaints are often transient and generally do not require discontinuation of the drug.

Disorders of the liver and biliary system.

Very rare: transient increases in AST, ALT, alkaline phosphatase, drug-induced hepatitis, intrahepatic cholestasis, possibly due to a hyperergic allergic reaction of liver tissue.

Such liver function disturbances are reversible after discontinuation of Maninil® 5, but may also lead to life-threatening liver failure.

Disorders of the skin and subcutaneous tissue.

Uncommon: pruritus, urticaria, nodular erythema, measles-like or maculopapular exanthema, increased photosensitivity, purpura.

These complaints are hypersensitivity reactions that are usually reversible, but very rarely may progress to life-threatening conditions associated with dyspnoea and decreased blood pressure, leading to shock.

Very rare: life-threatening allergic vasculitis, generalized hypersensitivity reactions including skin rash, arthralgia, fever, proteinuria, and jaundice.

Any skin reactions should be reported to a physician immediately.

Disorders of the kidneys and urinary system.

Very rare: mild diuretic effect, reversible proteinuria.

Other adverse reactions.

Not known: Ponceau 4R may cause allergic reactions.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

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

Storage conditions. Store at temperatures not exceeding 25 °C. Store in the original packaging in a place protected from light and moisture!

Packaging. 120 tablets in a bottle; 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

BERLIN-CHEMIE AG.

Address of manufacturer and location of business.

Glienicker Weg 125, 12489 Berlin, Germany.

Marketing authorization holder.

BERLIN-CHEMIE AG.

Address of marketing authorization holder.

Glienicker Weg 125, 12489 Berlin, Germany.